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Evaluations of treatment efficacy in Duchenne muscular dystrophy (DMD), a rare genetic disease that results in progressive muscle wasting, require an understanding of the meaningfulness of changes in functional measures. We estimated the minimal detectable change (MDC) for selected motor function measures in ambulatory DMD, i.e., the minimal degree of measured change needed to be confident that true underlying change has occurred rather than transient variation or measurement error. MDC estimates were compared across multiple data sources, representing >1000 DMD patients in clinical trials and real-world clinical practice settings. Included patients were ambulatory, aged ≥4 to 80% confidence in true change were 2.8 units for the North Star Ambulatory Assessment (NSAA) total score, 1.3 seconds for the 4-stair climb (4SC) completion time, 0.36 stairs/second for 4SC velocity and 36.3 meters for the 6-minute walk distance (6MWD). MDC estimates were similar across clinical trial and real-world data sources, and tended to be slightly larger than MCIDs for these measures. The identified thresholds can be used to inform endpoint definitions, or as benchmarks for monitoring individual changes in motor function in ambulatory DMD.

BackgroundApproximately 30% to 40% of older adults have hyperkyphosis, defined as excessive curvature of the thoracic spine. Hyperkyphosis is associated with increased morbidity and mortality. This study aimed to determine whether hyperkyphosis (Cobb's angle) and upper extremity tasks were independently associated with the 6-min walk test (6MWT) in community-dwelling older adults with hyperkyphosis.MethodsIn this cross-sectional study, we studied 71 women and 28 men aged 60-87 from the study of hyperkyphosis, exercise, and function trial (SHEAF) who had kyphosis, 3 timed upper extremity tasks and the 6MWT assessed at their baseline visit. We used standing lateral spine radiographs and a standardized protocol for thoracic kyphosis (T4-T12) to measure Cobb angle of kyphosis. In addition, 3 activity of daily living (ADL) extremity tests (putting on and removing a laboratory coat, picking up a penny from the floor, and lifting a 7-lb. book to a shelf) were used.ResultsThe mean ± SD age was 70.1 ± 6.1 years. The mean ± SD Cobb angle of kyphosis was 57.4 ± 12.5 degrees. On average ± SD, the participants walked 504.8 ± 84.2 m in 6 min and took 2.4 ± 2.2 prescription medications. The mean ± SD height was 164.7 ± 8.5 cm, weight was 68.7 ± 13.1 kg, and BMI was 25.2 ± 4.0 kg/m2. Multivariate regression revealed that age, height, upper extremity book lift task, and the number of prescribed medications were significant predictors of performance on the 6MWT (p

OBJECTIVE: To compare the six-minute walk test and the Modified Bruce treadmill test in paediatric patients with severe burns. SUBJECTS: A total of 67 children, aged 7-17 years, with severe burns. METHODS: Participants were assigned to perform the six-minute walk test and the Modified Bruce treadmill test in randomized order on discharge from acute burn care. Primary outcome measure was heart rate. Secondary outcome measures were distance walked, Borgs CR-10 rate of perceived exertion, and maximal oxygen uptake (VO2). RESULTS: A total of 67 participants were enrolled. Thirty-eight patients completed both tests. The mean six-minute walk test maximum heart rate was 135 ± 19 bpm (range 97-180 bpm) and the mean Modified Bruce treadmill test maximum heart rate was 148 ± 24 bpm (range 100-197 bpm; p ≤ 0.05), with a weak positive correlation of R² = 0.14. The mean six-minute walk test maximum distance was 294 ± 124 m (range 55 to 522 m) while the mean Modified Bruce treadmill test maximum distance was 439 ± 181 m (range 53 to 976 m; p ≤ 0.05), with no correlation of R² = 0.006. The mean RPE CR-10 score for the six-minute walk test was 3 ± 2.5 (range 0-10) vs a mean RPE CR-10 score of 10 ± 0 for the Modified Bruce treadmill test. CONCLUSION: The Modified Bruce treadmill test challenges the cardiorespiratory system significantly more than the six-minute walk test, as reflected by maximum heart rate measurements, and the perception of effort (i.e. rate of perceived exertion) by the patient. When possible, the Modified Bruce treadmill test should be used to assess cardiovascular functional capacity. However, the six-minute walk test may be more clinically feasible for use with paediatric patients with burns, and provides information about submaximal functional exercise capacity.

Age-related hyperkyphosis is associated with adverse health outcomes, such as falls, fractures, and mortality. However, few studies investigated the relationship between the severity of hyperkyphosis and physical endurance in older adults. This study examined whether a degree of hyperkyphosis curvature was independently associated with the 6-minute walk test (6MWT) distance. We analyzed the baseline data of 112 older adults aged 60-92 enrolled in the Specialized Center of Research (SCOR) Kyphosis trial. The majority of the sample had at least a college degree and were white. On average, participants walked 503.9 (SD 82.3) meters in 6 minutes. Multivariate regression results showed that the degree of hyperkyphosis curvature was not independently associated with the 6MWT distance, but taller height, lighter weight, and less prescription medication were significant predictors of better performance on the 6MWT distance. Validation of the study findings in a large, diverse older adult population is warranted.

PurposeCardiac rehabilitation (CR) is evolving to include both in-person and virtual delivery. Our objective was to compare, in CR patients, the association of in-person, hybrid, and virtual CR with change in performance on the 6-min walk test (6MWT) between enrollment and completion.MethodsPatients enrolled in CR between October 22, 2019, and May 10, 2021, were categorized into in-person, hybrid, or virtual groups by number of in-person and virtual visits. All patients received individualized exercise training and health behavior counseling. Cardiac rehabilitation was delivered to patients in the hybrid and virtual cohorts using synchronous video exercise and/or asynchronous telephone visits. Measurements at CR enrollment and completion included the 6MWT, blood pressure (BP), depression, anxiety, waist-to-hip ratio, and cardiac self-efficacy.ResultsOf 187 CR patients, 37/97 (38.1%) were in-person patients and 58/90 (64.4%) were hybrid/virtual patients ( P = .001). Compared to in-person (51.5 ± 59.4 m) improvement in the 6MWT was similar in hybrid (63.4 ± 55.6; P = .46) and virtual (63.2 ± 59.6; P = .55) compared with in-person (51.5 ± 59.4). Hybrid and virtual patients experienced similar improvements in BP control and anxiety. Virtual patients experienced less improvement in depression symptoms. There were no statistically significant changes in waist-to-hip ratio or cardiac self-efficacy. Qualitative themes included the adaptability of virtual CR, importance of relationships between patients and CR staff, and need for training and organizational adjustments to adopt virtual CR.ConclusionsHybrid and virtual CR were associated with similar improvements in functional capacity to in-person. Virtual and hybrid CR have the potential to expand availability without compromising outcomes.

BackgroundLower heart rate (HR) increases during exercise and slower HR recovery (HRR) after exercise are markers of worse autonomic function that may be associated with risk of acute respiratory events (ARE).MethodsData from 6-min walk testing (6MWT) in COPDGene were used to calculate the chronotropic index (CI) [(HR immediately post 6MWT - resting HR)/((220 - age) - resting HR)] and HRR at 1 min after 6MWT completion. We used zero-inflated negative binomial regression to test associations of CI and HRR with rates of any ARE (requiring steroids and/or antibiotics) and severe ARE (requiring emergency department visit or hospitalization), among all participants and in spirometry subgroups (normal, chronic obstructive pulmonary disease [COPD], and preserved ratio with impaired spirometry).ResultsAmong 4,484 participants, mean follow-up time was 4.1 years, and 1,966 had COPD. Among all participants, CI-6MWT was not associated with rate of any ARE [adjusted incidence rate ratio (aIRR) 0.98 (0.95-1.01)], but higher CI-6MWT was associated with lower rate of severe ARE [0.95 (0.92-0.99)]. Higher HRR was associated with a lower rate of both any ARE [0.97 (0.95-0.99)] and severe ARE [0.95 (0.92-0.98)]. Results were similar in the COPD spirometry subgroup.ConclusionHeart rate measures derived from 6MWT tests may have utility in predicting risk of acute respiratory events and COPD exacerbations.

BACKGROUND: Studies 4658-201/202 (201/202) evaluated treatment effects of eteplirsen over 4 years in patients with Duchenne muscular dystrophy and confirmed exon-51 amenable genetic mutations. Chart review Study 4658-405 (405) further followed these patients while receiving eteplirsen during usual clinical care. OBJECTIVE: To compare long-term clinical outcomes of eteplirsen-treated patients from Studies 201/202/405 with those of external controls. METHODS: Median total follow-up time was approximately 6 years of eteplirsen treatment. Outcomes included loss of ambulation (LOA) and percent-predicted forced vital capacity (FVC%p). Time to LOA was compared between eteplirsen-treated patients and standard of care (SOC) external controls and was measured from eteplirsen initiation in 201/202 or, in the SOC group, from the first study visit. Comparisons were conducted using univariate Kaplan-Meier analyses and log-rank tests, and multivariate Cox proportional hazards models with regression adjustment for baseline characteristics. Annual change in FVC%p was compared between eteplirsen-treated patients and natural history study patients using linear mixed models with repeated measures. RESULTS: Data were included from all 12 patients in Studies 201/202 and the 10 patients with available data from 405. Median age at LOA was 15.16 years. Eteplirsen-treated patients experienced a statistically significant longer median time to LOA by 2.09 years (5.09 vs. 3.00 years, p

AimsImprovement in exercise capacity is the primary goal of physical activity programmes for patients with heart failure (HF). Although activity programmes are effective for some patients, others do not benefit. Identifying factors related to a lack of improvement in submaximal exercise capacity may help us interpret findings and design new interventions. The aim of this study is to identify factors contributing to a lack of improvement in submaximal exercise capacity 3 months after physical activity advice or an exergame intervention in patients with HF. Additionally, we aimed to assess differences in lack of improvement in submaximal exercise capacity of patients whose baseline exercise capacity predicted a worse compared with better prognosis of HF.Methods and resultsThis secondary analysis of the HF-Wii study analysed baseline and 3 month data of the 6 min walk test (6MWT) from 480 patients (mean age 67 years, 72% male). Data were analysed separately in patients with a pre-defined 6 min walking distance at baseline of

BackgroundAttenuation of transforming growth factor β by blocking angiotensin II has been shown to reduce emphysema in a murine model. General population studies have demonstrated that the use of angiotensin converting enzyme inhibitors (ACEis) and angiotensin-receptor blockers (ARBs) is associated with reduction of emphysema progression in former smokers and that the use of ACEis is associated with reduction of FEV1 progression in current smokers.Research questionIs use of ACEi and ARB associated with less progression of emphysema and FEV1 decline among individuals with COPD or baseline emphysema?MethodsFormer and current smokers from the Genetic Epidemiology of COPD Study who attended baseline and 5-year follow-up visits, did not change smoking status, and underwent chest CT imaging were included. Adjusted linear mixed models were used to evaluate progression of adjusted lung density (ALD), percent emphysema (%total lung volume

Background In people with lower-extremity peripheral artery disease, the effects of exercise on patient-reported outcomes remain unclear. Methods and Results Four hundred four people with peripheral artery disease in 3 clinical trials were randomized to exercise (N=205) or a control group (N=199) and completed the 6-minute walk and the Walking Impairment Questionnaire distance score (score 0-100, 100=best) at baseline and 6-month follow-up. Compared with the control group, exercise improved 6-minute walk distance by +39.8 m (95% CI, 26.8-52.8, P

ObjectiveTo examine the associations of knee injury, radiographic osteoarthritis severity, and quadriceps strength with knee pain exacerbation during walking.DesignWithin-person knee-matched case-control study.MethodsParticipants from the Osteoarthritis Initiative who completed a 20-m walking test at the 24-month visit were included. Pain exacerbation was defined as an increase in pain intensity of 1 or more on a numeric rating scale (0 as no pain and 10 as the worst imaginable pain) while completing the 20-m walking test. We used conditional logistic regression to assess the relation of recent knee injury, Kellgren-Lawrence (KL) grade, and quadriceps strength to unilateral knee pain exacerbation during walking.ResultsWe included 277 people who experienced unilateral knee pain exacerbation during the walking test. Recent knee injury was associated with pain exacerbation during walking, with an odds ratio of 3.4 (95% confidence interval [CI]: 1.3, 9.2). Compared with knees with a KL grade of 0, the odds ratios of pain exacerbation during walking were 1.3 (95% CI: 0.7, 2.7), 3.3 (95% CI: 1.5, 7.1), and 8.1 (95% CI: 3.1, 21.1) for knees with KL grades of 2, 3, and 4, respectively. Painful knees with a deficit in quadriceps strength of greater than or equal to 4% had a 1.4-fold (95% CI: 1.0, 1.9) higher risk of pain exacerbation during walking than their pain-free counterparts.ConclusionRecent knee injury, more severe radiographic osteoarthritis, and lower quadriceps strength were associated with an increased risk of knee pain exacerbation during walking. J Orthop Sports Phys Ther 2021;51(6):298-304. Epub 10 May 2021. doi:10.2519/jospt.2021.9735.

BACKGROUND: There is a lack of mechanism-driven, clinically relevant biomarkers in chronic obstructive pulmonary disease (COPD). Mitochondrial dysfunction, a proposed disease mechanism in COPD, is associated with the release of mitochondrial DNA (mtDNA), but plasma cell-free mtDNA has not been previously examined prospectively for associations with clinical COPD measures. METHODS: P-mtDNA, defined as copy number of mitochondrially-encoded NADH dehydrogenase-1 (MT-ND1) gene, was measured by real-time quantitative PCR in 700 plasma samples from participants enrolled in the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) cohort. Associations between p-mtDNA and clinical disease parameters were examined, adjusting for age, sex, smoking status, and for informative loss to follow-up. RESULTS: P-mtDNA levels were higher in participants with mild or moderate COPD, compared to smokers without airflow obstruction, and to participants with severe COPD. Baseline increased p-mtDNA levels were associated with better CAT scores in female smokers without airflow obstruction and female participants with mild or moderate COPD on 1-year follow-up, but worse 6MWD in females with severe COPD. Higher p-mtDNA levels were associated with better 6MWD in male participants with severe COPD. These associations were no longer significant after adjusting for informative loss to follow-up. CONCLUSION: In this study, p-mtDNA levels associated with baseline COPD status but not future changes in clinical COPD measures after accounting for informative loss to follow-up. To better characterize mitochondrial dysfunction as a potential COPD endotype, these results should be confirmed and validated in future studies. TRIAL REGISTRATION:  ClinicalTrials.gov NCT01969344 (SPIROMICS).

This phase 2, double-blind, placebo-controlled, hypothesis-generating study evaluated the effects of oral reldesemtiv, a fast skeletal muscle troponin activator, in patients with spinal muscular atrophy (SMA). Patients ≥ 12 years of age with type II, III, or IV SMA were randomized into 2 sequential, ascending reldesemtiv dosing cohorts (cohort 1: 150 mg bid or placebo [2:1]; cohort 2: 450 mg bid or placebo [2:1]). The primary objective was to determine potential pharmacodynamic effects of reldesemtiv on 8 outcome measures in SMA, including 6-minute walk distance (6MWD) and maximum expiratory pressure (MEP). Changes from baseline to weeks 4 and 8 were determined. Pharmacokinetics and safety were also evaluated. Patients were randomized to reldesemtiv 150 mg, 450 mg, or placebo (24, 20, and 26, respectively). The change from baseline in 6MWD was greater for reldesemtiv 450 mg than for placebo at weeks 4 and 8 (least squares [LS] mean difference, 35.6 m [p = 0.0037] and 24.9 m [p = 0.058], respectively). Changes from baseline in MEP at week 8 on reldesemtiv 150 and 450 mg were significantly greater than those on placebo (LS mean differences, 11.7 [p = 0.038] and 13.2 cm H2O [p = 0.03], respectively). For 6MWD and MEP, significant changes from placebo were seen in the highest reldesemtiv peak plasma concentration quartile (Cmax > 3.29 μg/mL; LS mean differences, 43.3 m [p = 0.010] and 28.8 cm H2O [p = 0.0002], respectively). Both dose levels of reldesemtiv were well tolerated. Results suggest reldesemtiv may offer clinical benefit and support evaluation in larger SMA patient populations.

ObjectiveTo assess long-term (2 years) effects of bimagrumab in participants with sporadic inclusion body myositis (sIBM).MethodsParticipants (aged 36-85 years) who completed the core study (RESILIENT [Efficacy and Safety of Bimagrumab/BYM338 at 52 Weeks on Physical Function, Muscle Strength, Mobility in sIBM Patients]) were invited to join an extension study. Individuals continued on the same treatment as in the core study (10 mg/kg, 3 mg/kg, 1 mg/kg bimagrumab or matching placebo administered as IV infusions every 4 weeks). The co-primary outcome measures were 6-minute walk distance (6MWD) and safety.ResultsBetween November 2015 and February 2017, 211 participants entered double-blind placebo-controlled period of the extension study. Mean change in 6MWD from baseline was highly variable across treatment groups, but indicated progressive deterioration from weeks 24-104 in all treatment groups. Overall, 91.0% (n = 142) of participants in the pooled bimagrumab group and 89.1% (n = 49) in the placebo group had ≥1 treatment-emergent adverse event (AE). Falls were slightly higher in the bimagrumab 3 mg/kg group vs 10 mg/kg, 1 mg/kg, and placebo groups (69.2% [n = 36 of 52] vs 56.6% [n = 30 of 53], 58.8% [n = 30 of 51], and 61.8% [n = 34 of 55], respectively). The most frequently reported AEs in the pooled bimagrumab group were diarrhea 14.7% (n = 23), involuntary muscle contractions 9.6% (n = 15), and rash 5.1% (n = 8). Incidence of serious AEs was comparable between the pooled bimagrumab and the placebo group (18.6% [n = 29] vs 14.5% [n = 8], respectively).ConclusionExtended treatment with bimagrumab up to 2 years produced a good safety profile and was well-tolerated, but did not provide clinical benefits in terms of improvement in mobility. The extension study was terminated early due to core study not meeting its primary endpoint.Clinical trial registrationClinicaltrials.gov identifier NCT02573467.Classification of evidenceThis study provides Class IV evidence that for patients with sIBM, long-term treatment with bimagrumab was safe, well-tolerated, and did not provide meaningful functional benefit. The study is rated Class IV because of the open-label design of extension treatment period 2.

BACKGROUND: Among people with lower extremity peripheral artery disease (PAD), little is known about variation in response to supervised exercise therapy (SET). Clinical characteristics associated with greater responsiveness to SET have not been identified. METHODS: Data from participants with PAD in two randomized clinical trials comparing SET vs nonexercising control were combined. The exercise intervention consisted of three times weekly supervised treadmill exercise. The control groups received lectures on health-related topics. RESULTS: Of 309 unique participants randomized (mean age, 67.9 years [standard deviation, 9.3 years]; 132 [42.7%] women; 185 [59.9%] black), 285 (92%) completed 6-month follow-up. Compared with control, those randomized to SET improved 6-minute walk distance by 35.6 meters (95% confidence interval, 21.4-49.8; P < .001). In the 95 (62.1%) participants who attended at least 70% of SET sessions, change in 6-minute walk distance varied from -149.4 to +356.0 meters. Thirty-four (35.8%) had no 6-minute walk distance improvement. Among all participants, age, sex, race, body mass index, prior lower extremity revascularization, and other clinical characteristics did not affect the degree of improvement in 6-minute walk distance after SET relative to the control group. Participants with 6-minute walk distance less than the median of 334 meters at baseline had greater percentage improvement in 6-minute walk distance compared with those with baseline 6-minute walk distance above the median (+20.5% vs +5.3%; P for interaction = .0107). CONCLUSIONS: Among people with PAD, substantial variability exists in walking improvement after SET. Shorter 6-minute walk distance at baseline was associated with greater improvement after SET, but other clinical characteristics, including age, sex, prior lower extremity revascularization, and disease severity, did not affect responsiveness to exercise therapy.

BACKGROUND: Duchenne muscular dystrophy (DMD) is a rare, X-linked, fatal, degenerative neuromuscular disease caused by DMD gene mutations. A relationship between exon skipping and dystrophin production in exon 51-amenable patients treated with eteplirsen (EXONDYS 51®) is established. Once-weekly eteplirsen significantly increased dystrophin, with slower decline in ambulatory function compared to baseline. Long-term treatment with eteplirsen leads to accumulation of dystrophin over time and observed functional benefits in patients with DMD. OBJECTIVE: Compare long-term ambulatory function in eteplirsen-treated patients versus controls. METHODS: Study 201/202 included 12 eteplirsen-treated patients assessed twice/year for ambulatory function over 4 years. Ambulatory evaluations (6-minute walk test [6MWT], loss of ambulation, and North Star Ambulatory Assessment [NSAA]) were compared with matched controls from Italian Telethon and Leuven registries. RESULTS: At Years 3 and 4, eteplirsen-treated patients demonstrated markedly greater mean 6MWT than controls (difference in change from baseline of 132 m [95%CI (29, 235), p = 0.015] at Year 3 and 159 m [95%CI (66, 253), p = 0.002] at Year 4). At Year 4, a significantly greater proportion of eteplirsen-treated patients were still ambulant versus controls (10/12 vs 3/11; p = 0.020). At Year 3, eteplirsen-treated patients demonstrated milder NSAA decline versus controls (difference in change from baseline of 2.6, 95%CI [-6, 11]), however, the difference was not statistically significant; Year 4 control NSAA data were not available. CONCLUSION: In this retrospective matched control study, eteplirsen treatment resulted in attenuation of ambulatory decline over a 4-year observation period, supporting long-term benefit in patients with DMD.

ObjectiveThe 6-minute walk test is a common outcome measure in clinical trials of people with lower extremity peripheral artery disease (PAD). However, what constitutes a meaningful change in the 6-minute walk distance has not been well defined for people with PAD. The present study related the change in the 6-minute walk distance to the degree of participant-reported improvement or decline in the 6-minute walk distance to define a meaningful change in the 6-minute walk distance for those with PAD.MethodsParticipants with PAD from three observational longitudinal studies completed the walking impairment questionnaire (WIQ) distance score and 6-minute walk at baseline and 1 year later. The WIQ distance score measures participants' perceived difficulty walking seven different distances without stopping (ranging from walking around the home to walking 5 blocks) on a 0 to 4 Likert scale, with 0 representing an inability to walk the distance and 4 representing no difficulty. The mean changes in the 6-minute walk distance corresponding to the participants' report of no change, 1-unit change, or 2-unit change, respectively, in the Likert scale score between the baseline and 1-year follow-up measures were calculated for each WIQ distance.ResultsA total of 777 participants with PAD (mean age, 71.2 ± 8.8 years; mean baseline 6-minute walk distance, 350.1 ± 118.1 meters) completed 5439 questions about their difficulty walking each WIQ distance at baseline and follow-up. Participants with PAD who reported no change in their difficulty in walking each WIQ distance between baseline and follow-up had a decline of 7.2 meters (95% confidence interval [CI], -11.6 to -2.8 meters) in the 6-minute walk test. Relative to those reporting no change in difficulty walking, the participants reporting 1- and 2-point improvements in walking ability showed 6-minute walk distance improvements of 7.8 meters (95% CI, -0.3 to 15.9 meters) and 20.1 meters (95% CI, 1.1-39.2 meters), respectively. Relative to those reporting no change in walking difficulty, those reporting 1- and 2-point declines in perceived walking difficulty showed declines of -11.2 meters (95% CI, -19.0 to -3.4 meters) and -23.8 meters (95% CI, -37.4 to -10.3 meters) in the 6-minute walk distance.ConclusionsAmong people with PAD, ∼8- and ∼20-meter improvements in the 6-minute walk distance represent small and large improvements in walking ability, respectively. People with PAD who reported no change in their ability to walk distances over 1 year simultaneously declined by a mean of 7 meters in the 6-minute walk test. These findings will be useful for interpreting the results from randomized trials of interventions to improve the walking performance of people with PAD.

BackgroundSlow heart rate recovery (HRR) after exercise is associated with autonomic dysfunction and increased mortality. What HRR criterion at 1-minute after a 6-minute walk test (6MWT) best defines pulmonary impairment?.Study design and methodsA total of 5008 phase 2 COPDGene (NCT00608764) participants with smoking history were included. A total of 2127 had COPD and, of these, 385 were followed-up 5-years later. Lung surgery, transplant, bronchiectasis, atrial fibrillation, heart failure and pacemakers were exclusionary. HR was measured from pulse oximetry at end-walk and after 1-min seated recovery. A receiver operator characteristic (ROC) identified optimal HRR cut-off. Generalized linear regression determined HRR association with spirometry, chest CT, symptoms and exacerbations.ResultsHRR after 6MWT (bt/min) was categorized in quintiles: ≤5 (23.0% of participants), 6-10 (20.7%), 11-15 (18.9%), 16-22 (18.5%) and ≥23 (18.9%). Compared to HRR≤5, HRR≥11 was associated with (p

BackgroundPrevious studies have established a higher prevalence of vitamin D deficiency in patients with COPD, but the relationship between vitamin D levels and COPD exacerbations remains controversial. In addition, the effect of vitamin D levels on imaging characteristics remains mostly unexplored. Using cross-sectional and longitudinal follow up data from the COPDGene Study, we assessed the association between vitamin D levels on respiratory symptoms, exacerbations, and imaging characteristics. We hypothesized that vitamin D deficiency will be associated with worse respiratory-related outcomes.MethodsCurrent and former smokers between ages 45-80 were enrolled the COPDGene Study. Subjects completed questionnaires, spirometry, six-minute walk test, and chest computed tomography scans. A subset of subjects had measurement of serum concentration of 25-hydroxyvitamin D (25(OH)D). Vitamin D deficiency was defined as serum concentration less than 20 ng/mL. Longitudinal follow up was conducted via a web-based or telephone questionnaire.ResultsVitamin D levels were measured on 1544 current and former smokers, of which 981 subjects had sufficient vitamin D levels and 563 subjects had vitamin D deficiency. Subjects with vitamin D deficiency were younger with increased likelihood of being African American, being current smokers, having a lower percent predicted FEV1, and having COPD. Vitamin D deficiency was associated with worse quality of life, increased dyspnea, decreased exercise tolerance, and increased frequency of severe exacerbations. Vitamin D deficiency was also associated with increased segmental airway wall thickness on chest CT scans.ConclusionVitamin D deficiency was associated with increased respiratory symptoms, decreased functional status, increased frequency of severe exacerbations, as well as airway wall thickening on chest CT scans. Further research is needed to determine the potential impact of vitamin D supplementation to improve disease outcomes.

OBJECTIVE: To evaluate the suitability of real-world data (RWD) and natural history data (NHD) for use as external controls in drug evaluations for ambulatory Duchenne muscular dystrophy (DMD). METHODS: The consistency of changes in the 6-minute walk distance (Δ6MWD) was assessed across multiple clinical trial placebo arms and sources of NHD/RWD. Six placebo arms reporting 48-week Δ6MWD were identified via literature review and represented 4 sets of inclusion/exclusion criteria (n = 383 patients in total). Five sources of RWD/NHD were contributed by Universitaire Ziekenhuizen Leuven, DMD Italian Group, The Cooperative International Neuromuscular Research Group, ImagingDMD, and the PRO-DMD-01 study (n = 430 patients, in total). Mean Δ6MWD was compared between each placebo arm and RWD/NHD source after subjecting the latter to the inclusion/exclusion criteria of the trial for baseline age, ambulatory function, and steroid use. Baseline covariate adjustment was investigated in a subset of patients with available data. RESULTS: Analyses included ∼1,200 patient-years of follow-up. Differences in mean Δ6MWD between trial placebo arms and RWD/NHD cohorts ranged from -19.4 m (i.e., better outcomes in RWD/NHD) to 19.5 m (i.e., worse outcomes in RWD/NHD) and were not statistically significant before or after covariate adjustment. CONCLUSIONS: We found that Δ6MWD was consistent between placebo arms and RWD/NHD subjected to equivalent inclusion/exclusion criteria. No evidence for systematic bias was detected. These findings are encouraging for the use of RWD/NHD to augment, or possibly replace, placebo controls in DMD trials. Multi-institution collaboration through the Collaborative Trajectory Analysis Project rendered this study feasible.

CT measurement of body composition may improve lung transplant candidate selection. We assessed whether skeletal muscle adipose deposition on abdominal and thigh CT scans was associated with 6 min walk distance (6MWD) and wait-list survival in lung transplant candidates. Each ½-SD decrease in abdominal muscle attenuation (indicating greater lipid content) was associated with 14 m decrease in 6MWD (95% CI -20 to -8) and 20% increased risk of death or delisting (95% CI 10% to 40%). Each ½-standard deviation decrease in thigh muscle attenuation was associated with 15 m decrease in 6MWD (95% CI -21 to -10). CT imaging may improve candidate risk stratification.

The prognostic significance of the six-minute walk distance for lower extremity events in people with peripheral artery disease (PAD) is unknown. This longitudinal study assessed whether a poorer six-minute walk distance at baseline was associated with higher rates of subsequent lower extremity atherosclerotic disease events in PAD. A total of 369 patients (mean age 69.4 ± 10.0 years; mean ankle-brachial index (ABI) 0.67 ± 0.17; 31% women; 30% black individuals) from Chicago-area medical centers with PAD were enrolled. Participants underwent baseline six-minute walk testing and returned for annual study visits. Lower extremity events consisted of one or more of the following: ABI decline greater than 15% or medical record adjudicated lower extremity revascularization, critical limb ischemia, or amputation. At a mean follow-up of 33.3 months, lower extremity events occurred in 66/123 (53.7%) people in the first (worst) tertile of six-minute walk performance, 55/124 (44.4%) in the second tertile, and 56/122 (45.9%) in the third (best) tertile. After adjusting for age, sex, race, ABI, comorbidities, and other confounders, participants in the first (worst) tertile of six-minute walk distance at baseline had higher rates of lower extremity events during follow-up, compared to those in the best tertile at baseline (HR = 1.74, 95% CI 1.17-2.60, p = 0.0067). Among people with PAD, a poorer six-minute walk distance was associated with higher rates of subsequent lower extremity PAD-related events after adjusting for confounders. Further study is needed to determine whether interventions that improve six-minute walk distance can reduce lower extremity adverse events in people with PAD.

BackgroundRandomized trials of people with peripheral artery disease (PAD) and intermittent claudication have traditionally used maximal treadmill walking distance as the primary outcome, but the 6-minute walk test is increasingly used as a primary outcome in randomized trials of PAD. This study compared relative changes in maximal treadmill walking distance versus 6-minute walk distance in response to a therapeutic intervention or control in randomized trials of participants with PAD.MethodsData from four randomized trials of therapeutic interventions in participants with PAD that measured both 6-minute walk and treadmill walking performance at baseline and the 6-month follow-up were combined. Two trials studied supervised treadmill exercise, one studied home-based walking exercise, and one studied resveratrol.ResultsOf 467 participants (mean age, 69.8; standard deviation, 9.7), the mean ankle-brachial index was 0.66 (standard deviation, 0.17). At the 6-month follow-up, participants with PAD randomized to control or placebo significantly declined in 6-minute walk distance (-10.2 m; 95% confidence interval, -18.2 to -2.2; P = .013), but improved maximal treadmill walking distance (+25.7 m; 95% CI, +6.0 to +45.3 m; P = .010; difference between change in 6-minute walk versus maximal treadmill walking distance: -37.3 m; 95% CI, -56.4 to -18.2; P < .001). Home-based exercise improved the 6-minute walk distance by 43.2 m (95% CI, +28.4 to +57.9), and supervised treadmill exercise improved the 6-minute walk distance by 25.0 m (95% CI, +14.7 to +35.2; mean difference, +18.2 m favoring home-based exercise [95% CI, +0.2 to +36.2 m; P = .048]). Among all participants, the presence (vs absence) of treadmill exercise training was associated with a 141.3-m greater improvement in maximal treadmill walking distance compared to 6-minute walk distance (95% CI, 88.2-194.4; P < .001), suggesting a benefit from treadmill training on the treadmill outcome.ConclusionsMaximal treadmill walking distance and the 6-minute walk distance are not interchangeable outcomes in participants with PAD. Participants with PAD randomized to control groups improved treadmill walking distance but simultaneously meaningfully declined in 6-minute walk distance. Supervised treadmill exercise training amplified improvement in treadmill walking distance because of a training to the outcome measure phenomenon.

BackgroundExercise tolerance is an important endpoint in chronic obstructive pulmonary disease (COPD) clinical trials. Little is known about the comparative measurement properties of constant work rate cycle ergometry (CWRCE) and the endurance shuttle walking test (ESWT). The objective of this sub-analysis of the TORRACTO® study was to directly compare the endurance measurement properties of CWRCE and ESWT in patients with COPD in a multicentre, multinational setting. We predicted that both tests would be similarly reliable, but that the ESWT would be more responsive to bronchodilation than CWRCE.MethodsThis analysis included 151 patients who performed CWRCE and ESWT at baseline and week 6 after receiving once-daily placebo, tiotropium/olodaterol (T/O) 2.5/5 μg or T/O 5/5 μg. Reproducibility was assessed by comparing their respective performance at baseline and week 6 in the placebo group. Responsiveness to bronchodilation was assessed by comparing endurance time at week 6 with T/O with baseline values and placebo. The locus of symptom limitation and end-exercise Borg scales for breathing and leg discomfort for both tests were also analysed.ResultsThe intraclass correlation coefficients for CWRCE and ESWT were 0.56 [95% confidence interval (CI) 0.37-0.71] and 0.75 (95% CI 0.63-0.84). More patients were limited by breathing discomfort during the ESWT than during CWRCE, whereas more patients were limited by leg discomfort or breathing/leg discomfort during CWRCE than the ESWT (p

BACKGROUND: People with dysvascular lower limb amputation (LLA) achieve one-third of the recommended steps per day and experience severe disability. Although physical function improves with rehabilitation after dysvascular LLA, physical activity remains largely unchanged, and factors contributing to limited daily step count are unknown. OBJECTIVES: To identify factors that contribute to daily step count after dysvascular LLA. DESIGN: Cross-sectional, secondary data analysis. SETTING: Outpatient rehabilitation facilities. PARTICIPANTS: Fifty-eight patients with dysvascular major LLA (age: 64 ± 9 years, body mass index: 30 ± 8 kg/m2 , male: 95%, transtibial LLA: 95%). METHODS: Data were collected by a blinded assessor after dysvascular LLA. Candidate explanatory variables included (1) demographics, (2) LLA characteristics, (3) comorbidities and health behaviors, and (4) physical function. Variables with univariate associations with log steps/day (transformed due to non-normality) were included in a multiple linear regression model using backward elimination to identify factors that explained significant variability in log steps/day. PRIMARY OUTCOME MEASURE: The primary outcome, daily step count, was measured with accelerometer-based activity monitors worn by participants for 10 days. RESULTS: Participants took an average (± SD) of 1450 ± 1309 steps/day. After backward elimination, the final model included four variables explaining 62% of the overall daily step count (P

ObjectiveTo investigate thresholds of strength below which individuals with knee osteoarthritis (OA) may have more difficulty carrying out physical functions of daily life. Individuals below such thresholds might benefit more from strengthening interventions than those with greater strength.MethodsWe studied individuals with symptomatic OA at baseline in the Multicenter Osteoarthritis Study who had knee extensor strength measured isokinetically at 60º/second. Participants underwent a 20-meter walk test and a sit-to-stand test and answered questions from the Western Ontario and McMaster Universities Osteoarthritis Index. Physical function results were plotted against measures of quadriceps strength (Nm) (and as strength:body weight) for the worst knee. Loess technique was used to examine inflection points. Nonlinear relationships were examined in piecewise linear regression models. Differences were tested using linear and logistic regression models.ResultsThe study had 834 participants (65.8% women). The mean ± SD age of the participants was 62.9 ± 7.9 years. In women, there were thresholds of strength below which the slope of strength versus function was steeper: walking speed (

BackgroundPoor functional exercise capacity is common among those with obesity; however, objective measures of exercise capacity are rarely examined in behavioral treatments targeting obese individuals. We examined whether a 4-week acceptance and commitment therapy (ACT) intervention for disinhibited eating or a behavioral weight loss (BWL) intervention improved exercise capacity and explored demographic and disinhibited eating variables related to exercise capacity.MethodsVeterans (n = 61), randomized to receive ACT or BWL, completed an assessment of exercise capacity via the 6-min walk test (6MWT) at baseline and 6-month follow-up. Measures of disinhibited eating patterns and body mass index (BMI), at baseline and post-treatment, were also collected. Change in 6MWT distance and treatment group differences were examined using mixed ANOVAs. Characteristics related to baseline 6MWT and predictors of improvement in 6MWT at 6 months were examined with hierarchical multiple regression.ResultsThere were overall significant improvements on the 6MWT from baseline to 6-month follow-up (F(1,59) = 11.14, p = .001, ηp2 = .159) but no differences between the ACT and BWL groups. Baseline BMI (β = - .33, p = .005) was the only variable related to baseline 6MWT. Improvements on the 6MWT were related to younger age (β = - .41, p = 0.001), female gender (β = .36, p = .001), and treatment-related increases in dietary restraint behaviors (β = .42, p = .001).ConclusionsFunctional exercise capacity improved among participants completing behavioral interventions for weight and disinhibited eating. Improvements in dietary behavior regulatory skills may have generalized to improved regulation in other behavioral domains associated with exercise capacity.

Rationale: Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation. Spirometry loops are not smooth curves and have undulations and peaks that likely reflect heterogeneity of airflow.Objectives: To assess whether the Peak Index, the number of peaks adjusted for lung size, is associated with clinical outcomes.Methods: We analyzed spirometry data of 9,584 participants enrolled in the COPDGene study and counted the number of peaks in the descending part of the expiratory flow-volume curve from the peak expiratory flow to end-expiration. We adjusted the peaks count for the volume of the lungs from peak expiratory flow to end-expiration to derive the Peak Index. Multivariable regression analyses were performed to test associations between the Peak Index and lung function, respiratory morbidity, structural lung disease on computed tomography (CT), forced expiratory volume in 1 second (FEV1) decline, and mortality.Results: The Peak Index progressively increased from Global Initiative for Chronic Obstructive Lung Disease stage 0 through 4 (P

Background Among people with lower extremity peripheral artery disease, obesity is associated with faster functional decline than normal weight. The association of weight loss with functional decline in peripheral artery disease is unknown. Methods and Results Adults with an ankle-brachial index

ObjectiveTo assess the feasibility, safety, and efficacy of intracoronary allogeneic cardiosphere-derived cells (CAP-1002) in patients with Duchenne muscular dystrophy (DMD).MethodsThe Halt Cardiomyopathy Progression (HOPE)-Duchenne trial is a phase I/II, randomized, controlled, open-label trial (NCT02485938). Patients with DMD >12 years old, with substantial myocardial fibrosis, were randomized (1:1) to usual care (control) or global intracoronary infusion of CAP-1002 (75 million cells). Participants were enrolled at 3 US medical centers between January and August 2016 and followed for 12 months. An independent Data and Safety Monitoring Board provided safety oversight. Cardiac function and structure were assessed by MRI, and analyzed by a blinded core laboratory. Skeletal muscle function was assessed by performance of the upper limb (PUL).ResultsTwenty-five eligible patients (mean age 17.8 years; 68% wheelchair-dependent) were randomized to CAP-1002 (n = 13) or control (n = 12). Incidence of treatment-emergent adverse events was similar between groups. Compared to baseline, MRI at 12 months revealed significant scar size reduction and improvement in inferior wall systolic thickening in CAP-1002 but not control patients. Mid-distal PUL improved at 12 months in 8 of 9 lower functioning CAP-1002 patients, and no controls (p = 0.007).ConclusionsIntracoronary CAP-1002 in DMD appears safe and demonstrates signals of efficacy on both cardiac and upper limb function for up to 12 months. Thus, future clinical research on CAP-1002 treatment of DMD cardiac and skeletal myopathies is warranted.Classification of evidenceThis phase I/II study provides Class II evidence that for patients with DMD, intracoronary CAP-1002 is feasible and appears safe and potentially effective.

RationaleFrailty represents an increased vulnerability to adverse health outcomes. The frailty phenotype conceptual model (three or more patient attributes of wasting, exhaustion, low activity, slowness, and weakness) is associated with increased morbidity and mortality in geriatric populations.ObjectivesOur objective was to describe the risks associated with frailty in patients with chronic obstructive pulmonary disease.MethodsData from the National Emphysema Treatment Trial (NETT) were retrospectively analyzed. The frailty phenotype conceptual model was operationalized as three or more frailty parameters (a body mass index decrease of ≥5% over 12 months, self-reported exhaustion, low 6-minute walk distance, or physical activity or respiratory muscle strength in the lowest quartile). Frail participants were compared with participants with two or fewer frailty parameters. Participants were followed starting 12 months after NETT randomization (to minimize surgical effect) for 24 months. Univariate, multivariate, Kaplan-Meier, and Cox proportional hazard analyses were performed, adjusting for treatment arm, age, modified Medical Research Council dyspnea scale, sex, and baseline forced expiratory volume in 1 second (FEV1). Multiple imputation was used for missing values.ResultsThe participants (N = 902) were predominantly white (94.5%) males (59.5%), with a median age of 67 years (interquartile range, 63-70 yr) and a median FEV1% predicted of 26 (interquartile range, 20-33). Six percent of the participants (95% confidence interval [CI], 4.5 to 7.6) were frail. The incidence rate of frailty was 6.4 per 100 person-years. Frail participants reported significantly worse disease-specific and overall quality of life by St. George's Respiratory Questionnaire total score (mean difference of 11.6; 95% CI, 7.6 to 15.6; P < 0.001), mental composite on Medical Outcomes Survey Short Form-36 (mean difference -6.8; 95% CI, -10.0 to -3.6; P < 0.001), and physical composite scores on Medical Outcomes Survey Short Form-36 (mean difference -16.7; 95% CI, -21.3 to -12.1; P = 0.001). Frail participants had an increased rate of hospitalization (adjusted hazard ratio, 1.6; 95% CI, 1.1 to 2.5; P = 0.02) and an adjusted increase in hospital use of 8.0 days (95% CI, 4.4 to 11.6; P < 0.001) compared with nonfrail participants. Frail participants had a higher mortality rate (adjusted hazard ratio, 1.4; 95% CI, 0.97 to 2.0; P = 0.07).ConclusionsAmong adults with chronic obstructive pulmonary disease, our measure of frailty (modified from the Fried frailty phenotype) was associated with incident and longer-duration hospitalization, and with poor quality of life.

BackgroundAmbulatory function predicts morbidity and mortality and may be influenced by cardiopulmonary dysfunction. Persons living with HIV (PLWH) suffer from a high prevalence of cardiac and pulmonary comorbidities that may contribute to higher risk of ambulatory dysfunction as measured by 6-minute walk test distance (6-MWD). We investigated the effect of HIV on 6-MWD.MethodsPLWH and HIV-uninfected individuals were enrolled from 2 clinical centers and completed a 6-MWD, spirometry, diffusing capacity for carbon monoxide (DLCO) and St. George's Respiratory Questionnaire (SGRQ). Results of 6-MWD were compared between PLWH and uninfected individuals after adjusting for confounders. Multivariable linear regression analysis was used to determine predictors of 6-MWD.ResultsMean 6-MWD in PLWH was 431 meters versus 462 in 130 HIV-uninfected individuals (p = 0.0001). Older age, lower forced expiratory volume (FEV1)% or lower forced vital capacity (FVC)%, and smoking were significant predictors of decreased 6-MWD in PLWH, but not HIV-uninfected individuals. Lower DLCO% and higher SGRQ were associated with lower 6-MWD in both groups. In a combined model, HIV status remained an independent predictor of decreased 6-MWD (Mean difference = -19.9 meters, p = 0.005).ConclusionsHIV infection was associated with decreased ambulatory function. Airflow limitation and impaired diffusion capacity can partially explain this effect. Subjective assessments of respiratory symptoms may identify individuals at risk for impaired physical function who may benefit from early intervention.

INTRODUCTION: ACT DMD was a 48-week trial of ataluren for nonsense mutation Duchenne muscular dystrophy (nmDMD). Patients received corticosteroids for ≥6 months at entry and stable regimens throughout study. This post hoc analysis compares efficacy and safety for deflazacort and prednisone/prednisolone in the placebo arm. METHODS: Patients received deflazacort (n = 53) or prednisone/prednisolone (n = 61). Endpoints included change from baseline in 6-minute walk distance (6MWD), timed function tests, estimated age at loss of ambulation (extrapolated from 6MWD). RESULTS: Mean changes in 6MWD were -39.0 m (deflazacort; 95% confidence limit [CL], -68.85, -9.17) and -70.6 m (prednisone/prednisolone; 95% CL, -97.16, -44.02). Mean changes in 4-stair climb were 3.79 s (deflazacort; 95% CL, 1.54, 6.03) and 6.67 s (prednisone/prednisolone; 95% CL, 4.69, 8.64). CONCLUSIONS: This analysis, limited by its post hoc nature, suggests greater preservation of 6MWD and 4-stair climb with deflazacort vs. prednisone/prednisolone. A head-to-head comparison will better define these differences. Muscle Nerve 58: 639-645, 2018.

RationaleSocioeconomically disadvantaged patients with chronic obstructive pulmonary disease (COPD) often face barriers to evidence-based care that are difficult to address in public care settings with limited resources.ObjectivesTo determine the benefit of health coaching for patients with moderate to severe COPD relative to usual care.MethodsWe conducted a randomized controlled trial of 9 months of health coaching versus usual care for English- or Spanish-speaking patients at least 40 years of age with moderate to severe COPD. Primary outcomes were COPD-related quality of life and the dyspnea subscale of the Chronic Respiratory Disease Questionnaire. Secondary outcomes were self-efficacy for managing COPD, exercise capacity (6-min walk test), and number of COPD exacerbations. Additional outcomes were COPD symptoms, lung function (forced expiratory volume in 1 s percent predicted), smoking status, bed days owing to COPD, quality of care (Patient Assessment of Chronic Illness Care), COPD knowledge, and symptoms of depression (Patient Health Questionnaire). Outpatient visits, emergency department visits, and hospitalizations were assessed by review of medical records. Generalized linear modeling was used to adjust for baseline values and account for clustering by clinic.ResultsOf 192 patients enrolled, 158 (82%) completed 9 months of follow-up. There were no significant differences between study arms for the primary or secondary outcomes. At 9 months, patients in the coached group reported better quality of care (mean Patient Assessment of Chronic Illness Care score, 3.30 vs. 3.18; adjusted P = 0.02) and were less likely to report symptoms of moderate to severe depression (Patient Health Questionnaire score, ≥15) than those in the usual care arm (6% vs. 20%; adjusted P = 0.01). During the study, patients in the coaching arm had 48% fewer hospitalizations related to COPD (0.27/patient/yr vs. 0.52/patient/yr), but this difference was not significant in the adjusted analysis.ConclusionsThese results help inform expectations regarding the limitations and benefits of health coaching for patients with COPD. They may be useful to health policy experts in assessing the potential value of reimbursement and incentives for health coaching-type activities for patients with chronic disease. Clinical trial registered with www.clinicaltrials.gov (NCT02234284).

In people without lower extremity peripheral artery disease (PAD), mitochondrial DNA copy number declines with aging, and this decline is associated with declines in mitochondrial activity and functional performance. However, whether lower extremity ischemia is associated with lower mitochondrial DNA copy number and whether mitochondrial DNA copy number is associated with the degree of functional impairment in people with PAD is unknown. In people with and without PAD, age 65 years and older, we studied associations of the ankle-brachial index (ABI) with mitochondrial DNA copy number and associations of mitochondrial DNA copy number with functional impairment. Calf muscle biopsies were obtained from 34 participants with PAD (mean age: 73.5 years (SD 6.4), mean ABI: 0.67 (SD 0.15), mean 6-minute walk distance: 1191 feet (SD 223)) and 10 controls without PAD (mean age: 73.1 years (SD 4.7), mean ABI: 1.14 (SD 0.07), mean 6-minute walk distance: 1387 feet (SD 488)). Adjusting for age and sex, lower ABI values were associated with higher mitochondrial DNA copy number, measured in relative copy number (ABI

BackgroundFew studies have examined changes in the pain experience of patients with COPD and predictors of pain in these patients.ObjectivesThe objectives of the study were to examine whether distinct groups of COPD patients could be identified based on changes in the occurrence and severity of pain over 12 months and to evaluate whether these groups differed on demographic, clinical, and pain characteristics, and health-related quality of life (HRQoL).Patients and methodsA longitudinal study of 267 COPD patients with very severe COPD was conducted. Their mean age was 63 years, and 53% were females. The patients completed questionnaires including demographic and clinical variables, the Brief Pain Inventory, and the St Georges Respiratory Questionnaire at enrollment, and 3, 6, 9, and 12 months follow-up. In addition, spirometry and the 6 Minute Walk Test were performed. Latent class analysis was used to identify subgroups of patients with distinct pain profiles based on pain occurrence and worst pain severity.ResultsMost of the patients (77%) reported pain occurrence over 12 months. Of these, 48% were in the "high probability of pain" group, while 29% were in the "moderate probability of pain" group. For the worst pain severity, 37% were in the "moderate pain" and 39% were in the "mild pain" groups. Females and those with higher body mass index, higher number of comorbidities, and less education were in the pain groups. Patients in the higher pain groups reported higher pain interference scores, higher number of pain locations, and more respiratory symptoms. Few differences in HRQoL were found between the groups except for the symptom subscale.ConclusionPatients with COPD warrant comprehensive pain management. Clinicians may use this information to identify those who are at higher risk for persistent pain.

BACKGROUND:Remote monitoring of patients with heart failure (HF) using wearable devices can allow patient-specific adjustments to treatments and thereby potentially reduce hospitalizations. We aimed to assess HF state using wearable measurements of electrical and mechanical aspects of cardiac function in the context of exercise. METHODS AND RESULTS:Patients with compensated (outpatient) and decompensated (hospitalized) HF were fitted with a wearable ECG and seismocardiogram sensing patch. Patients stood at rest for an initial recording, performed a 6-minute walk test, and then stood at rest for 5 minutes of recovery. The protocol was performed at the time of outpatient visit or at 2 time points (admission and discharge) during an HF hospitalization. To assess patient state, we devised a method based on comparing the similarity of the structure of seismocardiogram signals after exercise compared with rest using graph mining (graph similarity score). We found that graph similarity score can assess HF patient state and correlates to clinical improvement in 45 patients (13 decompensated, 32 compensated). A significant difference was found between the groups in the graph similarity score metric (44.4±4.9 [decompensated HF] versus 35.2±10.5 [compensated HF]; P

Little is known about the prognostic significance of specific characteristics of magnetic resonance imaging (MRI) measured plaque in the superficial femoral artery (SFA). Associations of MRI-measured plaque quantity, lumen area, and plaque composition in the SFA with subsequent mobility loss were studied in people with lower extremity peripheral artery disease (PAD). Participants with an ankle-brachial index (ABI) < 1.00 were identified from Chicago medical centers and underwent direct visualization of atherosclerotic plaque in the SFA using MRI. Participants were followed annually for up to 4 years. Mobility loss was defined as becoming unable to walk up and down a flight of stairs or walk one-quarter of a mile without assistance among participants without mobility impairment at baseline. Analyses adjusted for age, sex, race, comorbidities, ABI, physical activity, and other confounders. Of 308 PAD participants without baseline mobility impairment, 100 (32.5%) developed mobility loss during follow-up. Compared to the lowest mean plaque area tertile at baseline, participants in the highest (worst) plaque area tertile had a higher rate of mobility loss (hazard ratio (HR) = 2.08, 95% confidence interval (CI) = 1.14-3.79, p = 0.018). Compared to the highest mean lumen area tertile, the smallest (worst) mean lumen area tertile was associated with greater mobility loss (HR = 2.18, 95% CI = 1.20-3.96, p = 0.011). Neither lipid rich necrotic core nor calcium in the SFA were associated with mobility loss. In conclusion, greater plaque quantity and smaller lumen area in the proximal SFA, but not lipid rich necrotic core or calcium, were associated with higher mobility loss in people with PAD.

BackgroundChronic obstructive pulmonary disease (COPD) severely hinders quality of life for those affected and is costly to the health care system. Care gaps in areas such as pharmacotherapy, inhaler technique, and knowledge of disease are prevalent, particularly for vulnerable populations served by community clinics. Non-professionally licensed health coaches have been shown to be an effective and cost-efficient solution in bridging care gaps and facilitating self-management for patients with other chronic diseases, but no research to date has explored their efficacy in improving care for people living with COPD.MethodThis is multi-site, single blinded, randomized controlled trial evaluates the efficacy of health coaches to facilitate patient self-management of disease and improve quality of life for patients with moderate to severe COPD. Spirometry, survey, and an exercise capacity test are conducted at baseline and at 9 months. A short survey is administered by phone at 3 and 6 months post-enrollment. The nine month health coaching intervention focuses on enhancing disease understanding and symptom awareness, improving use of inhalers; making personalized plans to increase physical activity, smoking cessation, or otherwise improve disease management; and facilitating care coordination.DiscussionThe results of this study will provide evidence regarding the efficacy and feasibility of health coaching to improve self-management and quality of life for urban underserved patients with moderate to severe COPD.Trial registrationClinicalTrials.gov identifier NCT02234284 . Registered 12 August 2014.

BackgroundCOPD is associated with reduced physical capacity. However, it is unclear whether pulmonary emphysema, which can occur without COPD, is associated with reduced physical activity in daily life, particularly among people without COPD and never smokers. We hypothesized that greater percentage of emphysema-like lung on CT scan is associated with reduced physical activity assessed by actigraphy and self-report.MethodsThe Multi-Ethnic Study of Atherosclerosis (MESA) enrolled participants free of clinical cardiovascular disease from the general population. Percent emphysema was defined as percentage of voxels

IntroductionData on the association between exercise capacity and risk for heart failure (HF) in older adults are limited.MethodsThis study examined the association of exercise capacity, and its change over time, with 10-year mortality and incident HF in 2,935 participants of the Health, Aging, and Body Composition Study without HF at baseline (age, 73.6 [SD=2.9] years; 52.1% women; 41.4% black; 58.6% white). This cohort was initiated in 1997-1998 and exercise capacity was evaluated with a long-distance corridor walk test (LDCW) at baseline and Year 4. Outcomes were collected in 2007-2008 and initial analysis performed in 2014.ResultsTen-year incident HF for completers (n=2,245); non-completers (n=331); and those excluded from LDCW for safety reasons (n=359) was 11.4%, 19.2%, and 23.0%, respectively. The corresponding 10-year mortality was 27.9%, 41.1%, and 42.4%. In models accounting for competing mortality, the adjusted subhazard ratio for HF was 1.37 (95% CI=1.00, 1.88; p=0.049) in non-completers and 1.41 (95% CI=1.06, 1.89; p=0.020) in those excluded versus completers. Non-completers (adjusted hazard ratio, 1.49; 95% CI=1.21, 1.84; p

RationaleThe 6-minute-walk distance (6MWD) test predicts mortality in chronic obstructive pulmonary disease (COPD). Whether variability in study type (observational vs. interventional) or region performed limits use of the test as a stratification tool or outcome measure for therapeutic trials is unclear.ObjectivesTo analyze the original data from several large observational studies and from randomized clinical trials with bronchodilators to support the qualification of the 6MWD test as a drug development tool in COPD.MethodsOriginal data from 14,497 patients with COPD from six observational (n = 9,641) and five interventional (n = 4,856) studies larger than 100 patients and longer than 6 months in duration were included. The geographical, anthropometrics, FEV1, dyspnea, comorbidities, and health status scores were measured. Associations between 6MWD and mortality, hospitalizations, and exacerbations adjusted by study type, age, and sex were evaluated. Thresholds for outcome prediction were calculated using receiver operating curves. The change in 6MWD after inhaled bronchodilator treatment and surgical lung volume reduction were analyzed to evaluate the responsiveness of the test as an outcome measure.Measurements and main resultsThe 6MWD was significantly lower in nonsurvivors, those hospitalized, or who exacerbated compared with those without events at 6, 12, and greater than 12 months. At these time points, the 6MWD receiver operating characteristic curve-area under the curve to predict mortality was 0.71, 0.70, and 0.68 and for hospitalizations was 0.61, 0.60, and 0.59, respectively. After treatment, the 6MWD was not different between placebo and bronchodilators but increased after surgical lung volume reduction compared with medical therapy. Variation across study types (observational or therapeutic) or regions did not confound the ability of 6MWD to predict outcome.ConclusionsThe 6MWD test can be used to stratify patients with COPD for clinical trials and interventions aimed at modifying exacerbations, hospitalizations, or death.

BackgroundHypoxemia is a major complication of COPD and is a strong predictor of mortality. We previously identified independent risk factors for the presence of resting hypoxemia in the COPDGene cohort. However, little is known about characteristics that predict onset of resting hypoxemia in patients who are normoxic at baseline. We hypothesized that a combination of clinical, physiologic, and radiographic characteristics would predict development of resting hypoxemia after 5-years of follow-up in participants with moderate to severe COPD METHODS: We analyzed 678 participants with moderate-to-severe COPD recruited into the COPDGene cohort who completed baseline and 5-year follow-up visits and who were normoxic by pulse oximetry at baseline. Development of resting hypoxemia was defined as an oxygen saturation ≤88% on ambient air at rest during follow-up. Demographic and clinical characteristics, lung function, and radiographic indices were analyzed with logistic regression models to identify predictors of the development of hypoxemia.ResultsForty-six participants (7%) developed resting hypoxemia at follow-up. Enrollment at Denver (OR 8.30, 95%CI 3.05-22.6), lower baseline oxygen saturation (OR 0.70, 95%CI 0.58-0.85), self-reported heart failure (OR 6.92, 95%CI 1.56-30.6), pulmonary artery (PA) enlargement on computed tomography (OR 2.81, 95%CI 1.17-6.74), and prior severe COPD exacerbation (OR 3.31, 95%CI 1.38-7.90) were independently associated with development of resting hypoxemia. Participants who developed hypoxemia had greater decline in 6-min walk distance and greater 5-year decline in quality of life compared to those who remained normoxic at follow-up.ConclusionsDevelopment of clinically significant hypoxemia over a 5-year span is associated with comorbid heart failure, PA enlargement and severe COPD exacerbation. Further studies are needed to determine if treatments targeting these factors can prevent new onset hypoxemia.Trial registrationCOPDGene is registered at ClinicalTrials.gov: NCT00608764 (Registration Date: January 28, 2008).

In COPD, body composition studies have focused primarily on low BMI. We examined obesity (BMI ≥ 30 kg/m(2)) as a risk factor for poor function and longitudinal functional decline. Data from a longitudinal cohort of adults with COPD (n = 1096) and an age- and sex-matched comparison group collected in two in-person visits ∼49 months apart were analyzed. Two measures of functioning were examined: six-minute walk distance (6MWD) and Short Physical Performance Battery (SPPB). Multivariate regression analyses examined relationships of obesity with functioning. Secondary analyses stratified by GOLD classification (GOLD-0/1, GOLD-2, GOLD-3/4). Obesity (53% of COPD cohort) was associated cross-sectionally with 6MWD and SPPB in COPD, and only with 6MWD in the comparison group. Obesity predicted significant functional decline in 6MWD for individuals with COPD (odds ratio (OR) for decline [95% CI] 1.8 [1.1, 2.9]), but not the comparison group. Secondary analyses revealed that the risk of decline was significant only in those with more severe COPD (GOLD 3/4, OR = 2.3 [1.0, 5.4]). Obesity was highly prevalent and was associated with poor function concurrently and with subsequent decline in 6MWD in COPD. Obesity in COPD should be considered a risk not only for more co-morbidities and greater health care use, but also for functional decline.