Meaningful changes in motor function in Duchenne muscular dystrophy (DMD): A multi-center study.

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 <18 years and receiving steroids. Minimal clinically important differences (MCIDs) for worsening were also estimated. Estimated MDC thresholds for >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.

Functional trajectories before and after loss of ambulation in Duchenne muscular dystrophy and implications for clinical trials.

This study examined functional trajectories of subjects during the transition phase between ambulatory and non-ambulatory Duchenne muscular dystrophy (DMD) to inform clinical trial designs for new therapeutics. Ambulatory, pulmonary, and upper limb function leading up to loss of ambulation (LoA) and non-ambulatory measures following LoA were quantified; time ordering of pulmonary and upper limb milestones relative to LoA were determined; and the 10-second time threshold for 10-meter walk/run (10MWR) as a marker of approaching LOA was explored. Included in this analysis were 51 subjects aged between 7 and 18 years who experienced LoA during follow-up in the PRO-DMD-01 natural history study. Mean age at LoA was 12.7 (7.1-18.6) years. Mean annual rates of decline in forced vital capacity (FVC) <80%-predicted and performance of upper limb (PUL) 1.2 total score were smaller before than after LoA, but not significantly (FVC %-predicted: 5.6% vs. 10.1%, p = 0.21; PUL 1.2 total score: 2.3 vs. 3.8 units, p = 0.20). More than half of patients experienced clinically significant deficits in FVC %-predicted and PUL 1.2 before experiencing LoA. Among subjects with baseline 10MWR >10 s, those with <1 year to LoA had similar mean ages but significantly worse mean ambulatory function at baseline compared to those with ≥1 year to LoA. Enriching DMD clinical trials for patients with declining pulmonary or upper limb function is achievable without restricting enrollment to non-ambulatory patients. The sequencing of LoA and initial deficits in pulmonary and upper limb function varied across patients and highlights the potential for composite outcomes or multi-outcome trial designs to assess disease-modifying therapies more comprehensively.

Effects of weight loss through dietary intervention on pain characteristics, functional mobility, and inflammation in adults with elevated adiposity.

Background: The relationship between adiposity and pain is complex. Excess weight increases the risk for chronic musculoskeletal pain (CMP), driven by increased biomechanical load and low-grade systemic inflammation. Pain limits physical function, impacting energy balance contributing to weight gain. The primary aims of this study were to profile pain characteristics in participants with overweight or obesity and determine if weight loss through dietary-induced energy restriction, and presence of CMP, or magnitude of weight loss, was associated with changes in adiposity, pain, functional mobility, and inflammation. Methods: This was a secondary analysis of data from adults (25-65 years) with overweight or obesity (BMI 27.5-34.9 kg/m2) enrolled in a 3-month, 30% energy-restricted dietary intervention to induce weight loss (January 2019-March 2021). Anthropometric measures (weight, waist circumference and fat mass), pain prevalence, pain severity (McGill Pain Questionnaire, MPQ), pain intensity (Visual Analog Scale, VAS), functional mobility (timed up and go, TUG) and inflammation (high sensitivity C-Reactive Protein, hsCRP) were assessed at baseline and 3-months. Results: One hundred and ten participants completed the intervention and had weight and pain assessed at both baseline and 3-months. Participants lost 7.0 ± 0.3 kg, representing 7.9% ± 3.7% of body mass. At 3-months, functional mobility improved (TUG -0.2 ± 0.1 s, 95% CI -0.3, -0.1), but there was no change in hsCRP. Compared to baseline, fewer participants reported CMP at 3-months (n = 56, 51% to n = 27, 25%, p < 0.001) and presence of multisite pain decreased from 22.7% to 10.9% (p < 0.001). Improvements in anthropometric measures and functional mobility did not differ between those presenting with or without CMP at baseline. Improvements in pain were not related to the magnitude of weight loss. Conclusion: Weight loss was effective in reducing pain prevalence and improving functional mobility, emphasizing the importance of considering weight-loss as a key component of pain management. Clinical trial registration: identifier, ACTRN12618001861246.

Characterising concurrent pain experience and dietary patterns in people with chronic musculoskeletal pain: a feasibility study protocol.

INTRODUCTION: Nutrition-related factors linked to pain chronicity and disability include weight status and dietary behaviours. Dietary patterns associated with concurrent pain episodes, however, remain poorly characterised. This paper outlines the protocol for a feasibility study that aims to characterise pain-related dietary and lifestyle behaviours in people experiencing chronic musculoskeletal pain. METHODS: The study will recruit participants who experience musculoskeletal pain on 5 or more days of the week for at least 3 months. Participants will attend two in-person clinic visits where physical measurements and a series of pain and lifestyle questionnaires will be completed. Visits will be conducted pre and post a 2-week self-monitoring period where participants will self-report concurrent diet, sleep, mood, and pain on four days and will wear a wrist-worn activity monitor (GENEActiv). Key feasibility metrics will evaluate participant recruitment, enrolment and retention rates, and compliance with the study data collection protocol. DISCUSSION: There remains a lack of evidence behind dietary advice as an adjunct pain management tool. Upon completion of the protocol, feasibility outcomes will identify challenges to guide the design and delivery of a dietary intervention for chronic musculoskeletal pain.