The Impact of a Lifestyle Intervention on Cardiometabolic Risk Factors among Postpartum Hispanic Women with Overweight and Obesity in a Randomized Controlled Trial (Proyecto Mamá).

INTRODUCTION: Maternal overweight or obesity has been associated with metabolic syndrome through 1 year postpartum, but it remains unknown whether a culturally-modified, motivationally-targeted, and individually-tailored Lifestyle Intervention could improve postpartum cardiometabolic health among Hispanic women with overweight or obesity. METHODS: Proyecto Mamá was a randomized controlled trial conducted in Western Massachusetts from 2014 to 2020 in which Hispanic women with overweight/obesity were randomized to a Lifestyle Intervention (LI) involving diet and exercise or to a comparison Health and Wellness Intervention (HW). Biomarkers of cardiovascular risk (i.e., lipids, C-reactive protein) and insulin resistance (fasting insulin, glucose, HbA1c, homeostasis model assessment [HOMA-IR], leptin, adiponectin) were measured at baseline (early pregnancy), mid-pregnancy, and 6 weeks, 6 months, and 12 months postpartum. Generalized linear mixed effect models were used to evaluate differences in the change in biomarkers over the course of postpartum follow-up time. RESULTS: In intent-to-treat analyses among eligible women (LI; n=51, HW; n=58) there were no significant differences in changes in biomarkers of CVD risk or insulin resistance over the postpartum year; for example, the intervention effect for total cholesterol was 6.98 (SE: 6.36, p=0.27) and for HbA1c was -0.01 (SE: 0.4, p=0.85). In pooled analyses, regardless of intervention arm, women who participated in any vigorous activity had less of an increase in HbA1c (intervention effect = -0.17, SE: 0.05, p=0.002) compared to those with no vigorous activity, and similarly beneficial associations with other cardiovascular risk biomarkers (p<0.05). DISCUSSION: Women who participated in vigorous activity, regardless of their assigned intervention arm, had more favorable changes in biomarkers of insulin resistance.

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.

Long-read single-molecule maps of the functional methylome.

We report on the development of a methylation analysis workflow for optical detection of fluorescent methylation profiles along chromosomal DNA molecules. In combination with Bionano Genomics genome mapping technology, these profiles provide a hybrid genetic/epigenetic genome-wide map composed of DNA molecules spanning hundreds of kilobase pairs. The method provides kilobase pair-scale genomic methylation patterns comparable to whole-genome bisulfite sequencing (WGBS) along genes and regulatory elements. These long single-molecule reads allow for methylation variation calling and analysis of large structural aberrations such as pathogenic macrosatellite arrays not accessible to single-cell second-generation sequencing. The method is applied here to study facioscapulohumeral muscular dystrophy (FSHD), simultaneously recording the haplotype, copy number, and methylation status of the disease-associated, highly repetitive locus on Chromosome 4q.

Mss51 deletion increases endurance and ameliorates histopathology in the mdx mouse model of Duchenne muscular dystrophy.

Mitochondrial derangement is an important contributor to the pathophysiology of muscular dystrophies and may be among the earliest cellular deficits. We have previously shown that disruption of Mss51, a mammalian skeletal muscle protein that localizes to the mitochondria, results in enhanced muscle oxygen consumption rate, increased endurance capacity, and improved limb muscle strength in mice with wildtype background. Here, we investigate whether Mss51 deletion in the mdx murine model of Duchenne muscular dystrophy (mdx-Mss51 KO) counteracts the muscle pathology and mitochondrial irregularities observed in mdx mice. We found that mdx-Mss51 KO mice had increased myofiber oxygen consumption rates and an amelioration of muscle histopathology compared to mdx counterparts. This corresponded with greater treadmill endurance and less percent fatigue in muscle physiology, but no improvement in forelimb grip strength or limb muscle force production. These findings suggest that although Mss51 deletion ameliorates the skeletal muscle mitochondrial respiration defects in mdx and improves fatigue resistance in vivo, the lack of improvement in force production suggests that this target alone may be insufficient for a therapeutic effect.

Home-based gait analysis as an exploratory endpoint during a multicenter phase 1 trial in limb girdle muscular dystrophy type R2 and facioscapulohumeral muscular dystrophy.

INTRODUCTION/AIMS: Limb girdle muscular dystrophy type 2B (LGMDR2) and facioscapulohumeral muscular dystrophy (FSHD) are genetic muscular dystrophies with an increasing number of potential therapeutic approaches. The aim of this study is to report the data of exploratory digital outcomes extracted from wearable magneto-inertial sensors used in a non-controlled environment for ambulant patients with FSHD and LGMDR2 in a short-term, multicenter clinical study. METHODS: Digital outcomes (stride length, stride speed, and walk parameters in a non-controlled environment) were used as exploratory outcomes in the open-label study ATYR1940-C-004 in ambulant patients during the 3 mo of ATYR1940 treatment and 1 mo of follow-up. Activity and gait variables were calculated from the data recorded in 30-day sub-periods using the sensors. For each sub-period, activity and gait parameters were compared between FSHD and LGMDR2 patients. Change from baseline over the 4-mo study period was assessed. RESULTS: Ten patients (5 FSHD, 5 LGMDR2) were ambulant and compliant for analysis. Gait parameters, but not activity variables, were significantly lower in LGMDR2 compared to FSHD patients at baseline. Longitudinal analyses showed a slight but significant decrease in stride speed at month 4 for all subjects. Activity variables such as total number of strides per day were highly variable from month to month in individual patients, and no visit effects were found for this variable. DISCUSSION: The present study suggests that home-recorded stride speed constitutes a precise and sensitive outcome in ambulant patients with FSHD and LGMDR2.

Quantitative muscle analysis in facioscapulohumeral muscular dystrophy using whole-body fat-referenced MRI: Protocol development, multicenter feasibility, and repeatability.

INTRODUCTION/AIMS: Functional performance tests are the gold standard to assess disease progression and treatment effects in neuromuscular disorders. These tests can be confounded by motivation, pain, fatigue, and learning effects, increasing variability and decreasing sensitivity to disease progression, limiting efficacy assessment in clinical trials with small sample sizes. We aimed to develop and validate a quantitative and objective method to measure skeletal muscle volume and fat content based on whole-body fat-referenced magnetic resonance imaging (MRI) for use in multisite clinical trials. METHODS: Subjects aged 18 to 65 years, genetically confirmed facioscapulohumeral muscular dystrophy 1 (FSHD1), clinical severity 2 to 4 (Ricci's scale, range 0-5), were enrolled at six sites and imaged twice 4-12 weeks apart with T1-weighted two-point Dixon MRI covering the torso and upper and lower extremities. Thirty-six muscles were volumetrically segmented using semi-automatic multi-atlas-based segmentation. Muscle fat fraction (MFF), muscle fat infiltration (MFI), and lean muscle volume (LMV) were quantified for each muscle using fat-referenced quantification. RESULTS: Seventeen patients (mean age ± SD, 49.4 years ±13.02; 12 men) were enrolled. Within-patient SD ranged from 1.00% to 3.51% for MFF and 0.40% to 1.48% for MFI in individual muscles. For LMV, coefficients of variation ranged from 2.7% to 11.7%. For the composite score average of all muscles, observed SDs were 0.70% and 0.32% for MFF and MFI, respectively; composite LMV coefficient of variation was 2.0%. DISCUSSION: We developed and validated a method for measuring skeletal muscle volume and fat content for use in multisite clinical trials of neuromuscular disorders.

Randomized phase 2 study of ACE-083, a muscle-promoting agent, in facioscapulohumeral muscular dystrophy.

INTRODUCTION/AIMS: Facioscapulohumeral muscular dystrophy (FSHD) is a slowly progressive muscular dystrophy without approved therapies. In this study we evaluated whether locally acting ACE-083 could safely increase muscle volume and improve functional outcomes in adults with FSHD. METHODS: Participants were at least 18 years old and had FSHD1/FSHD2. Part 1 was open label, ascending dose, assessing safety and tolerability (primary objective). Part 2 was randomized, double-blind for 6 months, evaluating ACE-083240 mg/muscle vs placebo injected bilaterally every 3 weeks in the biceps brachii (BB) or tibialis anterior (TA) muscles, followed by 6 months of open label. Magnetic resonance imaging measures included total muscle volume (TMV; primary objective), fat fraction (FF), and contractile muscle volume (CMV). Functional measures included 6-minute walk test, 10-meter walk/run, and 4-stair climb (TA group), and performance of upper limb midlevel/elbow score (BB group). Strength, patient-reported outcomes (PROs), and safety were also evaluated. RESULTS: Parts 1 and 2 enrolled 37 and 58 participants, respectively. Among 55 participants evaluable in Part 2, the least-squares mean (90% confidence interval, analysis of covariance) treatment difference for TMV was 16.4% (9.8%-23.0%) in the BB group (P < .0001) and 9.5% (3.2%-15.9%) in the TA group (P = .01). CMV increased significantly in the BB and TA groups and FF decreased in the TA group. There were no consistent improvements in functional or PRO measures in either group. The most common adverse events were mild or moderate injection-site reactions. DISCUSSION: Significant increases in TMV with ACE-083 vs placebo did not result in consistent functional or PRO improvements with up to 12 months of treatment.

Analysis of the Impact of the COVID-19 Pandemic on the Multidisciplinary Management of Breast Cancer: Review from the American Society of Breast Surgeons COVID-19 and Mastery Registries.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has resulted in rapid and regionally different approaches to breast cancer care. METHODS: In order to evaluate these changes, a COVID-19-specific registry was developed within the American Society of Breast Surgeons (ASBrS) Mastery that tracked whether decisions were usual or modified for COVID-19. Data on patient care entered into the COVID-19-specific registry and the ASBrS Mastery registry from 1 March 2020 to 15 March 2021 were reviewed. RESULTS: Overall, 177 surgeons entered demographic and treatment data on 2791 patients. Mean patient age was 62.7 years and 9.0% (252) were of African American race. Initial consultation occurred via telehealth in 6.2% (173) of patients and 1.4% (40) developed COVID-19. Mean invasive tumor size was 2.1 cm and 17.8% (411) were node-positive. In estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER+/HER2-) disease, neoadjuvant endocrine therapy (NET) was used as the usual approach in 6.9% (119) of patients and due to COVID-19 in an additional 31% (542) of patients. Patients were more likely to receive NET due to COVID-19 with increasing age and if they lived in the Northeast or Southeast (odds ratio [OR] 1.1, 2.3, and 1.7, respectively; p < 0.05). Genomic testing was performed on 51.5% (781) of estrogen-positive patients, of whom 20.7% (162) had testing on the core due to COVID-19. Patients were less likely to have core biopsy genomic testing due to COVID-19 if they were older (OR 0.89; p = 0.01) and more likely if they were node-positive (OR 4.0; p < 0.05). A change in surgical approach due to COVID-19 was reported for 5.4% (151) of patients. CONCLUSION: The ASBrS COVID-19 registry provided a platform for monitoring treatment changes due to the pandemic, highlighting the increased use of NET.

Safety, tolerability, and pharmacokinetics of casimersen in patients with Duchenne muscular dystrophy amenable to exon 45 skipping: A randomized, double-blind, placebo-controlled, dose-titration trial.

INTRODUCTION/AIMS: Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene resulting in the absence of dystrophin. Casimersen is a phosphorodiamidate morpholino oligomer designed to bypass frameshift DMD mutations and produce internally truncated, yet functional, dystrophin protein in patients amenable to exon 45 skipping. Our primary study objective was to evaluate safety and tolerability of casimersen; the secondary objective was to characterize the plasma pharmacokinetics. METHODS: This multicenter, phase 1/2 trial enrolled 12 participants (aged 7-21 years, who had limited ambulation or were nonambulatory) and comprised a 12-week, double-blind dose titration, then an open-label extension for up to 132 weeks. During dose titration, participants were randomized 2:1 to weekly casimersen infusions at escalating doses of 4, 10, 20, and 30 mg/kg (≥2 weeks per dose), or placebo. RESULTS: Participants received casimersen for a mean 139.6 weeks. Treatment-emergent adverse events (TEAEs) occurred in all casimersen- and placebo-treated participants and were mostly mild (over 91.4%) and unrelated to casimersen or its dose. There were no deaths, dose reductions, abnormalities in laboratory parameters or vital signs, or casimersen-related serious AEs. Casimersen plasma concentration increased with dose and declined similarly for all dose levels over 24 hours postinfusion. All pharmacokinetic parameters were similar at weeks 7 and 60. DISCUSSION: Casimersen was well tolerated in participants with DMD amenable to exon 45 skipping. Most TEAEs were mild, nonserious, and unrelated to casimersen. Plasma exposure was dose proportional with no suggestion of plasma accumulation. These results support further studies of casimersen in this population.

A phase Ib/IIa, open-label, multiple ascending-dose trial of domagrozumab in fukutin-related protein limb-girdle muscular dystrophy.

INTRODUCTION/AIMS: In this study we report the results of a phase Ib/IIa, open-label, multiple ascending-dose trial of domagrozumab, a myostatin inhibitor, in patients with fukutin-related protein (FKRP)-associated limb-girdle muscular dystrophy. METHODS: Nineteen patients were enrolled and assigned to one of three dosing arms (5, 20, or 40 mg/kg every 4 weeks). After 32 weeks of treatment, participants receiving the lowest dose were switched to the highest dose (40 mg/kg) for an additional 32 weeks. An extension study was also conducted. The primary endpoints were safety and tolerability. Secondary endpoints included muscle strength, timed function testing, pulmonary function, lean body mass, pharmacokinetics, and pharmacodynamics. As an exploratory outcome, muscle fat fractions were derived from whole-body magnetic resonance images. RESULTS: Serum concentrations of domagrozumab increased in a dose-dependent manner and modest levels of myostatin inhibition were observed in both serum and muscle tissue. The most frequently occurring adverse events were injuries secondary to falls. There were no significant between-group differences in the strength, functional, or imaging outcomes studied. DISCUSSION: We conclude that, although domagrozumab was safe in patients in limb-girdle muscular dystrophy type 2I/R9, there was no clear evidence supporting its efficacy in improving muscle strength or function.

Improving resident learning on vasectomy: a national survey on urology resident vasectomy training.

INTRODUCTION: Resident training in vasectomy, especially in the office setting on the awake patient, may be limited. The aim of this study is to understand resident exposure to vasectomy and to identify barriers to learning. MATERIALS AND METHODS: An anonymous 18-question survey was distributed to urology residents of the 135 ACGME-accredited urology residencies in the United States. Residents were asked to specify the total number of vasectomies they had performed and in what environment (operating room versus office), their comfort performing vasectomy independently, and any barriers to learning the procedure. RESULTS: In total, 119 residents responded to the survey, representing a 10% response rate. Vasectomy case volumes were variable, with 36.7% of residents logging ≤ 20 vasectomies by their final year of training. Total of 23.4% indicated they did not receive training in perioperative counseling for patients considering vasectomy. Only 64.7% of all residents felt comfortable in the office setting versus 89.1% who felt comfortable in the operating room (p < 0.001). This difference persisted throughout training, and 16.7% of residents in their final year of residency were uncomfortable performing office vasectomy. Total of 60.5% of respondents cited one or more barriers to training, with lack of surgical volume (38.7%), lack of vasectomies in the resident clinic (29.4%), and lack of autonomy when performing the procedure (22.7%) being the most common. CONCLUSIONS: Residents are significantly less comfortable performing vasectomy in the office setting versus in the operating room, including in their graduating year. Residents describe low volume and lack of autonomy as barriers to vasectomy training.

Diabetes, metformin and cancer risk in myotonic dystrophy type I.

Myotonic dystrophy type I (DM1) is an autosomal dominant multisystem disorder characterized by myotonia and muscle weakness. Type 2 diabetes (T2D) and cancer have been shown to be part of the DM1 phenotype. Metformin, a well-established agent for the management of T2D, is thought to have cancer-preventive effects in the general population. In our study, we aimed to assess the association between T2D, metformin use and the risk of cancer in DM1 patients. We identified a cohort of 913 DM1 patients and an age-, sex- and clinic-matched cohort of 12,318 DM1-free controls from the UK Clinical Practice Research Datalink, a large primary care records database. We used Cox regression models to assess cancer risk in T2D patients who were metformin users or nonusers compared to patients without T2D. Separate analyses were conducted for DM1 patients and controls. T2D was more prevalent in DM1 than in controls (8% vs. 3%, p < 0.0001). DM1 patients with T2D, compared to those without T2D, were more likely to develop cancer (hazard ratio [HR] = 3.60, 95% confidence interval [CI] = 1.18-10.97; p = 0.02), but not if they were treated with metformin (HR = 0.43, 95% CI = 0.06-3.35; p = 0.42). Among controls, we observed no significant associations between T2D and cancer risk in either users or nonusers of Metformin (HR = 1.28, 95% CI = 0.91-1.79; p = 0.16 and HR = 1.13, 95% CI = 0.72-1.79; p = 0.59, respectively). These results show an association between T2D and cancer risk in DM1 patients and may provide new insights into the possible benefits of Metformin use in DM1.

The elusive promise of myostatin inhibition for muscular dystrophy.

PURPOSE OF REVIEW: Recent terminations of clinical trials of myostatin inhibitors in muscular dystrophy have raised questions about the predictiveness of mouse models for this therapeutic strategy. RECENT FINDINGS: A variety of myostatin inhibitors have been developed for preclinical and clinical studies. These inhibitors have ameliorated the phenotype of many but not all mouse models of muscular dystrophy. However, randomized double-blinded placebo controlled trials in both pediatric and adult muscular dystrophies have, as of yet, not demonstrated functional improvement. SUMMARY: The present article will review the preclinical promise of myostatin inhibitors, the clinical trial experience to date of these inhibitors in muscular dystrophy, and the potential reasons for the lack of observed translation.

The care of patients with Duchenne, Becker, and other muscular dystrophies in the COVID-19 pandemic.

The coronavirus disease 2019 (COVID-19) pandemic has resulted in the reorganization of health-care settings affecting clinical care delivery to patients with Duchenne and Becker muscular dystrophy (DBMD) as well as other inherited muscular dystrophies. The magnitude of the impact of this public health emergency on the care of patients with DBMD is unclear as they are suspected of having an increased risk for severe manifestations of COVID-19. In this article, the authors discuss their consensus recommendations pertaining to care of these patients during the pandemic. We address issues surrounding corticosteroid and exon-skipping treatments, cardiac medications, hydroxychloroquine use, emergency/respiratory care, rehabilitation management, and the conduct of clinical trials. We highlight the importance of collaborative treatment decisions between the patient, family, and health-care provider, considering any geographic or institution-specific policies and precautions for COVID-19. We advocate for continuing multidisciplinary care for these patients using telehealth.

Longitudinal functional and imaging outcome measures in FKRP limb-girdle muscular dystrophy.

BACKGROUND: Pathogenic variants in the FKRP gene cause impaired glycosylation of α-dystroglycan in muscle, producing a limb-girdle muscular dystrophy with cardiomyopathy. Despite advances in understanding the pathophysiology of FKRP-associated myopathies, clinical research in the limb-girdle muscular dystrophies has been limited by the lack of normative biomarker data to gauge disease progression. METHODS: Participants in a phase 2 clinical trial were evaluated over a 4-month, untreated lead-in period to evaluate repeatability and to obtain normative data for timed function tests, strength tests, pulmonary function, and body composition using DEXA and whole-body MRI. Novel deep learning algorithms were used to analyze MRI scans and quantify muscle, fat, and intramuscular fat infiltration in the thighs. T-tests and signed rank tests were used to assess changes in these outcome measures. RESULTS: Nineteen participants were observed during the lead-in period for this trial. No significant changes were noted in the strength, pulmonary function, or body composition outcome measures over the 4-month observation period. One timed function measure, the 4-stair climb, showed a statistically significant difference over the observation period. Quantitative estimates of muscle, fat, and intramuscular fat infiltration from whole-body MRI corresponded significantly with DEXA estimates of body composition, strength, and timed function measures. CONCLUSIONS: We describe normative data and repeatability performance for multiple physical function measures in an adult FKRP muscular dystrophy population. Our analysis indicates that deep learning algorithms can be used to quantify healthy and dystrophic muscle seen on whole-body imaging. TRIAL REGISTRATION: This study was retrospectively registered in clinicaltrials.gov (NCT02841267) on July 22, 2016 and data supporting this study has been submitted to this registry.

AAV9 Edits Muscle Stem Cells in Normal and Dystrophic Adult Mice.

CRISPR editing of muscle stem cells (MuSCs) with adeno-associated virus serotype-9 (AAV9) holds promise for sustained gene repair therapy for muscular dystrophies. However, conflicting evidence exists on whether AAV9 transduces MuSCs. To rigorously address this question, we used a muscle graft model. The grafted muscle underwent complete necrosis before regenerating from its MuSCs. We injected AAV9.Cre into Ai14 mice. These mice express tdTomato upon Cre-mediated removal of a floxed stop codon. About 28%-47% and 24%-89% of Pax7+ MuSCs expressed tdTomato in pre-grafts and regenerated grafts (p > 0.05), respectively, suggesting AAV9 efficiently transduced MuSCs, and AAV9-edited MuSCs renewed successfully. Robust MuSC transduction was further confirmed by delivering AAV9.Cre to Pax7-ZsGreen-Ai14 mice in which Pax7+ MuSCs are genetically labeled by ZsGreen. Next, we co-injected AAV9.Cas9 and AAV9.gRNA to dystrophic mdx mice to repair the mutated dystrophin gene. CRISPR-treated and untreated muscles were grafted to immune-deficient, dystrophin-null NSG.mdx4cv mice. Grafts regenerated from CRISPR-treated muscle contained the edited genome and yielded 2.7-fold more dystrophin+ cells (p = 0.015). Importantly, increased dystrophin expression was not due to enhanced formation of revertant fibers or de novo transduction by residual CRISPR vectors in the graft. We conclude that AAV9 effectively transduces MuSCs. AAV9 CRISPR editing of MuSCs may provide enduring therapy.

Biological scaffold-mediated delivery of myostatin inhibitor promotes a regenerative immune response in an animal model of Duchenne muscular dystrophy.

Recent studies have reported that the immune system significantly mediates skeletal muscle repair and regeneration. Additionally, biological scaffolds have been shown to play a role in polarizing the immune microenvironment toward pro-myogenic outcomes. Moreover, myostatin inhibitors are known to promote muscle regeneration and ameliorate fibrosis in animal models of Duchenne muscular dystrophy (DMD), a human disease characterized by chronic muscle degeneration. Biological scaffolds and myostatin inhibition can potentially influence immune-mediated regeneration in the dystrophic environment, but have not been evaluated together. Toward this end, here we created an injectable biological scaffold composed of hyaluronic acid and processed skeletal muscle extracellular matrix. This material formed a cytocompatible hydrogel at physiological temperatures in vitro When injected subfascially above the tibialis anterior muscles of both WT and dystrophic mdx-5Cv mice, a murine model of DMD, the hydrogel spreads across the entire muscle before completely degrading at 3 weeks in vivo We found that the hydrogel is associated with CD206+ pro-regenerative macrophage polarization and elevated anti-inflammatory cytokine expression in both WT and dystrophic mice. Co-injection of both hydrogel and myostatin inhibitor significantly increased FoxP3+ regulatory T cell modulation and Foxp3 gene expression in the scaffold immune microenvironment. Finally, delivery of myostatin inhibitor with the hydrogel increased its bioactivity in vivo, and transplantation of immortalized human myoblasts with the hydrogel promoted their survival in vivo This study identifies a key role for biological scaffolds and myostatin inhibitors in modulating a pro-regenerative immune microenvironment in dystrophic muscle.

Clinical trial readiness to solve barriers to drug development in FSHD (ReSolve): protocol of a large, international, multi-center prospective study.

BACKGROUND: Facioscapulohumeral muscular dystrophy (FSHD) is a dominantly-inherited progressive muscular dystrophy caused by de-repression of the DUX4 gene, which causes disease by a toxic-gain-of-function. As molecularly targeted drugs move from preclinical testing into human trials, it is essential that we validate clinical trial tools and methodology to facilitate the drug development process. METHODS/DESIGN: The primary goal of this study is to hasten drug development for FSHD by validating two novel clinical outcome assessments (COAs) and refining clinical trial strategies. We will perform an 18-month longitudinal study in 220 genetically confirmed and clinically affected participants using our FSHD Clinical Trial Research Network, comprised of 8 sites in the United States, and 3 collaborating sites in Europe. Visits occur at baseline and months 3, 12, and 18. At each visit we will collect: 1) a novel FSHD functional composite COA made up of 18 evaluator-administered motor tasks in the domains of shoulder/arm, hand, core/abdominal, leg, and balance function; and 2) electrical impedance myography as a novel muscle quality biomarker (US sites). Other COAs include 1) Domain 1 of the Motor Function Measure; 2) Reachable workspace; 3) orofacial strength using the Iowa Oral Performance Instrument; 4) lean muscle mass using dual-energy X-ray absorptiometry (DEXA); 5) strength as measured by quantitative myometry and manual muscle testing; and 6) the FSHD Health Index and other patient-reported outcomes. Plasma, DNA, RNA, and serum will be collected for future biomarker studies. We will use an industry standard multi-site training plan. We will evaluate the test-retest reliability, validity, and sensitivity to disease progression, and minimal clinically important changes of our new COAs. We will assess associations between demographic and genetic factors and the rate of disease progression to inform refinement of eligibility criteria for future clinical trials. DISCUSSION: To the best of our knowledge, this is the largest collaborative study of patients with FSHD performed in the US and Europe. The results of this study will enable more efficient clinical trial design. During the conduct of the study, relevant data will be made available for investigators or companies pursuing novel FSHD therapeutics. TRIAL REGISTRATION: clinicaltrials.gov NCT03458832; Date of registration: 1/11/2018.

Outcomes and resource utilization in surgery for Chiari I malformation in a national network of children's hospitals.

INTRODUCTION: Chiari malformation type 1 (CM-1) is a common congenital or acquired malformation of the posterior fossa. We aimed to characterize preoperative risk factors, perioperative complications, and postoperative outcomes related to CM-1 surgery in pediatric populations across a nationwide network of pediatric hospitals in the United States (US). METHODS: The Children's Hospital Association's Pediatric Health Information System (PHIS) database was used to examine patients < 21 years old in the US-based nationwide database who underwent inpatient surgery for CM-1 from 2007 to 2015. Data analyzed included patient characteristics, preoperative comorbidities, perioperative outcomes, short-term postoperative surgical and medical complications, and healthcare resource utilization. RESULTS: Among the 5976 patients identified, those age 0-4 years had higher medical and surgical complication rates compared to older patients. Those with pre-existing comorbidity of hydrocephalus had higher odds of 30- and 90-day medical and surgical complications. Those with any complications at 90 days had an increased length of stay and higher healthcare costs compared to those without complications. 6.88% of complications were surgical and 1.67% medical. Patients with medical complications had the longer mean stay and associated costs compared to those with surgical complications (13 vs. 6.9 at 95% CI, and $71,300-94,500 vs. $110,400-195,000 at 95% CI). CONCLUSIONS: Use of a US-based national children's hospital database presents outcomes and resource utilization from a multi-institutional, real-world experience in pediatric hospitals. There was a higher risk of perioperative complications in younger patients and those with pre-existing comorbidities, namely hydrocephalus. Understanding preoperative risk factors, perioperative complications, and postoperative outcomes, as well as healthcare utilization and costs, can help target areas for improvement and guide preoperative counseling and risk stratification.

American Psychological Association practice guidelines for psychopharmacology: Ethical practice considerations for psychologists involving psychotropic use with children and adolescents.

OBJECTIVES: This study discusses the implications of the American Psychological Association's 2011 Practice Guidelines for Pharmacology as they apply to psychologists working with juvenile clients. Special considerations apply due to concerns about the developmental side effects that occur when psychotropic medications are prescribed to children and adolescents. METHODS OR DESIGN: This study provides recommendations for implementing each of the Practice Guidelines. Constructive criticism of the Practice Guidelines is also discussed with the aim of improving service delivery. RESULTS: This study provides specific recommendations for psychologists regarding obtaining adequate knowledge about psychopharmacology to inform clients or consult with physicians. Suggestions are made for continuing education requirements for psychologists who work with juveniles. CONCLUSIONS: Recommendations are made for psychologists working with juveniles to increase their knowledge of psychotropic medications for a more ethical and informed voice regarding the prescribing of such medications.