title: Enzyme replacement therapy for mucopolysaccharidosis I: a randomized, double-blinded, placebo-controlled, multinational study of recombinant human alpha-L-iduronidase (laronidase). Objective Assessment of the Cardiorespiratory Function of Adolescents With Idiopathic Scoliosis Through the Six-Minute Walk Test Six-minute-walk test in idiopathic pulmonary fibrosis: test validation and minimal clinically important difference. Six-minute walking test and the assessment of cardiorespiratory responses during weight-loss programmes in obese children. Systemic administration of PRO051 in Duchenne's muscular dystrophy. Determining the minimal clinically important difference for the six-minute walk test and the 200-meter fast-walk test during cardiac rehabilitation program in coronary artery disease patients after acute coronary syndrome. Feasibility and effects of a physical exercise programme in adults with myotonic dystrophy type 1: a randomized controlled pilot study. Development of a methodological PubMed search filter for finding studies on measurement properties of measurement instruments Effect of encouragement on walking test performance. Six-minute walking test to assess exercise tolerance and cardiorespiratory responses during training program in children with congenital heart disease. Reproducibility of Maximal and Submaximal Exercise Testing in “Normal Ambulatory” and “Community Ambulatory” Children and Adolescents With Spina Bifida: Which Is Best for the Evaluation and Application of Exercise Training? A step in the right direction: assessing exercise tolerance in cystic fibrosis.
abstract: OBJECTIVE To confirm the efficacy and safety of recombinant human alpha-L-iduronidase ( laronidase ) in patients with mucopolysaccharidosis I ( MPS I ) . STUDY DESIGN This was a r and omized , double-blinded , multinational study of 45 patients with MPS I administered 100 U/kg ( 0.58 mg/kg ) laronidase , or placebo intravenously weekly for 26 weeks . The co primary efficacy end points compared the median change from baseline to week 26 between groups in percentage of predicted normal forced vital capacity ( FVC ) and in 6-minute walk test ( 6MWT ) distance through the use of the Wilcoxon rank sum test . RESULTS The laronidase ( n=22 ) and placebo ( n=23 ) groups had similar baseline characteristics . After 26 weeks , patients receiving laronidase compared with placebo showed mean improvements of 5.6 percentage points in percent of predicted normal FVC ( median , 3.0 ; P=.009 ) and 38.1 meters in 6MWT distance ( median , 38.5 ; P=.066 ; P=.039 , analysis of covariance ) . Laronidase also significantly reduced hepatomegaly and urinary glycosaminoglycans , and , in more severely affected patients , improved sleep apnea/hypopnea and shoulder flexion .  Laronidase was well-tolerated . Nearly all patients receiving enzyme had development of IgG antibodies , without apparent clinical effects . CONCLUSIONS In patients with MPS I , laronidase significantly improves respiratory function and physical capacity , reduces glycosaminoglycan storage , and has a favorable safety profile Study Design . Clinical prospect i ve , r and om study . Objective . Analyze the results of the six-minute walk test ( 6MWT ) in patients with adolescent idiopathic scoliosis . Summary of Background Data . Although it is widely believed that Adolescent Idiopathic Scoliosis ( AIS ) causes cardiorespiratory dysfunctions , there is no report in literature of objective measurements of this restriction in the ventilatory performance during physical exertion . Methods . One hundred twenty-six adolescents matched by gender and age were prospect ively studied at a tertiary teaching institution : 40 patients without spine deformities ( group I – controls ) , and 86 patients with AIS with a spine curve ranging from 45 ° to 138 ° ( group II ) . All patients underwent radiographic evaluations and the 6MWT . Results . Normal controls presented significantly lower mean heart rate and Borg scores , as well as higher oxygen saturation and walked longer distances on the 6MWT . Conclusion . The 6MWT effectively demonstrated the cardiorespiratory restrictions presented by patients with AIS RATIONALE The 6-minute-walk test ( 6MWT ) is a practical and clinical ly meaningful measure of exercise tolerance with favorable performance characteristics in various cardiac and pulmonary diseases . Performance characteristics in patients with idiopathic pulmonary fibrosis ( IPF ) have not been systematic ally evaluated . OBJECTIVES To assess the reliability , validity , and responsiveness of the 6MWT and estimate the minimal clinical ly important difference ( MCID ) in patients with IPF . METHODS The study population included all subjects completing a 6MWT in a clinical trial evaluating interferon gamma-1b ( n = 822 ) .  Six-minute walk distance ( 6MWD )  and other parameters were measured at baseline and at 24-week intervals using a st and ardized protocol . Parametric and distribution-independent correlation coefficients were used to assess the strength of the relationships between 6MWD and measures of pulmonary function , dyspnea , and health-related quality of life . Both distribution-based and anchor-based methods were used to estimate the MCID . MEASUREMENTS AND MAIN RESULTS Comparison of two proximal measures of 6MWD ( mean interval , 24 d ) demonstrated good reliability ( coefficient = 0.83 ; P < 0.001 ) . 6MWD was weakly correlated with measures of physiologic function and health-related quality of life ; however , values were consistently and significantly lower for patients with the poorest functional status , suggesting good construct validity . Importantly , change in 6MWD was highly predictive of mortality ; a 24-week decline of greater than 50 m was associated with a fourfold increase in risk of death at 1 year ( hazard ratio , 4.27 ; 95 % confidence interval , 2.57- 7.10 ; P < 0.001 ) . The estimated MCID was 24 - 45 m. CONCLUSIONS The 6MWT is a reliable , valid , and responsive measure of disease status and a valid endpoint for clinical trials in IPF PURPOSE We assessed the exercise tolerance and cardiorespiratory responses during 2-month weight-loss programmes using the 6-minute walking test ( 6MWT ) in obese children . METHODS Twenty-eight male obese children were r and omly assigned to either a control group ( C ) , an energy restriction group ( R ) , an exercise training at maximum lipid-oxidation ( LIPOXmax ) group ( E ) , or an energy restriction/training group ( RE ) . The body composition , the submaximal incremental cycling exercise , and the 6MWT were performed before and after the 2-month programme . RESULTS . After the programme , RE group showed a significant improvement of body composition ( body weight reduced by 6.3 ± 1.5 kg , p < 0.01 ) , and an increase of 6-minute walking distance ( 6MWD ) ( + 13.7 % , p < 0.01 ) . Similarly , maximum oxygen uptake calculated according to the American College of Science Medicine guideline ( VO(2max ) ACSM ) and VO(2max ) predicted from 6MWD were respectively higher ( + 12.9 % and + 10.0 % , p < 0.01 ) than the R or E groups . Bl and -Altman analysis highlighted an agreement of these two methods of VO(2max ) measurement . Moreover , in all participants the 6MWD was significantly correlated with VO(2max ) ACSM and LIPOXmax ( r = 0.77 , p < 0.001 and r = 0.67 , p < 0.01 ; respectively ) before the programme as well as their changes in percentage over the programme ( r = 0.85 and r = 0.86 , p < 0.0001 ; respectively ) . CONCLUSIONS We concluded that a 2-month weight-loss programme including energy restriction and exercise training targeted at LIPOXmax improved body composition and cardiorespiratory tolerance in obese children . Furthermore , the 6MWT could be considered as a useful and reliable tool for the assessment and the follow-up of cardiorespiratory responses during weight-loss programme in obese children BACKGROUND Local intramuscular administration of the antisense oligonucleotide PRO051 in patients with Duchenne 's muscular dystrophy with relevant mutations was previously reported to induce the skipping of exon 51 during pre-messenger RNA splicing of the dystrophin gene and to facilitate new dystrophin expression in muscle-fiber membranes . The present phase 1 - 2a study aim ed to assess the safety , pharmacokinetics , and molecular and clinical effects of systemically administered PRO051 . METHODS We administered weekly abdominal subcutaneous injections of PRO051 for 5 weeks in 12 patients , with each of four possible doses ( 0.5 , 2.0 , 4.0 , and 6.0 mg per kilogram of body weight ) given to 3 patients . Changes in RNA splicing and protein levels in the tibialis anterior muscle were assessed at two time points . All patients subsequently entered a 12-week open-label extension phase , during which they all received PRO051 at a dose of 6.0 mg per kilogram per week . Safety , pharmacokinetics , serum creatine kinase levels , and muscle strength and function were assessed . RESULTS The most common adverse events were irritation at the administration site and , during the extension phase , mild and variable proteinuria and increased urinary α(1)-microglobulin levels ; there were no serious adverse events . The mean terminal half-life of PRO051 in the circulation was 29 days . PRO051 induced detectable , specific exon-51 skipping at doses of 2.0 mg or more per kilogram . New dystrophin expression was observed between approximately 60 % and 100 % of muscle fibers in 10 of the 12 patients , as measured on post-treatment biopsy , which increased in a dose-dependent manner to up to 15.6 % of the expression in healthy muscle . After the 12-week extension phase , there was a mean ( ±SD ) improvement of 35.2±28.7 m ( from the baseline of 384±121 m ) on the 6-minute walk test . CONCLUSIONS Systemically administered PRO051 showed dose-dependent molecular efficacy in patients with Duchenne 's muscular dystrophy , with a modest improvement in the 6-minute walk test after 12 weeks of extended treatment . ( Funded by Prosensa Therapeutics ; Netherl and s National Trial Register number , NTR1241 . ) OBJECTIVE To estimate the minimal clinical ly important difference ( MCID ) for the 6-minute walk test ( 6MWT ) and the 200-m fast-walk test ( FWT ) in patients with coronary artery disease ( CAD ) during a cardiac rehabilitation program . DESIGN Prospect i ve study using distribution- and anchor-based methods . SETTING Out patients from a cardiac rehabilitation unit . PARTICIPANTS Stable patients with CAD ( N=81 ; 77 men ; mean±SD age , 58.1±8.7y ) enrolled 31±12.1 days after an acute coronary syndrome ( ACS ) . INTERVENTIONS Not applicable . MAIN OUTCOME MEASURES  6MWT and 200-m FWT results before and after an 8-week cardiac rehabilitation program and at the 6th and 12th sessions . Patients and physiotherapists who supervised the training were asked to provide a global rating of perceived change in walking ability while blinded to changes in walk test performances . RESULTS Mean change in 6MWT distance ( 6MWD ) in patients who reported no change was -6.5 m versus 23.3 m in those who believed their performance had improved ( P<.001 ) . This result was consistent with the MCID determined by using the distribution method ( 23 m ) . Considering a 25-m cutoff , positive and negative predictive values were 0.9 and .63 , respectively . Conversely , there was no difference in 200-m FWT performance between these 2 groups ( 0.1 vs -1.4s , respectively ) . There was poor agreement with the physiotherapist 's perceived change . CONCLUSIONS The MCID for 6MWD in patients with CAD after ACS was 25 m . This result will help physicians interpret 6MWD change and help research ers estimate sample sizes in further studies using 6MWD as an endpoint OBJECTIVE To investigate the feasibility and effects of a physical exercise programme on functioning and health-related quality of life in adults with myotonic dystrophy type 1 . DESIGN A r and omized controlled trial . SUBJECTS Thirty-five adults with myotonic dystrophy type 1 . METHODS After stratification for level of functioning , study participants were assigned by lot to either a training group or a control group . Training-group participants attended a 60-minute comprehensive group-training programme , Friskis&Svettis ® Open Doors , twice a week for 14 weeks . The six-minute walk test was the primary outcome measure and the timed-st and s test , the timed up- and -go test , the Epworth sleepiness scale and the Short Form-36 health survey were secondary outcome measures . RESULTS Intention-to-treat analyses revealed no significant differences in any outcome measures , except for an increased between-group difference after intervention in the Short Form-36 mental health subscale and a decrease in the vitality subscale for the control group . The programme was well tolerated and many training-group participants perceived subjective changes for the better . No negative effects were reported . CONCLUSION The Friskis&Svettis ® Open Doors programme was feasible for adults with myotonic dystrophy type 1 who had been screened for cardiac involvement , had distal or mild-to-moderate proximal muscle impairment , and no severe cognitive impairments . No beneficial or detrimental effects were evident Objectives For the measurement of  patient-reported outcomes , such as ( health-related ) quality of life , often many measurement instruments exist that intend to measure the same construct . To facilitate instrument selection , our aim was to develop a highly sensitive search filter for finding studies on measurement properties of measurement instruments in PubMed and a more precise search filter that needs less abstract s to be screened , but at a higher risk of missing relevant studies . Methods A r and om sample of 10,000 PubMed records ( 01 - 01 - 1990 to 31 - 12 - 2006 ) was used as a gold st and ard . Studies on measurement properties were identified using an exclusion filter and h and search ing . Search terms were selected from the relevant records in the gold st and ard as well as from 100 systematic review s of measurement properties and combined based on sensitivity and precision . The performance of the filters was tested in the gold st and ard as well as in two validation sets , by calculating sensitivity , precision , specificity , and number needed to read . Results We identified 116 studies on measurement properties in the gold st and ard . The sensitive search filter was able to retrieve 113 of these 116 studies ( sensitivity 97.4 % , precision 4.4 % ) . The precise search filter had a sensitivity of 93.1 % and a precision of 9.4 % . Both filters performed very well in the validation sets . Conclusion The use of these search filters will contribute to evidence -based selection of measurement instruments in all medical fields Walking tests , frequently used to document effects of treatment on exercise capacity , have never been st and ardised . We studied the effects of encouragement on walking test performance in a r and omised study that controlled for the nature of the underlying disease , time of day , and order effects . We r and omised 43 patients with chronic airflow limitation or chronic heart failure or both to receive or not receive encouragement as they performed serial two and six minute walks every fortnight for 10 weeks . Simple encouragement improved performance ( p less than 0.02 for the six minute walk ) , and the magnitude of the effect was similar to that reported for patients in studies purporting to show beneficial effects of therapeutic manoeuvres . Age and test repetition also affected performance . These results demonstrate the need for careful st and ardisation of the performance of walking tests , and suggest caution in interpreting studies in which st and ardisation is not a major feature of the study design This study assessed the exercise tolerance and the cardiorespiratory responses to a training program by the six-minute walk test ( 6'WT ) in children with congenital heart disease ( CHD ) . Seventeen cardiac and 14 healthy children performed maximal cardiopulmonary exercise test ( CPET ) and 6'WT . Reliability of 6'WT was assessed in all subjects ( test-retest ) by Bl and -Altman plots . Cardiac subjects were r and omly divided in training ( T-CHD ) and control groups ( C-CHD ) . T-CHD underwent an individualized training exercise at the ventilatory threshold ( VT ) intensity during 12 weeks . We found that the 6'WT is a reliable and reproducible test . CHD children  walked a lower distance than healthy children before training ( 472.5 + /- 18.1 vs. 548.8 + /- 7.7 m , respectively , p < 0.001 ) . Likewise , power output , oxygen uptake ( V.O ( 2 ) ) , and heart rate ( HR ) at the maximum and the VT levels , were significantly lower in patients ( p < 0.001 ) . After training , a significant improvement of walking distance ( WD ) was shown in T-CHD ( 529.6 + /- 15.3 vs. 467.7 + /- 17.1 m , p < 0.001 ) . The power output , VO2 , HR , and V.E increased slightly ( 6 to 10 % , p > 0.05 ) at peak exercise and significantly at ventilatory threshold level ( p < 0.05 ) in T-CHD . Significant relationships between WD and VO2max as well as VO2 at VT were founded ( p < 0.05 ) . We concluded that the 6'WT is a useful and reliable tool in the assessment and follow-up of functional capacity during rehabilitation program in children with CHD Background With emerging interest in exercise and lifestyle interventions for children and adolescents with spina bifida , there is a need for appropriate measurements in exercise testing . Objective The purpose of this study was to assess both reliability and agreement of maximal and submaximal exercise measures in “ normal ambulatory ” and “ community ambulatory ” children and adolescents with spina bifida . Design This was a reproducibility study . Methods Twenty-three children and adolescents with spina bifida ( 10 normal ambulatory and 13 community ambulatory ) participated in the study . Maximal exercise outcomes were measured using a grade d treadmill test .  Peak measures ( peak oxygen uptake [ V̇o2peak ] , peak heart rate [ HRpeak ] , heart rate response [ HRR ] , and oxygen pulse ) were recorded . For submaximal measures , heart rate ( HR ) and oxygen uptake ( V̇o2 ) at the ventilatory threshold and oxygen uptake efficiency slope ( OUES ) were derived from the maximal measures . Functional performance was measured as the 6-minute walking distance and the maximal speed during the treadmill test . After checking for normality and heteroscedasticity , paired t tests , intraclass correlation coefficients ( ICCs ) , and the smallest detectable difference ( SDD ) or the coefficient of variation ( CV ) were calculated . Results Performance measures showed good reliability and agreement . For maximal measures , acceptable ICCs were found for all measures . For submaximal measures , only HR at the ventilatory threshold showed an ICC of less than .80 . Agreement showed a CV of less than 10 % for all measures , except for V̇o2 at the ventilatory threshold , HRR , and OUES . Limitations Limitations of the study include missing data due to equipment failure . Furthermore , the outcomes were limited to normal ambulatory and community ambulatory children and adolescents with spina bifida . Conclusions Both maximal and submaximal measures of exercise testing can be used for discriminative purpose s in ambulatory children and adolescents with spina bifida . For evaluative purpose s , HR measures are superior to V̇o2 measures , while taking into account the individual variation of 5 % to 8 % . The SDD was 0.5 km/h for peak speed and 36.3 m for 6-minute walking distance . Heart rate response , oxygen pulse , and OUES are not recommended in the evaluation of exercise testing in this population Exercise tolerance may be reduced in patients with cystic fibrosis , but it is not always possible to predict this from st and ard lung function measurements . Formal exercise testing may , therefore , be necessary , and the test should be simple and readily available . We have developed a " 3-minute step test " and compared it with the st and ard 6-minute walking test . Subjects stepped up and down a 15-cm-high single step at a rate of 30 steps per minute for 3 minutes . The effect of the step test on spirometry was tested first in 31 children with CF ( mean age , 12.0 years ) , who had a mean ( range ) baseline forced expired volume in 1 second ( FEV1 ) of 64 % ( 18 - 94 % ) of predicted values . The step test was then compared with the st and ard 6-minute walk in a further 54 patients with cystic fibrosis ( mean age , 12.5 years ) , with mean ( range ) baseline FEV1 of 61 % ( 14 - 103 % ) of predicted values . Outcome measures were minimum arterial oxygen saturation ( SaO2 ) , maximum pulse rate , and the modified Borg dyspnea score . Post-step test spirometry showed mean ( 95 % CI ) changes of -1.1 % ( -6.0 + 3.9 % ) for forced vital capacity , of -1.6 % ( -4.2 + 1.1 % ) for FEV1 , and + 0.25 % ( -2.8 + 3.3 % ) for peak expiratory flow , although 5/31 children showed > 15 % drop in one or more parameters . The step and walk tests both produced significant changes ( P < 0.0001 ) in all outcomes , with a mean ( range ) minimum SaO2 of 92 % ( 75 - 98 % ) versus 92 % ( 75 - 97 % ) , a maximum pulse rate of 145 b.p.m . ( 116 - 189 ) versus 132 ( 100 - 161 ) , and a Borg score of 2.5 ( 0 - 9 ) versus 1.0 ( 0 - 5 ) , respectively . Comparison of the two tests showed that the step test increased breathlessness ( mean change Borg score , 2.3 vs. 0.8 ; P < 0.0001 ) and pulse rate ( mean change , 38 % vs. 24 % , P < 0.0001 ) significantly more than the walk , whereas the decrease in SaO2 was similar ( mean change , -2.9 % vs. -2.6 % ; P = 0.12 ) . Some patients with a significant drop in SaO2 ( > 4 % ) would not have the decrease predicted from their baseline lung function . Reproducibility for the two tests was similar . The step test is quick , simple and portable , and is not dependent on patient motivation . Although the step test is more tiring , its effect on SaO2 is similar to the 6-minute walking test . It is a safe test that may prove to be a valuable measure of exercise tolerance in children with pulmonary disease , although longitudinal studies are now needed
target: Limited evidence to strong evidence was found for reliability in various chronic conditions .
  Little evidence was available for responsiveness and measurement error .
  Studies showed large variability in test procedures despite existing guidelines for the performance of the 6MWT .
  Evidence for measurement properties of the 6MWT  varies largely among chronic pediatric conditions .
background: BACKGROUND The Six-Minute Walk Test ( 6MWT ) is increasingly being used as a functional outcome measure for chronic pediatric conditions .
  Knowledge about its measurement properties is needed to determine whether it is an appropriate test to use .
  PURPOSE The purpose of this study was to systematic ally review all published clinimetric studies on the 6MWT in chronic pediatric conditions .