Duchenne muscular dystrophy: Canadian paediatric neuromuscular physicians survey

Background: Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy in childhood. Method: To assess the current care of paediatric DMD patients in Canada, a questionnaire was mailed to 17 physicians who were members of the Canadian paediatric neuromuscular group. Areas of enquiry included; 1) multidisciplinary team composition; 2) means of DMD diagnosis; 3) corticosteroid use; surveillance and management for: 4) orthopaedic, 5) respiratory and 6) cardiac complications and 7) health maintenance (nutrition & immunizations). Results: Completed surveys were returned by 14/17 (82%) of physicians. Twelve respondents followed DMD patients. All centres had multidisciplinary teams, including respirology (11/12), child neurology or physiatry (11), physiotherapy (9), occupational therapy (9) and orthopaedic surgery (7). Deflazacort 0.9mg/kg/d was used at all centres, which was continued after loss of independent ambulation (11), along with routine calcium and vitamin D supplementation (10). Night splints were prescribed at all centres. Routine surveillance studies included pulmonary function testing (11), sleep studies (10), EKG/echocardiogram (10), bone density (DEXA) scans (10), spine radiography (9), and dietician referral (4). Conclusion: Paediatric DMD patients are receiving relatively consistent care in multidisciplinary clinics across Canada, in accordance with recommended guidelines for DMD

1934: Abilene Christian College Bible Lectures - Full Text

INTRODUCTION The theme for the Lectures for 1934, “The New Testament Church in History,” is a very timely one and follows naturally the theme of the 1933 Lectures, “The Church We Read About in the New Testament.” There is no subject that is so vital in our work as Christians today as a proper understanding of the great spiritual kingdom of our Savior, the church which was built by Jesus Christ. It is a hard lesson to teach because all people are so dull of hearing concerning things spiritual. Just as Nicodemus marveled when the Christ told him of the spiritual kingdom so do people today wonder and marvel when they are told that there is only one great church, the spiritual kingdom of our Lord and Savior Jesus Christ, and that all the saved of earth belong to that church and that belonging to anything else profits little, and is unnecessary. Not only are numbers of denominational churches and people who have no religious affiliation ignorant of the true meaning of the church, but even those who claim to be members of the one body are lacking in understanding concerning the kingdom of Christ. It is therefore the purpose of the Abilene College Lectures last year, this year and next year to arouse a greater interest in the study and the teaching of this very vital matter. In this particular volume much valuable information is brought together on the trials and struggles of the church from its foundations to the present. The speakers have made careful preparation on their subjects and have given lessons that should prove helpful to all who desire to have a better understanding of the church. Our prayer is that these Lectures may be read by many and that they may do much good in the name of the Christ. Jas. F. Cox,President, Abilene Christian College. Nov. 6, 1934

Canadian paediatric neurology workforce survey and consensus statement

Background: Little knowledge exists on the availability of academic and community paediatric neurology positions. This knowledge is crucial for making workforce decisions. Our study aimed to: 1) obtain information regarding the availability of positions for paediatric neurologists in academic centres; 2) survey paediatric neurology trainees regarding their perceptions of employment issues and career plans; 3) survey practicing community paediatric neurologists 4) convene a group of paediatric neurologists to develop consensus regarding how to address these workforce issues. Methods: Surveys addressing workforce issues regarding paediatric neurology in Canada were sent to: 1) all paediatric neurology program directors in Canada (n=9) who then solicited information from division heads and from paediatric neurologists in surrounding areas; 2) paediatric neurology trainees in Canada (n=57) and; 3) community paediatric neurologists (n=27). A meeting was held with relevant stakeholders to develop a consensus on how to approach employment issues. Results: The response rate was 100% from program directors, 57.9% from residents and 44% from community paediatric neurologists. We found that the number of projected positions in academic paediatric neurology is fewer than the number of paediatric neurologists that are being trained over the next five to ten years, despite a clinical need for paediatric neurologists. Paediatric neurology residents are concerned about job availability and desire more career counselling. Conclusions: There is a current and projected clinical demand for paediatric neurologists despite a lack of academic positions. Training programs should focus on community neurology as a viable career option

The Canadian Neuromuscular Disease Registry: Connecting Patients to National and International Research Opportunities

Introduction Patient registries serve an important role in rare disease research, particularly for the recruitment and planning of clinical trials. The Canadian Neuromuscular Disease Registry was established with the primary objective of improving the future for neuromuscular (NM) patients through the enablement and support of research into potential treatments. Methods In this report, we discuss design and utilization of the Canadian Neuromuscular Disease Registry with special reference to the paediatric cohort currently enrolled in the registry. Results As of July 25, 2017, there are 658 paediatric participants enrolled in the registry, 249 are dystrophinopathies (229 are Duchenne muscular dystrophy), 57 are myotonic dystrophy participants, 98 spinal muscular atrophy participants and 65 are limb girdle muscular dystrophy. A total of 175 patients have another NM diagnosis. The registry has facilitated 20 clinical trial inquiries, 5 mail-out survey studies and 5 other studies in the paediatric population. Discussion The strengths of the registry are discussed. The registry has proven to be an invaluable tool to NM disease research and has increased Canada’s visibility as a competitive location for the conduct of clinical trials for NM therapies

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

Pan-viral serology implicates enteroviruses in acute flaccid myelitis.

Since 2012, the United States of America has experienced a biennial spike in pediatric acute flaccid myelitis (AFM)1-6. Epidemiologic evidence suggests non-polio enteroviruses (EVs) are a potential etiology, yet EV RNA is rarely detected in cerebrospinal fluid (CSF)2. CSF from children with AFM (n = 42) and other pediatric neurologic disease controls (n = 58) were investigated for intrathecal antiviral antibodies, using a phage display library expressing 481,966 overlapping peptides derived from all known vertebrate and arboviruses (VirScan). Metagenomic next-generation sequencing (mNGS) of AFM CSF RNA (n = 20 cases) was also performed, both unbiased sequencing and with targeted enrichment for EVs. Using VirScan, the viral family significantly enriched by the CSF of AFM cases relative to controls was Picornaviridae, with the most enriched Picornaviridae peptides belonging to the genus Enterovirus (n = 29/42 cases versus 4/58 controls). EV VP1 ELISA confirmed this finding (n = 22/26 cases versus 7/50 controls). mNGS did not detect additional EV RNA. Despite rare detection of EV RNA, pan-viral serology frequently identified high levels of CSF EV-specific antibodies in AFM compared with controls, providing further evidence for a causal role of non-polio EVs in AFM

1969: Abilene Christian College Bible Lectures - Full Text

GOD’S ETERNAL PURPOSE Being the Abilene Christian College Annual Bible Lectures 1969 Published by ABILENE CHRISTIAN COLLEGE BOOK STORE ACC Station Abilene, Texas 7960

Efficacy and Safety of Vamorolone Over 48 Weeks in Boys With Duchenne Muscular Dystrophy: A Randomized Controlled Trial

Background and Objectives Vamorolone is a dissociative agonist of the glucocorticoid receptor that has shown similar efficacy and reduced safety concerns in comparison with prednisone in Duchenne muscular dystrophy (DMD). This study was conducted to determine the efficacy and safety of vamorolone over 48 weeks and to study crossover participants (prednisone to vamorolone; placebo to vamorolone). Methods A randomized, double-blind, placebo-controlled and prednisone-controlled clinical trial of 2 doses of vamorolone was conducted in participants with DMD, in the ages from 4 years to younger than 7 years at baseline. The interventions were 2 mg/kg/d of vamorolone and 6 mg/kg/d of vamorolone for 48 weeks (period 1: 24 weeks + period 2: 24 weeks) and 0.75 mg/kg/d of prednisone and placebo for the first 24 weeks (before crossover). Efficacy was evaluated through gross motor outcomes and safety through adverse events, growth velocity, body mass index (BMI), and bone turnover biomarkers. This analysis focused on period 2. Results A total of 121 participants with DMD were randomized. Vamorolone at a dose of 6 mg/kg/d showed maintenance of improvement for all motor outcomes to week 48 (e.g., for primary outcome, time to stand from supine [TTSTAND] velocity, week 24 least squares mean [LSM] [SE] 0.052 [0.0130] rises/s vs week 48 LSM [SE] 0.0446 [0.0138]). After 48 weeks, vamorolone at a dose of 2 mg/kg/d showed similar improvements as 6 mg/kg/d for North Star Ambulatory Assessment (NSAA) (vamorolone 6 mg/kg/d–vamorolone 2 mg/kg/d LSM [SE] 0.49 [1.14]; 95% CI −1.80 to 2.78, p = 0.67), but less improvement for other motor outcomes. The placebo to vamorolone 6 mg/kg/d group showed rapid improvements after 20 weeks of treatment approaching benefit seen with 48-week 6 mg/kg/d of vamorolone treatment for TTSTAND, time to run/walk 10 m, and NSAA. There was significant improvement in linear growth after crossover in the prednisone to vamorolone 6 mg/kg/d group, and rapid reversal of prednisone-induced decline in bone turnover biomarkers in both crossover groups. There was an increase in BMI after 24 weeks of treatment that then stabilized for both vamorolone groups. Discussion Improvements of motor outcomes seen with 6 mg/kg/d of vamorolone at 24 weeks of treatment were maintained to 48 weeks of treatment. Vamorolone at a dose of 6 mg/kg/d showed better maintenance of effect compared with vamorolone at a dose of 2 mg/kg/d for most (3/5) motor outcomes. Bone morbidities of prednisone (stunting of growth and declines in serum bone biomarkers) were reversed when treatment transitioned to vamorolone. Trial Registration Information ClinicalTrials.gov Identifier: NCT03439670. Classification of Evidence This study provides Class I evidence that for boys with DMD, the efficacy of vamorolone at a dose of 6 mg/kg/d was maintained over 48 weeks

A National Spinal Muscular Atrophy Registry for Real-World Evidence.

BACKGROUND: Spinal muscular atrophy (SMA) is a devastating rare disease that affects individuals regardless of ethnicity, gender, and age. The first-approved disease-modifying therapy for SMA, nusinursen, was approved by Health Canada, as well as by American and European regulatory agencies following positive clinical trial outcomes. The trials were conducted in a narrow pediatric population defined by age, severity, and genotype. Broad approval of therapy necessitates close follow-up of potential rare adverse events and effectiveness in the larger real-world population. METHODS: The Canadian Neuromuscular Disease Registry (CNDR) undertook an iterative multi-stakeholder process to expand the existing SMA dataset to capture items relevant to patient outcomes in a post-marketing environment. The CNDR SMA expanded registry is a longitudinal, prospective, observational study of patients with SMA in Canada designed to evaluate the safety and effectiveness of novel therapies and provide practical information unattainable in trials. RESULTS: The consensus expanded dataset includes items that address therapy effectiveness and safety and is collected in a multicenter, prospective, observational study, including SMA patients regardless of therapeutic status. The expanded dataset is aligned with global datasets to facilitate collaboration. Additionally, consensus dataset development aimed to standardize appropriate outcome measures across the network and broader Canadian community. Prospective outcome studies, data use, and analyses are independent of the funding partner. CONCLUSION: Prospective outcome data collected will provide results on safety and effectiveness in a post-therapy approval era. These data are essential to inform improvements in care and access to therapy for all SMA patients

Abnormal fatty acid metabolism is a core component of spinal muscular atrophy

Objective: Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder leading to paralysis and subsequent death in young children. Initially considered a motor neuron disease, extra-neuronal involvement is increasingly recognized. The primary goal of this study was to investigate alterations in lipid metabolism in SMA patients and mouse models of the disease. Methods: We analyzed clinical data collected from a large cohort of pediatric SMA type I-III patients as well as SMA type I liver necropsy data. In parallel, we performed histology, lipid analysis, and transcript profiling in mouse models of SMA. Results: We identify an increased susceptibility to developing dyslipidemia in a cohort of 72 SMA patients and liver steatosis in pathological samples. Similarly, fatty acid metabolic abnormalities were present in all SMA mouse models studied. Specifically, Smn2B/- mice displayed elevated hepatic triglycerides and dyslipidemia, resembling non-alcoholic fatty liver disease (NAFLD). Interestingly, this phenotype appeared prior to denervation. Interpretation: This work highlights metabolic abnormalities as an important feature of SMA, suggesting implementation of nutritional and screening guidelines in patients, as such defects are likely to increase metabolic distress and cardiovascular risk. This study emphasizes the need for a systemic therapeutic approach to ensure maximal benefits for all SMA patients throughout their life