Test-Retest Reliability of Motor Function and Myometry Outcomes From the Vamorolone Trials in Duchenne Muscular Dystrophy.

Background And Objectives: Understanding the reliability of outcomes used in clinical care and trials is important to delineate intervention-induced change from random variability. Reliability, sensitivity, and clinical meaningfulness of change are all key aspects of choosing the most appropriate outcome measure for a clinical trial. Common outcome measures to monitor progression and treatment effect in Duchenne muscular dystrophy (DMD) include measures of strength (myometry) and motor function tests: stand from supine velocity (STANDV), North Star Ambulatory Assessment (NSAA), 6-minute walk distance (6MWD), 10-m run/walk (RWV), and 4-stair climb velocity (CLIMBV).

Height, weight, and body mass index trajectories and their correlation with functional outcome assessments in boys with Duchenne muscular dystrophy.

Aim: To examine the factors influencing height, weight, and body mass index (BMI) z-scores, and the relationship between them and motor performance, in boys with Duchenne muscular dystrophy (DMD).

Method: This was a randomized, double-blind, parallel group trial involving 32 study sites across five countries. Height, weight, BMI z-scores, and clinical outcome assessments (COAs)-rise from supine velocity, 10-m walk/run velocity, NorthStar Ambulatory Assessment, and 6-minute walk test-were analysed in 4-year-old to 7-year-old boys with DMD randomized to 0.

Creating an Inclusive Definition for High Users of Inpatient Hospital Systems That Considers Different Levels of Rurality.

Multiple definitions have been used to identify individuals who are high system users (HSUs), through economic costs, frequency of use, or length of stay for inpatient care users. However, no definition has been validated to be representative of those residing in rural communities, who face unique service accessibility. This paper identifies an HSU definition for rural Canada that is inclusive of various levels of rurality, longitudinal patient experiences, and types of hospitalizations experienced.

Multivariate Poisson lognormal distribution for modeling counts from modern biological data: An overview.

Modern biological data are often multivariate discrete counts, and there has been a dearth of statistical distributions to directly model such counts in an efficient manner. While mixed Poisson distributions, e.g.

Association of Gene Variant Classes With Motor Outcomes in a Drug Registration Clinical Trial Setting.

Background And Objectives: Duchenne muscular dystrophy (DMD) is caused by pathogenic variants of the gene, leading to the loss of dystrophin. Clinical variability in DMD can complicate interpretation of interventional data in clinical trials. One source of clinical variability is allelic heterogeneity (different pathogenic variants with different effects on dystrophin protein expression).

Findings from the Longitudinal CINRG Becker Natural History Study.

Background: Becker muscular dystrophy is an X-linked, genetic disorder causing progressive degeneration of skeletal and cardiac muscle, with a widely variable phenotype.

Objective: A 3-year, longitudinal, prospective dataset contributed by patients with confirmed Becker muscular dystrophy was analyzed to characterize the natural history of this disorder. A better understanding of the natural history is crucial to rigorous therapeutic trials.

Optimization of DOTAP/chol Cationic Lipid Nanoparticles for mRNA, pDNA, and Oligonucleotide Delivery.

Lipid nanoparticles (LNPs) can be used as delivery vehicles for nucleic acid biotherapeutics. In fact, LNPs are currently being used in the Pfizer/BioNTech and Moderna COVID-19 vaccines. Cationic LNPs composed of 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP)/cholesterol (chol) LNPs have been classified as one of the most efficient gene delivery systems and are being tested in numerous clinical trials.

Acute serum protein and cytokine response of single dose of prednisone in adult volunteers.

Pharmacological glucocorticoids are the most prescribed anti-inflammatory medications, and are chemical variants of cortisol, the circadian and stress hormone. Both endogenous and pharmacological glucocorticoids bind the glucocorticoid receptor (NR3C1) with high affinity, and both then bind downstream gene promoter elements (GRE) to drive positive gene transcription of many proteins. Glucocorticoid/GR complexes also bind distinct negative gene promoter elements (nGRE) to inhibit expression of genes involved in NF-κB innate immunity signaling.

Interrogation of Dystrophin and Dystroglycan Complex Protein Turnover After Exon Skipping Therapy.

Recently, the Food and Drug Administration granted accelerated approvals for four exon skipping therapies -Eteplirsen, Golodirsen, Viltolarsen, and Casimersen -for Duchenne Muscular Dystrophy (DMD). However, these treatments have only demonstrated variable and largely sub-therapeutic levels of restored dystrophin protein in DMD patients, limiting their clinical impact. To better understand variable protein expression and the behavior of truncated dystrophin protein in vivo, we assessed turnover dynamics of restored dystrophin and dystrophin glycoprotein complex (DGC) proteins in mdx mice after exon skipping therapy, compared to those dynamics in wild type mice, using a targeted, highly-reproducible and sensitive, in vivo stable isotope labeling mass spectrometry approach in multiple muscle tissues.

Comparison of Serum Pharmacodynamic Biomarkers in Prednisone-Versus Deflazacort-Treated Duchenne Muscular Dystrophy Boys.

Prednisone (Pred) and Deflazacort (Dfz) are commonly used glucocorticoids (GCs) for Duchenne muscular dystrophy (DMD) treatment and management. While GCs are known to delay the loss of ambulation and motor abilities, chronic use can result in onerous side effects, e.g.

Serum protein biomarkers for juvenile dermatomyositis: a pilot study.

Background: Blood accessible biomarkers to assess disease activity and their response to therapies in Juvenile Dermatomyositis (JDM) are urgently needed. This pilot study aims to identify serum protein biomarkers associated with clinical disease activity in untreated JDM and their response to medical therapy.

Methods: SomaScan® technology screened JDM patients for 1305 proteins at three points: 1) before start of treatment, 2) while on therapy, and 3) after treatment tapering when patients were clinically inactive.

Disease-specific and glucocorticoid-responsive serum biomarkers for Duchenne Muscular Dystrophy.

Extensive biomarker discoveries for DMD have occurred in the past 7 years, and a vast array of these biomarkers were confirmed in independent cohorts and across different laboratories. In these previous studies, glucocorticoids and age were two major confounding variables. In this new study, using SomaScan technology and focusing on a subset of young DMD patients who were not yet treated with glucocorticoids, we identified 108 elevated and 70 decreased proteins in DMD relative to age matched healthy controls (p value < 0.