Cardiac disease is a major cause of death in patients with muscular dystrophies. The use of feasible and reproducible echocardiographic measures of cardiac function is critical to advance the field ...of therapeutics for dystrophic cardiomyopathy.
Participants aged 8 to 18 years with genetically confirmed Duchenne muscular dystrophy (DMD), Becker muscular dystrophy, or limb-girdle muscular dystrophy were enrolled at five centers, and standardized echocardiographic examinations were performed. Measures of systolic and diastolic function and speckle-tracking echocardiography-derived cardiac strain were reviewed independently by two central readers. Furthermore, echocardiographic measures from participants with DMD were compared with those from retrospective age-matched control subjects from a single site to assess measures of myocardial function.
Forty-eight participants (mean age, 13.3 ± 2.7 years) were enrolled. Shortening fraction had a greater interobserver correlation (intraclass correlation coefficient ICC = 0.63) compared with ejection fraction (ICC = 0.49). One reader could measure ejection fraction in only 53% of participants. Myocardial performance index measured by pulse-wave Doppler and Doppler tissue imaging showed similar ICCs (0.55 and 0.54). Speckle-tracking echocardiography showed a high ICC (0.96). Focusing on participants with DMD (n = 33), significantly increased mitral A-wave velocities, lower E/A ratios, and lower Doppler tissue imaging mitral lateral E' velocities were observed compared with age-matched control subjects. Speckle-tracking echocardiography demonstrated subclinical myocardial dysfunction with decreased average circumferential and longitudinal strain in three distinct subgroups: participants with DMD with normal shortening fractions, participants with DMD aged < 13 years, and participants with DMD with myocardial performance index scores < 0.40 compared with control subjects.
In a muscular dystrophy cohort, assessment of cardiac function is feasible and reproducible using shortening fraction, diastolic measures, and myocardial performance index. Cardiac strain measures identified early myocardial disease in patients with DMD.
To review the growth and current penetration of ICU telemedicine programs, association with outcomes, studies of their impact on medical education, associations with medicolegal risks, identify ...program revenue sources and costs, regulatory aspects, and the ICU telemedicine research agenda.
Review of the published medical literature, governmental documents, and opinions of experts from the Society of Critical Care Medicine ICU Telemedicine Committee.
Formal ICU telemedicine programs now support 11% of nonfederal hospital critically ill adult patients. There is increasingly robust evidence of association with lower ICU (0.79; 95% CI, 0.65-0.96) and hospital mortality (0.83; 95% CI, 0.73-0.94) and shorter ICU (-0.62 d; 95% CI, -1.21 to -0.04 d) and hospital (-1.26 d; 95% CI, -2.49 to -0.03 d) length of stay. Physicians in training report experiences with telemedicine intensivists that are positive and increased patient safety. Early studies suggest that implementation of ICU telemedicine programs has been associated with lower numbers of malpractice claims and costs. The requirements for Medicare reimbursement and states with legislation addressing providing professional services by telemedicine are detailed.
The inclusion of an ICU telemedicine program as a major part of their critical care delivery paradigm has been implemented for 11% of critically ill U.S. adults as a solution for the problem of access to adult critical care services. Implementation of an ICU telemedicine program is one practical way to increase access and reduce mortality as well as length of stay. ICU telemedicine research including comparative effectiveness studies is urgently needed.
Introduction/Aims
Pulmonary decline is a major issue in patients with Duchenne muscular dystrophy (DMD). Eteplirsen is a United States–approved treatment for patients with DMD and exon 51 ...skip‐amenable mutations. Previous analyses have shown that eteplirsen is associated with a statistically significant attenuation of pulmonary decline. In this study we evaluate the effect of eteplirsen treatment from newly available data sources on pulmonary function over time in patients with DMD.
Methods
We used a post hoc pooled analysis to compare the percentage of predicted forced vital capacity (FVC%p) and projected time with pulmonary function milestones in patients with DMD and exon 51 skip‐amenable mutations receiving eteplirsen (Studies 204 and 301) or standard of care (SoC; Cooperative International Neuromuscular Research Group Duchenne Natural History Study). A mixed model for repeated‐measures framework was applied to evaluate the impact of eteplirsen.
Results
An average annual rate of FVC%p decline for eteplirsen‐treated patients was estimated to be 3.47%, a statistically significant attenuation from the 5.95% rate of decline estimated in SoC patients (P = .0001). Using linear extrapolations of the model‐estimated decline in FVC%p, the attenuation in FVC%p decline for eteplirsen‐treated patients corresponded to a delay of 5.72 years in time to needing continuous ventilation, 3.31 years in time to needing nighttime ventilation, and 2.11 years in time to needing a cough assist device compared with SoC patients.
Discussion
The attenuation of FVC%p decline suggests that eteplirsen‐treated patients had statistically significant and clinically meaningful attenuations in pulmonary decline compared with SoC patients.
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We report a first-in-patient study of vamorolone, a first-in-class dissociative steroidal anti-inflammatory drug, in Duchenne muscular dystrophy. This 2-week, open-label Phase IIa ...multiple ascending dose study (0.25, 0.75, 2.0, and 6.0 mg/kg/day) enrolled 48 boys with Duchenne muscular dystrophy (4 to <7 years), with outcomes including clinical safety, pharmacokinetics and pharmacodynamic biomarkers. The study design included pharmacodynamic biomarkers in three contexts of use: 1. Secondary outcomes for pharmacodynamic safety (insulin resistance, adrenal suppression, bone turnover); 2. Exploratory outcomes for drug mechanism of action; 3. Exploratory outcomes for expanded pharmacodynamic safety. Vamorolone was safe and well-tolerated through the highest dose tested (6.0 mg/kg/day) and pharmacokinetics of vamorolone were similar to prednisolone. Using pharmacodynamic biomarkers, the study demonstrated improved safety of vamorolone versus glucocorticoids as shown by reduction of insulin resistance, beneficial changes in bone turnover (loss of increased bone resorption and decreased bone formation only at the highest dose level), and a reduction in adrenal suppression. Exploratory biomarkers of pharmacodynamic efficacy showed an anti-inflammatory mechanism of action and a beneficial effect on plasma membrane stability, as demonstrated by a dose-responsive decrease in serum creatine kinase activity. With an array of pre-selected biomarkers in multiple contexts of use, we demonstrate the development of the first dissociative steroid that preserves anti-inflammatory efficacy and decreases steroid-associated safety concerns. Ongoing extension studies offer the potential to bridge exploratory efficacy biomarkers to clinical outcomes.
Limb contractures are a common impairment in neuromuscular diseases. They contribute to increased disability from decreased motor performance, mobility limitations, reduced functional range of ...motion, loss of function for activities of daily living, and increased pain. The pathogenesis of contractures is multifactorial. Myopathic conditions are associated with more severe limb contractures compared with neuropathic disorders. Although the evidence supporting the efficacy of multiple interventions to improve range of motion in neuromuscular diseases in a sustained manner is lacking, there are generally accepted principles with regard to splinting, bracing, stretching, and surgery that help minimize the impact or disability from contractures.
Differences in gait patterns of children with Duchenne muscular dystrophy (DMD) and typically developing (TD) peers are visible to the eye, but quantifications of those differences outside of the ...gait laboratory have been elusive. In this work, we measured vertical, mediolateral, and anteroposterior acceleration using a waist-worn iPhone accelerometer during ambulation across a typical range of velocities. Fifteen TD and fifteen DMD children from 3 to 16 years of age underwent eight walking/running activities, including five 25 m walk/run speed-calibration tests at a slow walk to running speeds (SC-L1 to SC-L5), a 6-min walk test (6MWT), a 100 m fast walk/jog/run (100MRW), and a free walk (FW). For clinical anchoring purposes, participants completed a Northstar Ambulatory Assessment (NSAA). We extracted temporospatial gait clinical features (CFs) and applied multiple machine learning (ML) approaches to differentiate between DMD and TD children using extracted temporospatial gait CFs and raw data. Extracted temporospatial gait CFs showed reduced step length and a greater mediolateral component of total power (TP) consistent with shorter strides and Trendelenberg-like gait commonly observed in DMD. ML approaches using temporospatial gait CFs and raw data varied in effectiveness at differentiating between DMD and TD controls at different speeds, with an accuracy of up to 100%. We demonstrate that by using ML with accelerometer data from a consumer-grade smartphone, we can capture DMD-associated gait characteristics in toddlers to teens.
ABSTRACT
Introduction: Therapeutic trials in Duchenne muscular dystrophy (DMD) often exclude non‐ambulatory individuals. Here we establish optimal and reliable assessments in a multicenter trial. ...Methods: Non‐ambulatory boys/men with DMD (N = 91; 16.7 ± 4.5 years of age) were assessed by trained clinical evaluators. Feasibility (percentage completing task) and reliability intraclass correlation coefficients (ICCs) between morning and afternoon tests were measured. Results: Forced vital capacity (FVC), assessed in all subjects, showed a mean of 47.8 ± 22% predicted (ICC 0.98). Brooke Upper Extremity Functional Rating (Brooke) and Egen Klassifikation (EK) scales in 100% of subjects showed ICCs ranging from 0.93 to 0.99. Manual muscle testing, range of motion, 9‐hole peg test, and Jebsen‐Taylor Hand Function Test (JHFT) demonstrated varied feasibility (99% to 70%), with ICCs ranging from 0.99 to 0.64. We found beneficial effects of different forms of corticosteroids for the Brooke scale, percent predicted FVC, and hand and finger strength. Conclusions: Reliable assessment of non‐ambulatory boys/men with DMD is possible. Clinical trials will have to consider corticosteroid use. Muscle Nerve 51: 522–532, 2015
ABSTRACT
Introduction: More than 90% of amyotrophic lateral sclerosis (ALS) patients have muscle cramps, but evidence‐based treatments have not been available. Methods: A multicenter, double‐blind, ...placebo‐controlled crossover trial of mexiletine 150 mg twice daily was conducted in ALS patients requesting treatment of symptomatic muscle cramps. Results: Muscle cramp frequency was reduced in 18 of 20 patients; 13 reductions were attributed to treatment (P < 0.05). The average reduction, based on t tests, was 1.8 cramps per day (a reduction from 5.3 with placebo to 3.5 with mexiletine). The estimated reduction of cramp severity was 15 units on a 100‐unit scale (P = 0.01) from a baseline average of 46. No effect on fasciculations was noted. One patient discontinued the study because of dizziness, and another patient discontinued the study to start open‐label mexiletine therapy. No serious adverse event occurred. Discussion: Mexiletine is a well tolerated and effective medication for controlling the symptom of muscle cramps in ALS. Muscle Nerve 58: 42–48, 2018
To correlate time to loss of ambulation (LoA) and different truncating DMD gene mutations in a large, prospective natural history study of Duchenne muscular dystrophy (DMD), with particular attention ...to mutations amenable to emerging molecular treatments.
We analyzed data from the Cooperative International Neuromuscular Research Group Duchenne Natural History Study for participants with DMD single- or multi-exon deletions or duplications with defined exon boundaries (n = 186), or small mutations identified by sequencing (n = 26, including 16 nonsense point mutations). We performed a time-to-event analysis of LoA, a strong indicator of overall disease severity, adjusting for glucocorticoid treatment and genetic modifiers.
Participants with deletions amenable to skipping of exon 44 had later LoA (median 14.8 years, hazard ratio 0.31, 95% confidence interval 0.14-0.69, p = 0.004). Age at LoA did not differ significantly in participants with deletions amenable to exon 45, 51, and 53 skipping, duplications, and small rearrangements. Nonsense mutation DMD also showed a typical median age at LoA (11.1 years), with a few outliers (ambulatory around or after 16 years of age) carrying stop codons within in-frame exons, more often situated in the rod domain.
As exon 44 skipping-amenable DMD has a later LoA, mutation-specific randomization and selection of placebo groups are essential for the success of clinical trials.
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