Safety and efficacy of losmapimod in facioscapulohumeral muscular dystrophy (ReDUX4): a randomised, double-blind, placebo-controlled phase 2b trial.

BACKGROUND: Facioscapulohumeral muscular dystrophy is a hereditary progressive myopathy caused by aberrant expression of the transcription factor DUX4 in skeletal muscle. No approved disease-modifying treatments are available for this disorder. We aimed to assess the safety and efficacy of losmapimod (a small molecule that inhibits p38α MAPK, a regulator of DUX4 expression, and p38ß MAPK) for the treatment of facioscapulohumeral muscular dystrophy. METHODS: We did a randomised, double-blind, placebo-controlled phase 2b trial at 17 neurology centres in Canada, France, Spain, and the USA. We included adults aged 18-65 years with type 1 facioscapulohumeral muscular dystrophy (ie, with loss of repression of DUX4 expression, as ascertained by genotyping), a Ricci clinical severity score of 2-4, and at least one skeletal muscle judged using MRI to be suitable for biopsy. Participants were randomly allocated (1:1) to either oral losmapimod (15 mg twice a day) or matching placebo for 48 weeks, via an interactive response technology system. The investigator, study staff, participants, sponsor, primary outcome assessors, and study monitor were masked to the treatment allocation until study closure. The primary endpoint was change from baseline to either week 16 or 36 in DUX4-driven gene expression in skeletal muscle biopsy samples, as measured by quantitative RT-PCR. The primary efficacy analysis was done in all participants who were randomly assigned and who had available data for assessment, according to the modified intention-to-treat principle. Safety and tolerability were assessed as secondary endpoints. This study is registered at ClinicalTrials.gov, number NCT04003974. The phase 2b trial is complete; an open-label extension is ongoing. FINDINGS: Between Aug 27, 2019, and Feb 27, 2020, 80 people were enrolled. 40 were randomly allocated to losmapimod and 40 to placebo. 54 (68%) participants were male and 26 (33%) were female, 70 (88%) were White, and mean age was 45·7 (SD 12·5) years. Least squares mean changes from baseline in DUX4-driven gene expression did not differ significantly between the losmapimod (0·83 [SE 0·61]) and placebo (0·40 [0·65]) groups (difference 0·43 [SE 0·56; 95% CI -1·04 to 1·89]; p=0·56). Losmapimod was well tolerated. 29 treatment-emergent adverse events (nine drug-related) were reported in the losmapimod group compared with 23 (two drug-related) in the placebo group. Two participants in the losmapimod group had serious adverse events that were deemed unrelated to losmapimod by the investigators (alcohol poisoning and suicide attempt; postoperative wound infection) compared with none in the placebo group. No treatment discontinuations due to adverse events occurred and no participants died during the study. INTERPRETATION: Although losmapimod did not significantly change DUX4-driven gene expression, it was associated with potential improvements in prespecified structural outcomes (muscle fat infiltration), functional outcomes (reachable workspace, a measure of shoulder girdle function), and patient-reported global impression of change compared with placebo. These findings have informed the design and choice of efficacy endpoints for a phase 3 study of losmapimod in adults with facioscapulohumeral muscular dystrophy. FUNDING: Fulcrum Therapeutics.

Fostering Flexibility: How Medicare Advantage Potentially Accelerated Telehealth Benefits.

In 2018, the US Congress enacted a policy permitting Medicare Advantage (MA) plans to cover telehealth services in a beneficiary's home and through audio-only means as part of the basic benefit package of services, where prior to the policy change such benefits were only allowed to be covered as a supplemental benefit. MA plans were afforded 2 years of lead time for strategizing, negotiating, and capital investment prior to the start date (January 1, 2020) of the new coverage option. Our data analysis found basic benefit telehealth was offered by plans comprising 71% of enrollment in 2020 and increased to 95% in 2021. At the same time, remote access telehealth was offered as a supplemental benefit for 69% of enrollees in 2020, a decrease of 23% compared to 2019. These efforts by MA plans may have enabled traditional Medicare (TM) to leverage an existing telehealth infrastructure as a solution to the access issues created by public health policies requiring sheltering in place and social distancing during the COVID-19 pandemic. The success of this MA policy prompts consideration of additional flexibility beyond the standard basic benefit package, and whether such benefits reduce costs while improving access and/or outcomes in the context of a managed care environment like MA. Subject to oversight, such flexibility could potentially improve value in MA, and facilitate future changes in TM, as appropriate.

The impact of a lifestyle intervention on postpartum weight retention among US Hispanic women with overweight and obesity.

Introduction: To evaluate the effect of a culturally-modified, motivationally-targeted, individually-tailored lifestyle intervention on postpartum weight retention among Hispanic women with overweight/obesity. Materials and methods: Proyecto Mamá was a randomized controlled trial conducted in western Massachusetts (2014-2020). Hispanic women with overweight/obese pre-pregnancy BMI (n = 148) were randomized in early pregnancy to a Lifestyle Intervention (LI) or a Health & Wellness (HW) comparison arm. The LI was based upon theoretical concepts, used a low-cost, high-reach strategy, and focused on healthy exercise and diet with follow-up through 12-months postpartum. The primary outcome of change in weight was calculated as the difference between pre-pregnancy weight and 6-week, 6-month, and 12-month postpartum weight. The secondary outcome was achievement of 5 % weight reduction from pre-pregnancy weight. Retention was 68.2 % in the overall postpartum period and 31.0 % at 12-months. Results: In intent-to-treat analyses, compared to the HW arm, there was no difference in postpartum weight retention at 6-weeks (0.0 kg, 95 % CI: -3.4, 3.5), 6-months (-1.8 kg, 95 % CI: -5.6, 2.0), or 12-months (-2.0 kg, 95 % CI: -7.0, 3.1). In a secondary complete case analysis, compared to the HW arm, the LI arm had 5.5 times higher odds of meeting the postpartum weight reduction goal (aOR = 5.5, 95 % CI: 1.7, 17.9) adjusting for pre-pregnancy weight. Conclusions: A lifestyle intervention among at-risk Hispanic women with overweight/obesity had no overall impact on postpartum weight, but a beneficial impact among those who completed the trial. Future studies should focus on increasing the feasibility and acceptability of the intervention in this at-risk population.

The Clinical Development of Taldefgrobep Alfa: An Anti-Myostatin Adnectin for the Treatment of Duchenne Muscular Dystrophy.

INTRODUCTION: Duchenne muscular dystrophy (DMD) is a genetic muscle disorder that manifests during early childhood and is ultimately fatal. Recently approved treatments targeting the genetic cause of DMD are limited to specific subpopulations of patients, highlighting the need for therapies with wider applications. Pharmacologic inhibition of myostatin, an endogenous inhibitor of muscle growth produced almost exclusively in skeletal muscle, has been shown to increase muscle mass in several species, including humans. Taldefgrobep alfa is an anti-myostatin recombinant protein engineered to bind to and block myostatin signaling. Preclinical studies of taldefgrobep alfa demonstrated significant decreases in myostatin and increased lower limb volume in three animal species, including dystrophic mice. METHODS: This manuscript reports the cumulative data from three separate clinical trials of taldefgrobep alfa in DMD: a phase 1 study in healthy adult volunteers (NCT02145234), and two randomized, double-blind, placebo-controlled studies in ambulatory boys with DMD-a phase 1b/2 trial assessing safety (NCT02515669) and a phase 2/3 trial including the North Star Ambulatory Assessment (NSAA) as the primary endpoint (NCT03039686). RESULTS: In healthy adult volunteers, taldefgrobep alfa was generally well tolerated and resulted in a significant increase in thigh muscle volume. Treatment with taldefgrobep alfa was associated with robust dose-dependent suppression of free myostatin. In the phase 1b/2 trial, myostatin suppression was associated with a positive effect on lean body mass, though effects on muscle mass were modest. The phase 2/3 trial found that the effects of treatment did not meet the primary endpoint pre-specified futility analysis threshold (change from baseline of ≥ 1.5 points on the NSAA total score). CONCLUSIONS: The futility analysis demonstrated that taldefgrobep alfa did not result in functional change for boys with DMD. The program was subsequently terminated in 2019. Overall, there were no safety concerns, and no patients were withdrawn from treatment as a result of treatment-related adverse events or serious adverse events. TRIAL REGISTRATION: NCT02145234, NCT02515669, NCT03039686.

The goal of this program was to develop a treatment to improve muscle function in patients with Duchenne muscular dystrophy (DMD). Muscle weakness in patients with DMD is progressive, leading to the irreversible loss of walking ability and eventually death due to cardiorespiratory failure. One potential way of improving muscle function is to target a protein known as myostatin that acts in healthy muscle to regulate muscle size. Studies in animals have shown that blocking myostatin can increase muscle size. Taldefgrobep alfa is a drug designed to block myostatin and it was shown to induce muscle growth in animals. A study in healthy volunteers found that taldefgrobep alfa was able to increase muscle size in humans and was not associated with safety concerns. Following this, a study was conducted in boys with DMD who were either treated with taldefgrobep alfa or a placebo. This first study in patients found that treatment was able to reduce myostatin levels and had a small effect on muscle size, supporting a larger trial in more patients with DMD. The aim of the larger trial was to test if taldefgrobep alfa had a meaningful effect on muscle function in patients with DMD. Results from this key trial did not meet the targeted improvement in function and a decision was made to end the trial and halt the use of taldefgrobep alfa as a potential treatment for DMD. No patients stopped treatment with taldefgrobep alfa as a result of adverse safety effects and no safety concerns were identified.

Racial and ethnic diversity in global neuroscience clinical trials.

Background: Despite efforts to increase diversity in neuroscience trials, racial and ethnic minority groups remain underrepresented. Disparities in clinical trial participation could reflect unequal opportunities to participate and may contribute to decreased generalizability of findings and failure to identify important differences in efficacy and safety outcomes. Methods: We retrospectively reviewed the F. Hoffmann-La Roche database for global, multicenter, neuroscience clinical trials from February 2016 to February 2021 and summarized and stratified race and ethnicity distributions by clinical trial therapeutic area and by country. These data were then compared to national population data for each study's targeted age group (available for studies conducted in the US, Canada, and the UK). The underrepresentation or overrepresentation of each racial and ethnic group was summarized. Results: The analysis population included 8015 participants from 47 countries. Globally, 85.6 % of participants were White, 7.1 % were Asian, 1.6 % were Black, 1.3 % were American Indian or Alaska Native, less than 0.1 % were Native Hawaiian or other Pacific Islander, 0.7 % were of multiple races, and 3.6 % were of other/unknown race. White individuals predominated in all but one trial. Black individuals were underrepresented in all trials but one. Asian individuals were overrepresented in approximately 20 % of trials. In the US, 7.3 % of participants were of Hispanic or Latino ethnicity vs 16.4 % of the US population. Conclusion: The findings and learnings from this summary and analysis demonstrate the need for continued awareness and new approaches in designing studies that reflect population diversity.

The Impact of a Lifestyle Intervention on Postpartum Cardiometabolic Risk Factors Among Hispanic Women With Abnormal Glucose Tolerance During Pregnancy: Secondary Analysis of a Randomized Trial.

BACKGROUND: Women with abnormal glucose tolerance during pregnancy are at risk for cardiovascular disease (CVD), with higher rates among Hispanics. However, studies on the impact of lifestyle interventions on postpartum CVD profiles are sparse. METHODS: This is a secondary analysis of a controlled trial among a subsample of Hispanic women with abnormal glucose tolerance participating in Estudió PARTO (Project Aiming to Reduce Type twO diabetes; mean age = 28.2 y, SD: 5.8) who were randomized to a culturally modified Lifestyle intervention (n = 45) or a comparison Health and Wellness intervention (n = 55). Primary endpoints were biomarkers of cardiovascular risk (lipids, C-reactive protein, fetuin-A, and albumin-to-creatinine ratio) and insulin resistance (fasting insulin, glucose, HbA1c, homeostasis model assessment, leptin, tumor necrosis factor-alpha, and adiponectin) measured at baseline (6-wk postpartum) and 6 and 12 months. RESULTS: In intent-to-treat analyses, there were no significant differences in changes in biomarkers of CVD risk or insulin resistance over the postpartum year. In prespecified sensitivity analyses, women adherent with the Lifestyle Intervention had more favorable improvements in insulin (intervention effect = -4.87, SE: 1.93, P = .01) and HOMA-IR (intervention effect = -1.15, SE: 0.53, P = .03) compared with the Health and Wellness arm. In pooled analyses, regardless of intervention arm, women with higher postpartum sports/exercise had greater increase in HDL-cholesterol (intervention effect = 6.99, SE: 1.72, P = .0001). CONCLUSIONS: In this randomized controlled trial among Hispanic women with abnormal glucose tolerance, we did not observe a significant effect on postpartum biomarkers of CVD risk or insulin resistance. Women adherent to the intervention had more favorable changes in insulin and HOMA-IR.

Lean tissue mass measurements by dual-energy X-ray absorptiometry and associations with strength and functional outcome measures in facioscapulohumeral muscular dystrophy.

Facioscapulohumeral muscular dystrophy (FSHD) is a slowly progressive disease of skeletal muscle. Dual energy X-ray absorptiometry (DEXA) is a widely available, cost-effective and sensitive technique for measuring whole body and regional lean tissue mass and has been used in prior clinical trials in neuromuscular diseases. The Clinical Trial Readiness to Solve Barriers to Drug Development in FSHD (ReSolve) study is a prospective, longitudinal, observational multisite study. We obtained concurrent DEXA scans and functional outcome measurements in 185 patients with FSHD at the baseline visit. We determined the associations between lean tissue mass in the upper and lower extremities and corresponding clinical outcome measures. There were moderate correlations between upper and lower extremity lean tissue mass and their corresponding strengths and function. Lean tissue mass obtained by DEXA scan may be useful as a biomarker in future clinical trials in FSHD.

"Things Will Get Worse Before They Get Better": LGBTQ + People's Reactions to the 2020 US Presidential Election.

Introduction: Previous research has found that political discourse over proposed legislation that impacts lesbian, gay, bisexual, transgender, and queer or questioning (LGBTQ +) people serves as a distal stressor which is associated with poorer mental and physical health. This study sought to document responses to the 2020 US Presidential election among LGBTQ + people living in the USA. Methods: Nineteen LGBTQ + people ages 20 to 76 (M = 47.20; SD = 17.66) living across the USA were interviewed via Zoom video conferencing software between October and early December 2020. The modal participant was female (36.8%), identified as gay or lesbian (47.3%), and White (84.2%). Interviews were coded using Interpretative Phenomenological Analysis (Smith & Osborn, 2003). Results: Seventeen codes emerged, which were grouped into three themes. Participants viewed specific political figures, namely then-President Trump and Supreme Court nominee Coney-Barrett, as symbolic of the potential loss of rights and disenfranchisement of LGBTQ + people. Participants exhibited uncertainty about the future; however, a Biden presidential win was viewed as potentially instilling complacency and leading to fracturing of the LGBTQ + community. While some participants avoided news, most were engaged with the political process as a means of coping with election uncertainty. Conclusions: The findings have implications for better understanding the concerns of LGBTQ + folks as it relates to how they view political discourse and the future of the equality movement. Policy Implications: Policies which beneficially impact and engage a diverse range of LGBTQ + people would facilitate mobilization of LGBTQ + political communities.

Risdiplam in Patients Previously Treated with Other Therapies for Spinal Muscular Atrophy: An Interim Analysis from the JEWELFISH Study.

INTRODUCTION: Risdiplam is a survival of motor neuron 2 (SMN2) splicing modifier for the treatment of patients with spinal muscular atrophy (SMA). The JEWELFISH study (NCT03032172) was designed to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of risdiplam in previously treated pediatric and adult patients with types 1-3 SMA. Here, an analysis was performed after all patients had received at least 1 year of treatment with risdiplam. METHODS: Patients with a confirmed diagnosis of 5q-autosomal recessive SMA between the ages of 6 months and 60 years were eligible for enrollment. Patients were previously enrolled in the MOONFISH study (NCT02240355) with splicing modifier RG7800 or treated with olesoxime, nusinersen, or onasemnogene abeparvovec. The primary objectives of the JEWELFISH study were to evaluate the safety and tolerability of risdiplam and investigate the PK after 2 years of treatment. RESULTS: A total of 174 patients enrolled: MOONFISH study (n = 13), olesoxime (n = 71 patients), nusinersen (n = 76), onasemnogene abeparvovec (n = 14). Most patients (78%) had three SMN2 copies. The median age and weight of patients at enrollment was 14.0 years (1-60 years) and 39.1 kg (9.2-108.9 kg), respectively. About 63% of patients aged 2-60 years had a baseline total score of less than 10 on the Hammersmith Functional Motor Scale-Expanded and 83% had scoliosis. The most common adverse event (AE) was upper respiratory tract infection and pyrexia (30 patients each; 17%). Pneumonia (four patients; 2%) was the most frequently reported serious AE (SAE). The rates of AEs and SAEs per 100 patient-years were lower in the second 6-month period compared with the first. An increase in SMN protein was observed in blood after risdiplam treatment and was comparable across all ages and body weight quartiles. CONCLUSIONS: The safety and PD of risdiplam in patients who were previously treated were consistent with those of treatment-naïve patients.

Microdystrophin Expression as a Surrogate Endpoint for Duchenne Muscular Dystrophy Clinical Trials.

Duchenne muscular dystrophy (DMD) is a serious, rare genetic disease, affecting primarily boys. It is caused by mutations in the DMD gene and is characterized by progressive muscle degeneration that results in loss of function and early death due to respiratory and/or cardiac failure. Although limited treatment options are available, some for only small subsets of the patient population, DMD remains a disease with large unmet medical needs. The adeno-associated virus (AAV) vector is the leading gene delivery system for addressing genetic neuromuscular diseases. Since the gene encoding the full-length dystrophin protein exceeds the packaging capacity of a single AAV vector, gene replacement therapy based on AAV-delivery of shortened, yet, functional microdystrophin genes has emerged as a promising treatment. This article seeks to explain the rationale for use of the accelerated approval pathway to advance AAV microdystrophin gene therapy for DMD. Specifically, we provide support for the use of microdystrophin expression as a surrogate endpoint that could be used in clinical trials to support accelerated approval.

Investing in Black LGBTQ+ liberation as white people: A call to action for community psychology.

Due to systemic racialized homophobia and transphobia, Black lesbian, gay, bisexual, transgender, and queer (LGBTQ+) people continue to experience worse life outcomes in comparison to both their Black cisgender and heterosexual, and White LGBTQ+ counterparts. Community psychologists have the tools and training to address these disparities. Using a critical whiteness studies lens, we draw on qualitative data with 17 White LGBTQ+ people to describe how white supremacy manifests in LGBTQ+ spaces. Our research indicates White LGBTQ+ people want to create intersectional spaces but lack the necessary skills to effectively confront anti-Black racism. This resulted in actions which upheld and reinforced white supremacy, despite stated commitments to Black LGBTQ+ liberation. We conclude with recommendations for community psychologists, including engaging in intersectional coalition-building, training centered around queer critical race theory, working to address racialized homophobia and transphobia alongside existing efforts to deconstruct anti-Black racism within community psychology, and consciousness-raising work with White people involved in LGBTQ+ equality movements to dismantle white supremacist structures within their organizations.

Dual-energy X-ray absorptiometry measures of lean body mass as a biomarker for progression in boys with Duchenne muscular dystrophy.

We evaluated whether whole-body dual-energy X-ray absorptiometry (DXA) measures of lean body mass can be used as biomarkers for disease progression and treatment effects in patients with Duchenne muscular dystrophy. This post hoc analysis utilized data from a randomized, 2-period study of domagrozumab versus placebo in 120 ambulatory boys with DMD. DXA measures of lean body mass were obtained from the whole body (excluding head), arms, legs and appendicular skeleton at baseline and every 16 weeks. Treatment effects on DXA measures for domagrozumab versus placebo were assessed at Week 49. At Week 49, domagrozumab statistically significantly increased lean body mass versus placebo in the appendicular skeleton (p = 0.050) and arms (p < 0.001). The relationship between lean body mass at Week 49 and functional endpoints at Week 97 was evaluated. Changes in lean body mass at Week 49 in all regions except arms were significantly correlated with percent change from baseline in 4-stair climb (4SC) at Week 97. DXA-derived percent lean mass at Week 49 also correlated with 4SC and North Star Ambulatory Assessment at Week 97. These data indicate that whole-body DXA measures can be used as biomarkers for treatment effects and disease progression in patients with DMD, and warrant further investigation.Trial registration: ClinicalTrials.gov, NCT02310763; registered 8 December 2014.

Engineering Skeletal Muscle Grafts with PAX7::GFP-Sorted Human Pluripotent Stem Cell-Derived Myogenic Progenitors on Fibrin Microfiber Bundles for Tissue Regeneration.

Tissue engineering strategies that combine human pluripotent stem cell-derived myogenic progenitors (hPDMs) with advanced biomaterials provide promising tools for engineering 3D skeletal muscle grafts to model tissue development in vitro and promote muscle regeneration in vivo. We recently demonstrated (i) the potential for obtaining large numbers of hPDMs using a combination of two small molecules without the overexpression of transgenes and (ii) the application of electrospun fibrin microfiber bundles for functional skeletal muscle restoration following volumetric muscle loss. In this study, we aimed to demonstrate that the biophysical cues provided by the fibrin microfiber bundles induce hPDMs to form engineered human skeletal muscle grafts containing multinucleated myotubes that express desmin and myosin heavy chains and that these grafts could promote regeneration following skeletal muscle injuries. We tested a genetic PAX7 reporter line (PAX7::GFP) to sort for more homogenous populations of hPDMs. RNA sequencing and gene set enrichment analyses confirmed that PAX7::GFP-sorted hPDMs exhibited high expression of myogenic genes. We tested engineered human skeletal muscle grafts derived from PAX7::GFP-sorted hPDMs within in vivo skeletal muscle defects by assessing myogenesis, engraftment and immunogenicity using immunohistochemical staining. The PAX7::GFP-sorted groups had moderately high vascular infiltration and more implanted cell association with embryonic myosin heavy chain (eMHC) regions, suggesting they induced pro-regenerative microenvironments. These findings demonstrated the promise for the use of PAX7::GFP-sorted hPDMs on fibrin microfiber bundles and provided some insights for improving the cell-biomaterial system to stimulate more robust in vivo skeletal muscle regeneration.

Long-Term Outcome of Necrotizing Enterocolitis and Spontaneous Intestinal Perforation.

OBJECTIVES: Necrotizing enterocolitis (NEC) and spontaneous intestinal perforation (SIP) are complications in preterm infants associated with high morbidity, mortality, impaired growth, and neurodevelopmental (ND) outcomes. Few studies have reported growth or ND outcomes of infants born extremely preterm with NEC/SIP beyond early childhood. Here, we compared anthropometric and ND outcomes, at 10 and 15 years, for children with medical NEC, surgical NEC, SIP, and neither NEC nor SIP. METHODS: Participants from the prospective longitudinal extremely low gestational age newborns study were evaluated at ages 10 and 15 years for anthropometrics, neurocognition, attention-deficit/hyperactivity disorder, epilepsy, and gross motor function. RESULTS: At age 10 years, 889 children were followed-up (medical NEC = 138, surgical NEC = 33, SIP = 29, no NEC/SIP = 689), and 694 children were followed up-at 15 years. Children with medical NEC had similar weight, BMI, height, and head circumference compared with controls at both 10 and 15 years. At 15 years, children with surgical NEC had lower weight z-score (adjusted ß: -0.75, 95% confidence interval [CI]: -1.25 to -0.25), lower BMI z-score (adjusted ß: -0.55, 95% CI: -1.09 to -0.01), and lower height z-score (adjusted ß: -0.65, 95% CI: -1.16 to -0.14). Children with SIP had lower weight and height z-scores at age 10 years when adjusted for sample attrition, but these differences were not significant when adjusted for confounders. We observed no differences in long-term ND outcomes. CONCLUSIONS: Surgical NEC- and SIP-associated growth impairment may persist through late childhood. ND outcomes among school-aged children born extremely preterm with any NEC or SIP are no different from children without NEC/SIP.

Novel approaches to analysis of the North Star Ambulatory Assessment (NSAA) in Duchenne muscular dystrophy (DMD): Observations from a phase 2 trial.

INTRODUCTION: The North Star Ambulatory Assessment (NSAA) tool is a key instrument for measuring clinical outcomes in patients with Duchenne muscular dystrophy (DMD). To gain a better understanding of the longitudinal utility of the NSAA, we evaluated NSAA data from a phase II trial of 120 patients with DMD treated with domagrozumab or placebo. METHODS: The NSAA exploratory analyses included assessment of individual skills gained/lost, total skills gained/lost, cumulative loss of function, and the impact of transient loss of function due to a temporary disability on NSAA total score (temporary zero score). RESULTS: There was no significant difference in the total number of NSAA skills gained (mean 1.41 and 1.04, respectively; p = 0.3314) or lost (3.90 vs. 5.0; p = 0.0998) between domagrozumab- vs. placebo-treated patients at week 49. However, domagrozumab-treated patients were less likely to lose the ability to perform a NSAA item (hazard ratio 0.80, 95% confidence interval [CI]: 0.65-0.98, p = 0.029) over 48-weeks vs. placebo-treated patients. When temporary zero scores were changed to "not obtainable" (8 values from 7 patients), domagrozumab-treated patients scored higher on the NSAA total score versus placebo-treated patients (difference at week 49: 2.0, 95% CI: 0.1-3.9, p = 0.0359). CONCLUSIONS: These exploratory analyses reveal additional approaches to interpreting the NSAA data beyond just change in NSAA total score. These observations also highlight the importance of reporting items as "not obtainable" for a patient with a temporary/transient physical disability that impacts their ability to perform the NSAA test. CLINICALTRIALS.GOV IDENTIFIER: NCT02310763.

Quantitative Muscle Analysis in FSHD Using Whole-Body Fat-Referenced MRI: Composite Scores for Longitudinal and Cross-sectional Analysis.

BACKGROUND AND OBJECTIVES: Facioscapulohumeral muscular dystrophy (FSHD) is a rare, debilitating disease characterized by progressive muscle weakness. MRI is a sensitive assessment of disease severity and progression. We developed a quantitative whole-body (WB) musculoskeletal MRI (WB-MSK-MRI) protocol analyzing muscles in their entirety. This study aimed to assess WB-MSK-MRI as a potential imaging biomarker providing reliable measurements of muscle health that capture disease heterogeneity and clinically meaningful composite assessments correlating with severity and more responsive to change in clinical trials. METHODS: Participants aged 18-65 years, with genetically confirmed FSHD1, clinical severity 2 to 4 (Ricci scale, range 0-5), and ≥1 short tau inversion recovery-positive lower extremity muscle eligible for needle biopsy, enrolled at 6 sites and were imaged twice 4-12 weeks apart. Volumetric analysis of muscle fat infiltration (MFI), muscle fat fraction (MFF), and lean muscle volume (LMV) in 18 (36 total) muscles from bilateral shoulder, proximal arm, trunk, and legs was performed after automated atlas-based segmentation, followed by manual verification. A WB composite score, including muscles at highest risk for progression, and functional cross-sectional composites for correlation with relevant functional outcomes including timed up and go (TUG), FSHD-TUG, and reachable workspace (RWS), were developed. RESULTS: Seventeen participants enrolled in this study; 16 follow-up MRIs were performed at 52 days (range 36-85 days). Functional cross-sectional composites (MFF and MFI) showed moderate to strong correlations: TUG (ρ = 0.71, ρ = 0.83), FSHD-TUG (ρ = 0.73, ρ = 0.73), and RWS (left arm: ρ = -0.71, ρ = -0.53; right arm: ρ = -0.61, ρ = -0.65). WB composite variability: LMVtot, coefficient of variation (CV) 1.9% and 3.4%; MFFtot, within-subject SD (Sw) 0.5% and 1.5%; and MFItot (Sw), 0.3% and 0.4% for normal and intermediate muscles, respectively. CV and Sw were higher in intermediate (MFI ≥0.10; MFF <0.50) than in normal (MFI <0.10, MFF <0.50) muscles. DISCUSSION: We developed a WB-MSK-MRI protocol and composite measures that capture disease heterogeneity and assess muscle involvement as it correlates with FSHD-relevant clinical endpoints. Functional composites robustly correlate with functional assessments. Stability of the WB composite shows that it could be an assessment of change in therapeutic clinical trials. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that quantitative WB-MSK-MRI findings associate with FSHD1 severity measured using established functional assessments.

Piezo1: opening the way to preventing muscle atrophy.

The loss of skeletal muscle mass and size, or muscle atrophy, is a common human experience, linked to disability, for which there are no widely accepted pharmacological therapies. Piezo1 is a mechanosensitive cation channel that opens upon alteration of the plasma membrane lipid bilayer, such as through increased membrane tension. In this issue of the JCI, Hirata et al. identified Piezo1 and its downstream effectors, Krüppel-like factor 15 (KLF15) and interleukin-6 (IL-6), as an important signaling pathway in a murine model of disuse atrophy. Through genetic and pharmacological modulation of the pathway, the authors demonstrated that immobilization resulted in downregulation of Piezo1 and basal intracellular calcium concentration ([Ca2+]i), increasing expression of Klf15 and its downstream target Il6 and thereby inducing muscle atrophy. Piezo1 has been considered a therapeutic target for diverse disorders, including atherosclerosis and kidney fibrosis, and with this publication should now also be considered a viable target for disuse atrophy.

The role of paid family leave in labor supply responses to a spouse's disability or health shock.

Disability onset and major health shocks can affect the labor supply of those experiencing the event and their family members, who face a tradeoff between time spent earning income and providing care. This decision could be affected by the availability of paid family leave. We examine the role of paid leave mandates in caregiving and labor supply decisions after a spouse's disability or health shock. Using data from the Survey of Income and Program Participation, we show that paid leave mandates reduce the likelihood that potential caregivers report decreasing their paid work hours to provide caregiving after a spouse's health shock. However, if caregivers are unlikely to have access to job protection, paid leave mandates also increase the likelihood of leaving the labor market to provide caregiving and working fewer weeks. There is limited evidence of an effect of paid leave on other employment outcomes. Our findings demonstrate that paid leave has some influence on household labor supply decisions after spousal health shocks, but its role should be considered together with the availability of job protection.