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This work aimed to assess inter-rater reliability and agreement of a magnetic resonance imaging (MRI)-based Kellgren and Lawrence (K&L) grading for patellofemoral joint osteoarthritis (OA) and to validate it against the MRI Osteoarthritis Knee Score (MOAKS). MRI scans from people aged 45 to 75 years with chronic knee pain participating in a randomised clinical trial evaluating dietary supplements were utilised. Fifty participants were randomly selected and scored using the MRI-based K&L grading using axial and sagittal MRI scans. Raters conducted inter-rater reliability, blinded to clinical information, radiology reports and other rater results. Intra- and inter-rater reliability and agreement were evaluated using the intra-class correlation coefficient (ICC) and Cohen’s weighted kappa. There was a 2-week interval between the first and second readings for intra-rater reliability. Validity was assessed using the MOAKS and evaluated using Spearman’s correlation coefficient. Intra-rater reliability of the K&L system was excellent: ICC 0.91 (95% CI 0.82-0.95); weighted kappa (ĸ = 0.69). Inter-rater reliability was high (ICC 0.88; 95% CI 0.79-0.93), while agreement between raters was moderate (ĸ = 0.49-0.57). Validity analysis demonstrated a strong correlation between the total MOAKS features score and the K&L grading system (ρ = 0.62-0.67) but weak correlations when compared with individual MOAKS features (ρ = 0.19-0.61). The high reliability and good agreement show consistency in grading the severity of patellofemoral OA with the MRI-based K&L score. Our validity results suggest that the scale may be useful, particularly in the clinical environment. Future research should validate this method against clinical findings. [ABSTRACT FROM AUTHOR]

Infantile or early onset is estimated to occur in around 10% of all facioscapulohumeral dystrophy (FSHD) patients. Although small series of early onset FSHD patients have been reported, comprehensive data on the clinical phenotype is missing. We performed a systematic literature search on the clinical features of early onset FSHD comprising a total of 43 articles with individual data on 227 patients. Additional data from four cohorts was provided by the authors. Mean age at reporting was 18.8 years, and 40% of patients were wheelchair-dependent at that age. Half of the patients had systemic features, including hearing loss (40%), retinal abnormalities (37%) and developmental delay (8%). We found an inverse correlation between repeat size and disease severity, similar to adult-onset FSHD. De novo FSHD1 mutations were more prevalent than in adult-onset FSHD. Compared to adult FSHD, our findings indicate that early onset FSHD is overall characterized by a more severe muscle phenotype and a higher prevalence of systemic features. However, similar as in adults, a significant clinical heterogeneity was observed. Based on this, we consider early onset FSHD to be on the severe end of the FSHD disease spectrum. We found natural history studies and treatment studies to be very scarce in early onset FSHD, therefore longitudinal studies are needed to improve prognostication, clinical management and trial-readiness. [ABSTRACT FROM AUTHOR]

Purpose: To report the results of a randomized controlled trial using an electronic monitoring device (EM) plus a motivational interviewing (MI) intervention to enhance adherence to disease-modifying therapies (DMT) in pediatric MS.Methods: Fifty-two youth with MS (16.03 ± 2.2 years) were randomized to receive either MI (n = 25) (target intervention) or a MS medication video (n = 27) (attention control). Primary endpoint was change in adherence. Secondary outcomes included changes in quality of life, well-being and self-efficacy. Random effects modeling and Cohen's effect size computation evaluated intervention impact.Results: Longitudinal random effect models revealed that the MI group decreased their EM adherence (GroupxTime interaction = -0.19), while increasing frequency of parental DMT reminder (26.01)/administration (11.69). We found decreased EM use in the MI group at 6 months (Cohen's d = -0.61), but increased pharmacy refill adherence (d = 0.23). Parental reminders about medication increased in MI subjects vs controls (d = 0.59 at 3 months; d = 0.70 at 6 months). We found increases in self-reported adherence (d = 0.21) at 3 but not 6 months, fewer barriers to adherence at three (d = -0.58) and six months (d = -0.31), better physical (d = 0.23 at 3 months; d = 0.45 at 6 months), emotional (d = 0.25 at 3 months) and self-efficacy function (d = 0.55 at 3 months; 0.48 at 6 months), but worse well-being, including self-acceptance (d = -0.53 at 6 months) and environmental mastery (d = -0.42 at 3 and 6 months) in intervention as compared to control patients.Conclusions: Participants receiving MI + EM experienced worsening on objective measures of adherence and increased parental involvement, but improved on some self- and parent-reported measures. MI participants reported improvements in quality of life and self-efficacy, but worsened well-being. [ABSTRACT FROM AUTHOR]

Serum metabolite profiling in Duchenne muscular dystrophy (DMD) may enable discovery of valuable molecular markers for disease progression and treatment response. Serum samples from 51 DMD patients from a natural history study and 22 age-matched healthy volunteers were profiled using liquid chromatography coupled to mass spectrometry (LC-MS) for discovery of novel circulating serum metabolites associated with DMD. Fourteen metabolites were found significantly altered (1% false discovery rate) in their levels between DMD patients and healthy controls while adjusting for age and study site and allowing for an interaction between disease status and age. Increased metabolites included arginine, creatine and unknown compounds at m/z of 357 and 312 while decreased metabolites included creatinine, androgen derivatives and other unknown yet to be identified compounds. Furthermore, the creatine to creatinine ratio is significantly associated with disease progression in DMD patients. This ratio sharply increased with age in DMD patients while it decreased with age in healthy controls. Overall, this study yielded promising metabolic signatures that could prove useful to monitor DMD disease progression and response to therapies in the future. [ABSTRACT FROM AUTHOR]

Serum biomarkers in Duchenne muscular dystrophy (DMD) may provide deeper insights into disease pathogenesis, suggest new therapeutic approaches, serve as acute read-outs of drug effects, and be useful as surrogate outcome measures to predict later clinical benefit. In this study a large-scale biomarker discovery was performed on serum samples from patients with DMD and agematched healthy volunteers using a modified aptamer-based proteomics technology. Levels of 1,125 proteins were quantified in serum samples from two independent DMD cohorts: cohort 1 (The Parent Project Muscular Dystrophy-Cincinnati Children's Hospital Medical Center), 42 patients with DMD and 28 age-matched normal volunteers; and cohort 2 (The Cooperative International Neuromuscular Research Group, Duchenne Natural History Study), 51 patients with DMD and 17 age-matched normal volunteers. Forty-four proteins showed significant differences that were consistent in both cohorts when comparing DMD patients and healthy volunteers at a 1% false-discovery rate, a large number of significant protein changes for such a small study. These biomarkers can be classified by known cellular processes and by age-dependent changes in protein concentration. Our findings demonstrate both the utility of this unbiased biomarker discovery approach and suggest potential new diagnostic and therapeutic avenues for ameliorating the burden of DMD and, we hope, other rare and devastating diseases. [ABSTRACT FROM AUTHOR]

ABSTRACT Introduction: We studied the potential for motor unit number estimation (MUNE) to detect subclinical changes in motor unit numbers in children with type 1 diabetes mellitus (DM). Methods: Blinded observers performed clinical assessment, electrophysiology, and multipoint MUNE of the extensor digitorum brevis muscle in children with DM for ≥5 years and age-matched healthy controls. Results: For 51 DM subjects, the disease duration was 9.1 ± 2.6 years. Subjects with DM and healthy controls ( n = 21) had similar demographics. There were no clinical symptoms or signs of peripheral neuropathy in any subject, nor differences in standard electrophysiology between cohorts. Estimated motor unit numbers were decreased significantly in children with DM (224 ± 87 vs. 274 ± 101, P = 0.036). Conclusion: Despite the absence of clinical or standard electrophysiological differences from normal control subjects, MUNE can detect a small significant difference in children with DM, suggesting that motor unit loss begins early and subclinically in the disease. Muscle Nerve 50: 593-598, 2014 [ABSTRACT FROM AUTHOR]

Summary: Background: HLA-DRB1*15 genotype, previous infection with Epstein-Barr virus, and vitamin D insufficiency are susceptibility factors for multiple sclerosis, but whether they act synergistically to increase risk is unknown. We aimed to assess the contributions of these risk factors and the effect of established precursors of multiple sclerosis, such as brain lesions on MRI and oligoclonal bands in CSF at the time of incident demyelination, on development of multiple sclerosis in children. Methods: In our prospective national cohort study, we assessed children who presented with incident CNS demyelination to any of the 16 paediatric health-care facilities or seven regional health-care facilities in Canada. We did univariate and multivariable analyses to assess contributions of HLA-DRB1*15, Epstein-Barr virus, vitamin D status, MRI evidence of brain lesions, and CSF oligoclonal bands as determinants of multiple sclerosis. We used classification and regression tree analyses to generate a risk stratification algorithm for clinical use. Findings: Between Sept 1, 2004, and June 30, 2010, we screened 332 children of whom 302 (91%) were eligible and followed-up for a median of 3·14 years (IQR 1·61–4·51). 63 (21%) children were diagnosed with multiple sclerosis after a median of 127 days (99–222). Although the risk of multiple sclerosis was increased with presence of one or more HLA-DRB1*15 alleles (hazard ratio [HR] 2·32, 95% CI 1·25–4·30), reduced serum 25-hydroxyvitamin D concentration (HR per 10 nmol/L decrease 1·11, 1·00–1·25), and previous Epstein-Barr-virus infection (HR 2·04, 0·99–4·20), no interactions between these variables were detected on multivariate analysis. Multiple sclerosis was strongly associated with baseline MRI evidence of one or more brain lesion (HR 37·9, 5·26–273·85) or CSF oligoclonal bands (6·33, 3·35–11·96), suggesting established disease. One patient diagnosed with multiple sclerosis had a normal MRI scan, and therefore sensitivity of an abnormal MRI scan for multiple sclerosis diagnosis was 98·4%. Interpretation: Risk of multiple sclerosis in children can be stratified by presence of HLA-DRB1*15 alleles, remote Epstein-Barr virus infection, and low serum 25-hydroxyvitamin D concentrations. Similar to previous studies in adults, brain lesions detected on MRI and CSF oligoclonal bands in children are probable precursors to the clinical onset of multiple sclerosis. Children with a normal MRI are very likely to have a monophasic illness. Funding: Canadian Multiple Sclerosis Scientific Research Foundation. [Copyright &y& Elsevier]

Summary: Background: The full spectrum of clinical manifestations and outcome, and the potential importance of regional or demographic features or viral triggers in paediatric multiple sclerosis (MS), has yet to be fully characterised. Our aim was to determine some of these characteristics in children with MS. Methods: 137 children with MS and 96 control participants matched by age and geographical region were recruited in a multinational study. They underwent structured clinical-demographic interviews, review of academic performance, physical examination, disability assessment (MS patients only), and standardised assays for IgG antibodies directed against Epstein-Barr virus, cytomegalovirus, parvovirus B19, varicella zoster virus, and herpes simplex virus. Findings: MS was relapsing-remitting at diagnosis in 136 (99%) children. The first MS attack resembled acute disseminated encephalomyelitis (ADEM) in 22 (16%) of the children, most under 10 years old (mean age 7·4 [SD 4·2] years). Children with ADEM-like presentations were significantly younger than were children with polyfocal (11·2 [4·5] years; p<0·0001) or monofocal (12·0 [3·8] years; p=0·0005) presentations. Permanent physical disability (EDSS≥4·0) developed within 5 years in 15 (13%) of the 120 children for whom EDSS score was available. 23 (17%) had impaired academic performance, which was associated with increasing disease duration (p=0·02). Over 108 (86%) of the children with MS, irrespective of geographical residence, were seropositive for remote EBV infection, compared with only 61 (64%) of matched controls (p=0·025, adjusted for multiple comparisons). Children with MS did not differ from controls in seroprevalence of the other childhood viruses studied, nor with respect to month of birth, sibling number, sibling rank, or exposure to young siblings. Interpretation: Paediatric MS is a relapsing-remitting disease, with presenting features that vary by age at onset. MS in children might be associated with exposure to EBV, suggesting a possible role for EBV in MS pathobiology. [Copyright &y& Elsevier]

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.

Background and Objectives: Spinal muscular atrophy (SMA) is a neurodegenerative disorder manifesting with progressive muscle weakness and atrophy. SMA type 1 used to be fatal within the first 2 years of life, but is now treatable with therapies targeting splicing modification and gene replacement. Nusinersen, risdiplam, and onasemnogene abeparvovec-xioi improve survival, motor strength, endurance, and ability to thrive, allowing many patients to potentially attain a normal life; all have been recently approved by major regulatory agencies. Although these therapies have revolutionized the world of SMA, they are associated with a high economic burden, and access to these therapies is limited in some countries. The primary objective of this study was to compare the availability and implementation of treatment of SMA from different regions of the world., Methods: In this qualitative study, we surveyed health care providers from 21 countries regarding their experiences caring for patients with SMA. The main outcome measures were provider survey responses on newborn screening, drug availability/access, barriers to treatment, and related questions., Results: Twenty-four providers from 21 countries with decades of experience (mean 26 years) in treating patients with SMA responded to the survey. Nusinersen was the most available therapy for SMA. Our survey showed that while genetic testing is usually available, newborn screening is still unavailable in many countries. The provider-reported treatment cost also varied between countries, and economic burden was a major barrier in treating patients with SMA., Discussion: Overall, this survey highlights the global inequality in managing patients with SMA. The spread of newborn screening is essential in ensuring improved access to care for patients with SMA. With the advancement of neurotherapeutics, more genetic diseases will soon be treatable, and addressing the global inequality in clinical care will require novel approaches to mitigate such inequality in the future., Competing Interests: V.D. Armengol reports no disclosures relevant to the manuscript; B.T. Darras reports grants and non-financial support from, and being the FIREFISH Study Steering Committee Chair and an ad hoc scientific advisory board member for Roche/Genentech, which manufactures risdiplam, grant support from and being an ad hoc scientific board member for Biogen, which manufactures nusinersen; non-financial support from and being an ad hoc scientific board member for Novartis Gene Therapies (AveXis), which manufactures onasemnogene abeparvovec, grant support for the ENDEAR, CHERISH, and CS2/CS12 studies from Ionis Pharmaceuticals, grants from and being an ad hoc scientific board member for Sarepta Pharmaceuticals, grants from PTC Therapeutics, Fibrogen, Summit, the US NIH and National Institute of Neurological Disorders and Stroke, Slaney Family Fund for SMA, Spinal Muscular Atrophy Foundation, CureSMA, and Working on Walking Fund, being an ad hoc scientific board member for Vertex, and a data and safety monitoring board member for Amicus Inc; A.A. Abulaban reports no disclosures relevant to the manuscript; A. Alshehri reports no disclosures relevant to the manuscript; N. Barišić is investigator for Roche clinical trials, served as advisor or consultant, speaker or member of Advisory Boards for: Roche, Novartis, PTC, and Biogen/Medis-Adria; T. Ben-Omran reports no disclosures relevant to the manuscript; G. Bernert has served on Advisory boards for Avexis/Novartis Gene Therapies, Biogen, PTC, Roche, Pfizer and Santhera, he has received funding for travel or speaker honoraria for Biogen, Novartis, Pfizer, PTC, Roche, Santhera, and Merz, he has served as PI for DELOS, SIDEROS (SANTHERA), LELANTOS 1 + 2 (Fibrogen), and STRIDE Registry (PTC); C. Castiglioni has participated in advisory and educational activities by Biogen, Roche and Novartis and received honoraria for these activities; Y.H. Chien has served on advisory boards for Biogen and Novartis Gene Therapies and received honoraria for educational activities; M.A. Farrar is funded by a National Health and Medical Research Council of Australia Investigator grant (APP1194940), she has served on advisory boards for Biogen, Roche and Novartis Gene Therapies and received honoraria for educational activities; G. Kandawasvika reports no disclosures relevant to the manuscript; S. Khadilkar reports no disclosures relevant to the manuscript; J.K. Mah received research grants as PI in studies sponsored by Biogen, Roche, and the Alberta Children's Hospital Foundation; C. Marini-Bettolo reports participation in Scientific Advisory boards and teaching initiatives for Avexis, Biogen, and Roche, she is involved as an investigator in clinical trials from Avexis, and she is principal investigator for the UK SMA patient registry funded by SMA UK; D. Osredkar reports participation in scientific advisory boards and teaching initiatives for Biogen, Medis, Novartis Gene Therapies, PTC, Roche, and Serapta, and he is PI in studies sponsored partly by Biogen and PTC; G. Pfeffer reports no disclosures relevant to the manuscript; F. Piazzon reports no disclosures relevant to the manuscript; I. Pitarch-Castellano has participated in advisory and educational activities by Biogen, Roche and Novartis; S. Quijano-Roy is PI for clinical trials of Biogen (DEVOTE), Novartis Gene Therapies (SMART), and Roche (OLEOS), has served on advisory boards for Biogen, Novartis GT and Roche, and has received travel and speaker honoraria from Biogen Novartis and Roche; K. Saito is funded by the Practical Research Project for Rare/Intractable Diseases of the Japan Agency for Medical Research and Development, AMED (grant number: 22ek0109472h0003), and she is Principal Investigator for clinical trials of Biogen (DEVOTE), Novartis Gene Therapies, Inc./Novartis (SPR1NT, LT-002), and Chugai (Roche) (SUNFISH), has served on advisory boards for Biogen, Novartis Gene Therapies, Inc./Novartis, and Chugai (Roche), and has received honoraria from Biogen, Novartis and Chugai; J.H. Shin reports no disclosures relevant to the manuscript; J.F. Vázquez-Costa is funded by grants of the Instituto de Salud Carlos III (JR19/00030, PI Vázquez), served on advisory boards for Biogen and Roche and received travel and speaker honoraria from Biogen and Roche; M.C. Walter has served on advisory boards for Avexis, Biogen, Novartis, Roche, Santhera, Sarepta, PTC Therapeutics, Ultragenyx, Wave Sciences, received funding for Travel or Speaker Honoraria from Novartis, Biogen, Ultragenyx, Santhera, PTC Therapeutics, and worked as an ad hoc consultant for AskBio, Audentes Therapeutics, Biogen Pharma GmbH, Fulcrum Therapeutics, Novartis, PTC Therapeutics, Roche; J. Wanigasinghe receives support as principal investigator from NIH grant 1R21HD093563-01; H. Xiong is one of the investigators of Biogen (DEVOTE), Roche (FIREFISH, SUNFISH) and Novartis (STEER), but has no conflicts of interest related to this study; R.C. Griggs serves as Co-PI of a training grant from the NINDS for the Experimental Therapeutics of Neurological Diseases. He receives grant funding from the NIH, the Muscular Dystrophy Association, and the Parent Project for Muscular Dystrophy in support of clinical trials, and he also receives support from PTC Therapeutics, Sarepta Pharmaceuticals and Santhera Pharmaceutics for clinical trial data, and he serves as Chair of a DSMB for Solid Pharmaceuticals, Chair of the Research Advisory Committee of the American Brain Foundation, inaugural Chair of the American Academy of Neurology Section on Experimental Neurotherapeutics, and he receives compensation as an Editor of Cecil Textbook of Medicine; B. Roy has served as a consultant for Alexion Pharmaceuticals (now part of AstraZeneca), Takeda Pharmaceuticals, and argenx, but he has no conflicts directly related to this work. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp. TAKE-HOME POINTS → Stark global disparities in access to disease-modifying therapy (DMT) for spinal muscular atrophy (SMA) currently exist, and these disparities are not driven simply by differences in countries' wealth.→ The economic burden of DMT was identified by a majority of survey respondents as a barrier to treatment of SMA, with several other barriers also noted.→ Most respondents reported access to genetic testing, but newborn screening is unavailable in several countries included in this survey and is only implemented regionally in others.→ Increased awareness of unequal access to treatment is the first step toward mitigating inequities in rare neurologic diseases., (© 2023 American Academy of Neurology.)

Objectives: Spinal muscular atrophy (SMA) is a leading genetic cause of infant death and represents a significant burden of care. An improved understanding of the epidemiology of SMA in Canada may help inform strategies to improve the standard of care for individuals living with SMA., Methods: We employed a multisource approach to estimate the minimal incidence and prevalence of 5q SMA and to gain greater insight into recent clinical practices and treatment trends for the Canadian SMA population. Data sources included the Canadian Paediatric Surveillance Program (CPSP), Canadian Neuromuscular Disease Registry (CNDR), and molecular genetics laboratories in Canada., Results: The estimated annual minimum incidence of 5q SMA was 4.38, 3.44, and 7.99 cases per 100,000 live births in 2020 and 2021, based on CPSP, CNDR, and molecular genetics laboratories data, respectively, representing approximately 1 in 21,472 births (range 12,516-29,070) in Canada. SMA prevalence was estimated to be 0.85 per 100,000 persons aged 0-79 years. Delay in diagnosis exists across all SMA subtypes. Most common presenting symptoms were delayed milestones, hypotonia, and muscle weakness. Nusinersen was the most common disease-modifying treatment received. Most patients utilized multidisciplinary clinics for management of SMA., Conclusion: This study provides data on the annual minimum incidence of pediatric 5q SMA in Canada. Recent therapeutic advances and newborn screening have the potential to drastically alter the natural history of SMA. Findings underline the importance of ongoing surveillance of the epidemiology and long-term health outcomes of SMA in the Canadian population.

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., Methods: A cohort of 83 patients with Becker muscular dystrophy (5-75 years at baseline) were followed for up to 3 years with annual assessments. Muscle and pulmonary function outcomes were analyzed herein. Age-stratified statistical analysis and modeling were conducted to analyze cross-sectional data, time-to-event data, and longitudinal data to characterize these clinical outcomes., Results: Deletion mutations of dystrophin exons 45-47 or 45-48 were most common. Subgroup analysis showed greater pairwise association between motor outcomes at baseline than association between these outcomes and age. Stronger correlations between outcomes for adults than for those under 18 years were also observed. Using cross-sectional binning analysis, a ceiling effect was seen for North Star Ambulatory Assessment but not for other functional outcomes. Longitudinal analysis showed a decline in percentage predicted forced vital capacity over the life span. There was relative stability or improved median function for motor functional outcomes through childhood and adolescence and decreasing function with age thereafter., Conclusions: There is variable progression of outcomes resulting in significant heterogeneity of the clinical phenotype of Becker muscular dystrophy. Disease progression is largely manifest in adulthood. There are implications for clinical trial design revealed by this longitudinal analysis of a Becker natural history dataset.

Spinal muscular atrophy (SMA) is a progressive neuromuscular disease caused by biallelic pathogenic/likely pathogenic variants of the survival motor neuron 1 ( SMN1 ) gene. Early diagnosis via newborn screening (NBS) and pre-symptomatic treatment are essential to optimize health outcomes for affected individuals. We developed a multiplex quantitative polymerase chain reaction (qPCR) assay using dried blood spot (DBS) samples for the detection of homozygous absence of exon 7 of the SMN1 gene. Newborns who screened positive were seen urgently for clinical evaluation. Confirmatory testing by multiplex ligation-dependent probe amplification (MLPA) revealed SMN1 and SMN2 gene copy numbers. Six newborns had abnormal screen results among 47,005 newborns screened during the first year and five were subsequently confirmed to have SMA. Four of the infants received SMN1 gene replacement therapy under 30 days of age. One infant received an SMN2 splicing modulator due to high maternally transferred AAV9 neutralizing antibodies (NAb), followed by gene therapy at 3 months of age when the NAb returned negative in the infant. Early data show that all five infants made excellent developmental progress. Based on one year of data, the incidence of SMA in Alberta was estimated to be 1 per 9401 live births.

Background: Despite recommendations for regular lung volume recruitment (LVR) use in clinical practice guidelines for children with neuromuscular disease, adherence to LVR is poor. We aimed to describe the experience of LVR by boys with Duchenne muscular dystrophy (DMD), their families, and healthcare providers (HCPs), as well as to identify the barriers and facilitators to LVR use., Methods: This multicenter, qualitative study evaluated boys with DMD (n = 11) who used twice-daily LVR as part of a randomized controlled trial, as well as their parents (n = 11), and HCPs involved in the clinical use of LVR (n = 9). Semistructured interviews were conducted to identify participants' understanding of LVR therapy and their beliefs, barriers and facilitators to its use. Thematic analysis was conducted using an inductive approach. A subanalysis compared adherent and nonadherent children., Results: Seven themes were identified related to participants' beliefs and experiences with LVR: emotional impact, adaptation to LVR, perceived benefits of LVR, routine, family engagement, clinical resources, and equipment-related factors. Strategies to improve adherence were also identified, including education, reinforcement and demonstration of LVR benefit, as well as clinician support. There were no thematic differences between adherent and nonadherent children., Discussion: Despite the benefits of LVR and positive experiences with it by many families, there remain barriers to adherence to treatment. HCPs need to balance the need for early introduction to give families time to adapt to LVR while ensuring that the benefit of LVR outweighs the burden. Clinician support is important for family engagement., (© 2022 Wiley Periodicals LLC.)

Background: Duchenne muscular dystrophy (DMD) is caused by DMD gene mutations, resulting in absence of functional dystrophin protein. Viltolarsen, an exon 53 skipping therapy, significantly increased dystrophin levels in patients with DMD. Presented here are completed study results of > 4 years of functional outcomes in viltolarsen-treated patients compared to a historical control group (Cooperative International Neuromuscular Research Group Duchenne Natural History Study [CINRG DNHS])., Objective: To evaluate the efficacy and safety of viltolarsen for an additional 192 weeks in boys with DMD., Methods: This phase 2, open-label, 192-week long-term extension (LTE) study (NCT03167255) evaluated the efficacy and safety of viltolarsen in participants aged 4 to < 10 years at baseline with DMD amenable to exon 53 skipping. All 16 participants from the initial 24-week study enrolled into this LTE. Timed function tests were compared to the CINRG DNHS group. All participants received glucocorticoid treatment. The primary efficacy outcome was time to stand from supine (TTSTAND). Secondary efficacy outcomes included additional timed function tests. Safety was continuously assessed., Results: For the primary efficacy outcome (TTSTAND), viltolarsen-treated patients showed stabilization of motor function over the first two years and significant slowing of disease progression over the following two years compared with the CINRG DNHS control group which declined. Viltolarsen was well tolerated, with most reported treatment-emergent adverse events being mild or moderate. No participants discontinued drug during the study., Conclusions: Based on the results of this 4-year LTE, viltolarsen can be an important treatment strategy for DMD patients amenable to exon 53 skipping.

Importance: Corticosteroidal anti-inflammatory drugs are widely prescribed but long-term use shows adverse effects that detract from patient quality of life., Objective: To determine if vamorolone, a structurally unique dissociative steroidal anti-inflammatory drug, is able to retain efficacy while reducing safety concerns with use in Duchenne muscular dystrophy (DMD)., Design, Setting, and Participants: Randomized, double-blind, placebo- and prednisone-controlled 24-week clinical trial, conducted from June 29, 2018, to February 24, 2021, with 24 weeks of follow-up. This was a multicenter study (33 referral centers in 11 countries) and included boys 4 to younger than 7 years of age with genetically confirmed DMD not previously treated with corticosteroids., Interventions: The study included 4 groups: placebo; prednisone, 0.75 mg/kg per day; vamorolone, 2 mg/kg per day; and vamorolone, 6 mg/kg per day., Main Outcomes and Measures: Study outcomes monitored (1) efficacy, which included motor outcomes (primary: time to stand from supine velocity in the vamorolone, 6 mg/kg per day, group vs placebo; secondary: time to stand from supine velocity [vamorolone, 2 mg/kg per day], 6-minute walk distance, time to run/walk 10 m [vamorolone, 2 and 6 mg/kg per day]; exploratory: NorthStar Ambulatory Assessment, time to climb 4 stairs) and (2) safety, which included growth, bone biomarkers, and a corticotropin (ACTH)-challenge test., Results: Among the 133 boys with DMD enrolled in the study (mean [SD] age, 5.4 [0.9] years), 121 were randomly assigned to treatment groups, and 114 completed the 24-week treatment period. The trial met the primary end point for change from baseline to week 24 time to stand velocity for vamorolone, 6 mg/kg per day (least-squares mean [SE] velocity, 0.05 [0.01] m/s vs placebo -0.01 [0.01] m/s; 95% CI, 0.02-0.10; P = .002) and the first 4 sequential secondary end points: time to stand velocity, vamorolone, 2 mg/kg per day, vs placebo; 6-minute walk test, vamorolone, 6 mg/kg per day, vs placebo; 6-minute walk test, vamorolone, 2 mg/kg per day, vs placebo; and time to run/walk 10 m velocity, vamorolone, 6 mg/kg per day, vs placebo. Height percentile declined in prednisone-treated (not vamorolone-treated) participants (change from baseline [SD]: prednisone, -1.88 [8.81] percentile vs vamorolone, 6 mg/kg per day, +3.86 [6.16] percentile; P = .02). Bone turnover markers declined with prednisone but not with vamorolone. Boys with DMD at baseline showed low ACTH-stimulated cortisol and high incidence of adrenal insufficiency. All 3 treatment groups led to increased adrenal insufficiency., Conclusions and Relevance: In this pivotal randomized clinical trial, vamorolone was shown to be effective and safe in the treatment of boys with DMD over a 24-week treatment period. Vamorolone may be a safer alternative than prednisone in this disease, in which long-term corticosteroid use is the standard of care., Trial Registration: ClinicalTrials.gov Identifier: NCT03439670.

Background: Impaired cough results in airway secretion retention, atelectasis and pneumonia in individuals with Duchenne muscular dystrophy (DMD). Lung volume recruitment (LVR) stacks breaths to inflate the lungs to greater volumes than spontaneous effort. LVR is recommended in DMD clinical care guidelines but is not well studied. We aimed to determine whether twice-daily LVR, compared with standard of care alone, attenuates the decline in FVC at 2 years in boys with DMD., Methods: In this multicentre, assessor-blinded, randomised controlled trial, boys with DMD, aged 6-16 years with FVC >30% predicted, were randomised to receive conventional treatment or conventional treatment plus manual LVR twice daily for 2 years. The primary outcome was FVC % predicted at 2 years, adjusted for baseline FVC % predicted, age and ambulatory status. Secondary outcomes included change in chest wall distensibility (maximal insufflation capacity minus FVC) and peak cough flow., Results: Sixty-six boys (36 in LVR group, 30 in control) were evaluated (median age (IQR): 11.5 years (9.5-13.5), median baseline FVC (IQR): 85% predicted (73-96)). Adjusted mean difference in FVC between groups at 2 years was 1.9% predicted (95% CI -6.9% to 10.7%; p=0.68) in the direction of treatment benefit. We found no differences in secondary outcomes., Conclusion: There was no difference in decline in FVC % predicted with use of twice-daily LVR for boys with DMD and relatively normal lung function. The burden associated with routine LVR may outweigh the benefit. Benefits of LVR to maintain lung health in boys with worse baseline lung function still need to be clarified., Trial Registration Number: NCT01999075., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Importance: Corticosteroids improve strength and function in boys with Duchenne muscular dystrophy. However, there is uncertainty regarding the optimum regimen and dosage., Objective: To compare efficacy and adverse effects of the 3 most frequently prescribed corticosteroid regimens in boys with Duchenne muscular dystrophy., Design, Setting, and Participants: Double-blind, parallel-group randomized clinical trial including 196 boys aged 4 to 7 years with Duchenne muscular dystrophy who had not previously been treated with corticosteroids; enrollment occurred between January 30, 2013, and September 17, 2016, at 32 clinic sites in 5 countries. The boys were assessed for 3 years (last participant visit on October 16, 2019)., Interventions: Participants were randomized to daily prednisone (0.75 mg/kg) (n = 65), daily deflazacort (0.90 mg/kg) (n = 65), or intermittent prednisone (0.75 mg/kg for 10 days on and then 10 days off) (n = 66)., Main Outcomes and Measures: The global primary outcome comprised 3 end points: rise from the floor velocity (in rise/seconds), forced vital capacity (in liters), and participant or parent global satisfaction with treatment measured by the Treatment Satisfaction Questionnaire for Medication (TSQM; score range, 0 to 100), each averaged across all study visits after baseline. Pairwise group comparisons used a Bonferroni-adjusted significance level of .017., Results: Among the 196 boys randomized (mean age, 5.8 years [SD, 1.0 years]), 164 (84%) completed the trial. Both daily prednisone and daily deflazacort were more effective than intermittent prednisone for the primary outcome (P < .001 for daily prednisone vs intermittent prednisone using a global test; P = .017 for daily deflazacort vs intermittent prednisone using a global test) and the daily regimens did not differ significantly (P = .38 for daily prednisone vs daily deflazacort using a global test). The between-group differences were principally attributable to rise from the floor velocity (0.06 rise/s [98.3% CI, 0.03 to 0.08 rise/s] for daily prednisone vs intermittent prednisone [P = .003]; 0.06 rise/s [98.3% CI, 0.03 to 0.09 rise/s] for daily deflazacort vs intermittent prednisone [P = .017]; and -0.004 rise/s [98.3% CI, -0.03 to 0.02 rise/s] for daily prednisone vs daily deflazacort [P = .75]). The pairwise comparisons for forced vital capacity and TSQM global satisfaction subscale score were not statistically significant. The most common adverse events were abnormal behavior (22 [34%] in the daily prednisone group, 25 [38%] in the daily deflazacort group, and 24 [36%] in the intermittent prednisone group), upper respiratory tract infection (24 [37%], 19 [29%], and 24 [36%], respectively), and vomiting (19 [29%], 17 [26%], and 15 [23%])., Conclusions and Relevance: Among patients with Duchenne muscular dystrophy, treatment with daily prednisone or daily deflazacort, compared with intermittent prednisone alternating 10 days on and 10 days off, resulted in significant improvement over 3 years in a composite outcome comprising measures of motor function, pulmonary function, and satisfaction with treatment; there was no significant difference between the 2 daily corticosteroid regimens. The findings support the use of a daily corticosteroid regimen over the intermittent prednisone regimen tested in this study as initial treatment for boys with Duchenne muscular dystrophy., Trial Registration: ClinicalTrials.gov Identifier: NCT01603407.

Importance: Vamorolone is a synthetic steroidal drug with potent anti-inflammatory properties. Initial open-label, multiple ascending dose-finding studies of vamorolone among boys with Duchenne muscular dystrophy (DMD) found significant motor function improvement after 6 months treatment in higher-dose (ie, ≥2.0 mg/kg/d) groups., Objective: To investigate outcomes after 30 months of open-label vamorolone treatment., Design, Setting, and Participants: This nonrandomized controlled trial was conducted by the Cooperative International Neuromuscular Research Group at 11 US and non-US study sites. Participants were 46 boys ages 4.5 to 7.5 years with DMD who completed the 6-month dose-finding study. Data were analyzed from July 2020 through November 2021., Interventions: Participants were enrolled in a 24-month, long-term extension (LTE) study with vamorolone dose escalated to 2.0 or 6.0 mg/kg/d., Main Outcomes and Measures: Change in time-to-stand (TTSTAND) velocity from dose-finding baseline to end of LTE study was the primary outcome. Efficacy assessments included timed function tests, 6-minute walk test, and NorthStar Ambulatory Assessment (NSAA). Participants with DMD treated with glucocorticoids from the Duchenne Natural History Study (DNHS) and NorthStar United Kingdom (NSUK) Network were matched and compared with participants in the LTE study receiving higher doses of vamorolone., Results: Among 46 boys with DMD who completed the dose-finding study, 41 boys (mean [SD] age, 5.33 [0.96] years) completed the LTE study. Among 21 participants treated with higher-dose (ie, ≥2.0 mg/kg/d) vamorolone consistently throughout the 6-month dose-finding and 24-month LTE studies with data available at 30 months, there was a decrease in mean (SD) TTSTAND velocity from baseline to 30 months (0.206 [0.070] rises/s vs 0.189 (0.124) rises/s), which was not a statistically significant change (-0.011 rises/s; CI, -0.068 to 0.046 rises/s). There were no statistically significant differences between participants receiving higher-dose vamorolone and matched participants in the historical control groups receiving glucocorticoid treatment (75 patients in DNHS and 110 patients in NSUK) over a 2-year period in NSAA total score change (0.22 units vs NSUK; 95% CI, -4.48 to 4.04]; P = .92), body mass index z score change (0.002 vs DNHS SD/mo; 95% CI, -0.006 to 0.010; P = .58), or timed function test change. Vamorolone at doses up to 6.0 mg/kg/d was well tolerated, with 5 of 46 participants discontinuing prematurely and for reasons not associated with study drug. Participants in the DNHS treated with glucocorticoids had significant growth delay in comparison with participants treated with vamorolone who had stable height percentiles (0.37 percentile/mo; 95% CI, 0.23 to 0.52 percentile/mo) over time., Conclusions and Relevance: This study found that vamorolone treatment was not associated with a change in TTSTAND velocity from baseline to 30 months among boys with DMD aged 4 to 7 years at enrollment. Vamorolone was associated with maintenance of muscle strength and function up to 30 months, similar to standard of care glucocorticoid therapy, and improved height velocity compared with growth deceleration associated with glucocorticoid treatment, suggesting that vamorolone may be an attractive candidate for treatment of DMD., Trial Registration: ClinicalTrials.gov Identifier: NCT03038399.

Background: Duchenne muscular dystrophy (DMD) is a rare, genetic disease caused by mutations in the DMD gene resulting in an absence of functional dystrophin protein. Viltolarsen, an exon 53 skipping therapy, has been shown to increase endogenous dystrophin levels. Herein, long-term (>2 years) functional outcomes in viltolarsen treated patients were compared to a matched historical control group., Objective: To evaluate long-term efficacy and safety of the anti-sense oligonucleotide viltolarsen in the treatment of patients with DMD amenable to exon 53 skipping therapy., Methods: This trial (NCT03167255) is the extension of a previously published 24-week trial in North America (NCT02740972) that examined dystrophin levels, timed function tests compared to a matched historical control group (Cooperative International Neuromuscular Research Group Duchenne Natural History Study, CINRG DNHS), and safety in boys 4 to < 10 years (N = 16) with DMD amenable to exon 53 skipping who were treated with viltolarsen. Both groups were treated with glucocorticoids. All 16 participants elected to enroll in this long-term trial (up to 192 weeks) to continue evaluation of motor function and safety., Results: Time to stand from supine and time to run/walk 10 meters showed stabilization from baseline through week 109 for viltolarsen-treated participants whereas the historical control group showed decline (statistically significant differences for multiple timepoints). Safety was similar to that observed in the previous 24-week trial, which was predominantly mild. There have been no treatment-related serious adverse events and no discontinuations., Conclusions: Based on these results at over 2 years, viltolarsen can be a new treatment option for patients with DMD amenable to exon 53 skipping.

This phase 2, double-blind, placebo-controlled, hypothesis-generating study evaluated the effects of oral reldesemtiv, a fast skeletal muscle troponin activator, in patients with spinal muscular atrophy (SMA). Patients ≥ 12 years of age with type II, III, or IV SMA were randomized into 2 sequential, ascending reldesemtiv dosing cohorts (cohort 1: 150 mg bid or placebo [2:1]; cohort 2: 450 mg bid or placebo [2:1]). The primary objective was to determine potential pharmacodynamic effects of reldesemtiv on 8 outcome measures in SMA, including 6-minute walk distance (6MWD) and maximum expiratory pressure (MEP). Changes from baseline to weeks 4 and 8 were determined. Pharmacokinetics and safety were also evaluated. Patients were randomized to reldesemtiv 150 mg, 450 mg, or placebo (24, 20, and 26, respectively). The change from baseline in 6MWD was greater for reldesemtiv 450 mg than for placebo at weeks 4 and 8 (least squares [LS] mean difference, 35.6 m [p = 0.0037] and 24.9 m [p = 0.058], respectively). Changes from baseline in MEP at week 8 on reldesemtiv 150 and 450 mg were significantly greater than those on placebo (LS mean differences, 11.7 [p = 0.038] and 13.2 cm H 2 O [p = 0.03], respectively). For 6MWD and MEP, significant changes from placebo were seen in the highest reldesemtiv peak plasma concentration quartile (C max  > 3.29 μg/mL; LS mean differences, 43.3 m [p = 0.010] and 28.8 cm H 2 O [p = 0.0002], respectively). Both dose levels of reldesemtiv were well tolerated. Results suggest reldesemtiv may offer clinical benefit and support evaluation in larger SMA patient populations., (© 2021. The Author(s).)

Aims: To evaluate the cost-effectiveness of fingolimod versus interferon (IFN)-β1a at a dose of 30 μg per week for the treatment of relapsing pediatric-onset multiple sclerosis (POMS) in Canada., Material and Methods: A discrete-time Markov model was developed to compare fingolimod with IFN β-1a over a time horizon of two years representing patients followed up to mean age of 18 years from a Canadian health care system perspective. Twenty-one health states based on the Expanded Disability Status Scale (EDSS) were considered: EDSS 0‒9 for relapsing multiple sclerosis (MS), EDSS 0‒9 for secondary progressive MS, and "Death." Relative treatment efficacy for fingolimod versus IFN-β1a was estimated from the PARADIGMS study. Costs and resource use were obtained from published literature and Canadian sources. Utilities were estimated by mapping the Pediatric Quality of Life inventory data onto the Child Health Utility Index-9 Dimension using a published mapping algorithm. Future costs and benefits were discounted at 1.5% per annum., Results: Compared with IFN β-1a, fingolimod led to an increase in quality-adjusted life-years (QALYs) (0.125) with incremental costs (Canadian dollars [CAD] 2,977) and to an incremental cost-effectiveness ratio (ICER) of CAD 23,886/QALY over a time horizon of two years representing patients followed up to mean age of 18 years. The monetary benefits of fingolimod treatment versus IFN β-1a at a willingness-to-pay (WTP) threshold of CAD 50,000 per QALY gained were higher than the costs. One-way sensitivity analysis and probabilistic sensitivity analysis (PSA) both confirmed the robustness of the results., Limitations: The main limitations of this analysis primarily stem from the limited data availability in POMS., Conclusions: Fingolimod is cost effective compared with IFN β-1a for the treatment of POMS over a time horizon of two years representing patients followed up to a mean age of 18 years in Canada.

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.

Objective: To study vamorolone, a first-in-class steroidal anti-inflammatory drug, in Duchenne muscular dystrophy (DMD)., Methods: An open-label, multiple-ascending-dose study of vamorolone was conducted in 48 boys with DMD (age 4-<7 years, steroid-naive). Dose levels were 0.25, 0.75, 2.0, and 6.0 mg/kg/d in an oral suspension formulation (12 boys per dose level; one-third to 10 times the glucocorticoid dose in DMD). The primary goal was to define optimal doses of vamorolone. The primary outcome for clinical efficacy was time to stand from supine velocity., Results: Oral administration of vamorolone at all doses tested was safe and well tolerated over the 24-week treatment period. The 2.0-mg/kg/d dose group met the primary efficacy outcome of improved muscle function (time to stand; 24 weeks of vamorolone treatment vs natural history controls), without evidence of most adverse effects of glucocorticoids. A biomarker of bone formation, osteocalcin, increased in vamorolone-treated boys, suggesting possible loss of bone morbidities seen with glucocorticoids. Biomarker outcomes for adrenal suppression and insulin resistance were also lower in vamorolone-treated patients with DMD relative to published studies of glucocorticoid therapy., Conclusions: Daily vamorolone treatment suggested efficacy at doses of 2.0 and 6.0 mg/kg/d in an exploratory 24-week open-label study., Classification of Evidence: This study provides Class IV evidence that for boys with DMD, vamorolone demonstrated possible efficacy compared to a natural history cohort of glucocorticoid-naive patients and appeared to be tolerated., (Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular condition caused by mutations in the dystrophin gene leading to skeletal muscle weakness and dilated cardiomyopathy. The prevalence of DMD-related cardiomyopathy increases with age and is almost universal by the third decade of life. Myocardial fibrosis and progressive left ventricular dysfunction lead to the development of heart failure and premature death. With modern advances in medical and surgical management for patients with DMD increasing their life expectancy, cardiac dysfunction represents an increasing cause of morbidity and mortality in these patients. Early diagnosis of dilated cardiomyopathy before symptom development enables the initiation of potentially disease-modifying therapies, but requires regular dedicated imaging surveillance with sufficient sensitivity to detect subclinical changes in cardiac structure and function. Currently, transthoracic echocardiography (TTE) and cardiac magnetic resonance imaging (CMR) are commonly used and have complementary roles. TTE is rapid and readily available, whereas CMR is the gold standard for the quantification of ventricular structure and function and can detect the presence and extent of myocardial fibrosis, an increasingly appreciated marker for early disease. This review describes the clinical applications, advantages, and disadvantages of cardiac imaging screening and surveillance for the myocardial manifestations of DMD, with a particular focus on TTE and CMR.

Aims/hypothesis: Small cohort studies raise the hypothesis that corneal nerve abnormalities (including corneal nerve fibre length [CNFL]) are valid non-invasive imaging endpoints for diabetic sensorimotor polyneuropathy (DSP). We aimed to establish concurrent validity and diagnostic thresholds in a large cohort of participants with and without DSP., Methods: Nine hundred and ninety-eight participants from five centres (516 with type 1 diabetes and 482 with type 2 diabetes) underwent CNFL quantification and clinical and electrophysiological examination. AUC and diagnostic thresholds were derived and validated in randomly selected samples using receiver operating characteristic analysis. Sensitivity analyses included latent class models to address the issue of imperfect reference standard., Results: Type 1 and type 2 diabetes subcohorts had mean age of 42 ± 19 and 62 ± 10 years, diabetes duration 21 ± 15 and 12 ± 9 years and DSP prevalence of 31% and 53%, respectively. Derivation AUC for CNFL was 0.77 in type 1 diabetes (p < 0.001) and 0.68 in type 2 diabetes (p < 0.001) and was approximately reproduced in validation sets. The optimal threshold for automated CNFL was 12.5 mm/mm 2 in type 1 diabetes and 12.3 mm/mm 2 in type 2 diabetes. In the total cohort, a lower threshold value below 8.6 mm/mm 2 to rule in DSP and an upper value of 15.3 mm/mm 2 to rule out DSP were associated with 88% specificity and 88% sensitivity., Conclusions/interpretation: We established the diagnostic validity and common diagnostic thresholds for CNFL in type 1 and type 2 diabetes. Further research must determine to what extent CNFL can be deployed in clinical practice and in clinical trials assessing the efficacy of disease-modifying therapies for DSP.

Background: Trials in rare diseases have many challenges, among which are the need to set up multiple sites in different countries to achieve recruitment targets and the divergent landscape of clinical trial regulations in those countries. Over the past years, there have been initiatives to facilitate the process of international study set-up, but the fruits of these deliberations require time to be operationally in place. FOR-DMD (Finding the Optimum Steroid Regimen for Duchenne Muscular Dystrophy) is an academic-led clinical trial which aims to find the optimum steroid regimen for Duchenne muscular dystrophy, funded by the National Institutes of Health (NIH) for 5 years (July 2010 to June 2015), anticipating that all sites (40 across the USA, Canada, the UK, Germany and Italy) would be open to recruitment from July 2011. However, study start-up was significantly delayed and recruitment did not start until January 2013., Method: The FOR-DMD study is used as an example to identify systematic problems in the set-up of international, multi-centre clinical trials. The full timeline of the FOR-DMD study, from funding approval to site activation, was collated and reviewed. Systematic issues were identified and grouped into (1) study set-up, e.g. drug procurement; (2) country set-up, e.g. competent authority applications; and (3) site set-up, e.g. contracts, to identify the main causes of delay and suggest areas where anticipatory action could overcome these obstacles in future studies., Results: Time from the first contact to site activation across countries ranged from 6 to 24 months. Reasons of delay were universal (sponsor agreement, drug procurement, budgetary constraints), country specific (complexity and diversity of regulatory processes, indemnity requirements) and site specific (contracting and approvals). The main identified obstacles included (1) issues related to drug supply, (2) NIH requirements regarding contracting with non-US sites, (3) differing regulatory requirements in the five participating countries, (4) lack of national harmonisation with contracting and the requirement to negotiate terms and contract individually with each site and (5) diversity of languages needed for study materials. Additionally, as with many academic-led studies, the FOR-DMD study did not have access to the infrastructure and expertise that a contracted research organisation could provide, organisations often employed in pharmaceutical-sponsored studies. This delay impacted recruitment, challenged the clinical relevance of the study outcomes and potentially delayed the delivery of the best treatment to patients., Conclusion: Based on the FOR-DMD experience, and as an interim solution, we have devised a checklist of steps to not only anticipate and minimise delays in academic international trial initiation but also identify obstacles that will require a concerted effort on the part of many stakeholders to mitigate.

Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy in childhood. Mutations of the DMD gene destabilize the dystrophin associated glycoprotein complex in the sarcolemma. Ongoing mechanical stress leads to unregulated influx of calcium ions into the sarcoplasm, with activation of proteases, release of proinflammatory cytokines, and mitochondrial dysfunction. Cumulative damage and reparative failure leads to progressive muscle necrosis, fibrosis, and fatty replacement. Although there is presently no cure for DMD, scientific advances have led to many potential disease-modifying treatments, including dystrophin replacement therapies, upregulation of compensatory proteins, anti-inflammatory agents, and other cellular targets. Recently approved therapies include ataluren for stop codon read-through and eteplirsen for exon 51 skipping of eligible individuals. The purpose of this chapter is to summarize the clinical features of DMD, to describe current outcome measures used in clinical studies, and to highlight new emerging therapies for affected individuals.

Purpose of Review: This article uses a case-based approach to highlight the clinical features as well as recent advances in molecular genetics, muscle imaging, and pathophysiology of the congenital myopathies., Recent Findings: Congenital myopathies refer to a heterogeneous group of genetic neuromuscular disorders characterized by early-onset muscle weakness, hypotonia, and developmental delay. Congenital myopathies are further classified into core myopathies, centronuclear myopathies, nemaline myopathies, and congenital fiber-type disproportion based on the key pathologic features found in muscle biopsies. Genotype and phenotype correlations are hampered by the diverse clinical variability of the genes responsible for congenital myopathies, ranging from a severe neonatal course with early death to mildly affected adults with late-onset disease. An increasing number of genes have been identified, which, in turn, are associated with overlapping morphologic changes in the myofibers. Precise genetic diagnosis has important implications for disease management, including family counseling; avoidance of anesthetic-related muscle injury for at-risk individuals; monitoring for potential cardiac, respiratory, or orthopedic complications; as well as for participation in clinical trials or potential genetic therapies., Summary: Collaboration with neuromuscular experts, geneticists, neuroradiologists, neuropathologists, and other specialists is needed to ensure accurate and timely diagnosis based on clinical and pathologic features. An integrated multidisciplinary model of care based on expert-guided standards will improve quality of care and optimize outcomes for patients and families with congenital myopathies.

Background: The muscular dystrophies are a heterogeneous group of genetic muscle diseases with variable distribution of weakness and mode of inheritance., Methods: We previously performed a systematic review of worldwide population-based studies on Duchenne and Becker muscular dystrophies; the current study focused on the epidemiology of other muscular dystrophies using Medline and EMBASE databases. Two reviewers independently reviewed all abstracts, full-text articles, and abstracted data from 1985 to 2011. Pooling of prevalence estimates was performed using random-effect models., Results: A total of 1104 abstracts and 167 full-text articles were reviewed. Thirty-one studies met all eligibility criteria and were included in the final analysis. The overall pooled prevalence of combined muscular dystrophies was 16.14 (confidence interval [CI], 11.21-23.23) per 100,000. The prevalence estimates per 100,000 were 8.26 (CI, 4.99-13.68) for myotonic dystrophy, 3.95 (CI, 2.89-5.40) for facioscapulohumeral dystrophy, 1.63 (CI, 0.94-2.81) for limb girdle muscular dystrophy, and 0.99 (CI, 0.62-1.57) for congenital muscular dystrophies., Conclusions: The studies differed widely in their approaches to case ascertainment, and substantial gaps remain in the global estimates of many other types of muscular dystrophies. Additional epidemiological studies using standardized diagnostic criteria as well as multiple sources of case ascertainment will help address the economic impact and health care burden of muscular dystrophies worldwide.

Purpose: The purpose of this study was to comprehensively review the literature addressing the physiological effects of hypothermia and its association with the appropriate core body temperature for extubation following coronary artery bypass surgery., Methods: The electronic databases MEDLINE, CINAHL and Web of Science via OVID were used to identify studies for the literature review. Search words used included 'core temperature', 'arrhythmia', 'cardiac', 'cardiac surgery', 'hypothermia', 'extubation', 'temperature', 'rewarming', and 'shivering'., Results: The literature search yielded 55 articles that met our inclusion criteria. No studies specifically identified the benefit of extubation at 36.5 ° C. Although temperatures varied, arrhythmias resulting from hypothermia were not reported until core body temperature dropped below 33 ° C., Conclusion: This comprehensive literature review suggests extubation at lower temperatures (between 34 ° C and 36 ° C) may be viable if shivering and other factors known to contribute to myocardial stress can be controlled. These findings offer the possibility of earlier extubation which may promote beneficial health outcomes., (Copyright © 2014 Elsevier Inc. All rights reserved.)

It is expected that serum protein biomarkers in Duchenne muscular dystrophy (DMD) will reflect disease pathogenesis, progression and aid future therapy developments. Here, we describe use of quantitative in vivo stable isotope labeling in mammals to accurately compare serum proteomes of wild-type and dystrophin-deficient mdx mice. Biomarkers identified in serum from two independent dystrophin-deficient mouse models (mdx-Δ52 and mdx-23) were concordant with those identified in sera samples of DMD patients. Of the 355 mouse sera proteins, 23 were significantly elevated and 4 significantly lower in mdx relative to wild-type mice (P-value < 0.001). Elevated proteins were mostly of muscle origin: including myofibrillar proteins (titin, myosin light chain 1/3, myomesin 3 and filamin-C), glycolytic enzymes (aldolase, phosphoglycerate mutase 2, beta enolase and glycogen phosphorylase), transport proteins (fatty acid-binding protein, myoglobin and somatic cytochrome-C) and others (creatine kinase M, malate dehydrogenase cytosolic, fibrinogen and parvalbumin). Decreased proteins, mostly of extracellular origin, included adiponectin, lumican, plasminogen and leukemia inhibitory factor receptor. Analysis of sera from 1 week to 7 months old mdx mice revealed age-dependent changes in the level of these biomarkers with most biomarkers acutely elevated at 3 weeks of age. Serum analysis of DMD patients, with ages ranging from 4 to 15 years old, confirmed elevation of 20 of the murine biomarkers in DMD, with similar age-related changes. This study provides a panel of biomarkers that reflect muscle activity and pathogenesis and should prove valuable tool to complement natural history studies and to monitor treatment efficacy in future clinical trials., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: The chronic cerebrospinal venous insufficiency theory proposes that altered cerebral venous hemodynamics play a role in the pathophysiology of multiple sclerosis. We aimed to explore the validity of this hypothesis by assessing the diagnostic criteria for chronic cerebrospinal venous insufficiency in persons with and without multiple sclerosis., Methods: We compared the proportion of venous outflow abnormalities between patients with multiple sclerosis and healthy controls using extracranial Doppler ultrasonography and gadolinium-enhanced magnetic resonance venography. Interpreting radiologists were blinded to the clinical status of participants., Results: We enrolled 120 patients with multiple sclerosis and 60 healthy controls. High proportions of both patients (67/115 [58%]) and controls (38/60 [63%]) met 1 or more of the proposed ultrasound criteria for diagnosis of chronic cerebrospinal venous insufficiency (p = 0.6). A minority of patients (23/115 [20%]) and controls (6/60 [10%]) fulfilled 2 or more of the proposed criteria (p = 0.1). There were no differences between patients and controls in the prevalence of each individual ultrasound criterion. Similarly, there were no differences in intracranial or extracranial venous patency between groups, as measured by magnetic resonance venography., Interpretation: We detected no differences in the proportion of venous outflow abnormalities between patients with multiple sclerosis and healthy controls. Moreover, our study revealed significant methodologic concerns regarding the proposed diagnostic criteria for chronic cerebrospinal venous insufficiency that challenge their validity., (© 2014 Canadian Medical Association or its licensors.)

The muscular dystrophies are a broad group of hereditary muscle diseases with variable severity. Population-based prevalence estimates have been reported but pooled estimates are not available. We performed a systematic review of worldwide population-based studies reporting muscular dystrophies prevalence and/or incidence using MEDLINE and EMBASE databases. The search strategy included key terms related to muscular dystrophies, incidence, prevalence and epidemiology. Two reviewers independently reviewed all abstracts, full text articles and abstracted data using standardized forms. Pooling of prevalence estimates was performed using random effect models. 1104 abstracts and 167 full text articles were reviewed. Thirty-one studies met all eligibility criteria and were included in the final analysis. The studies differed widely in their approaches to case ascertainment, resulting in significant methodological heterogeneity and varied data quality. The pooled prevalence of DMD and BMD was 4.78 (95% CI 1.94-11.81) and 1.53 (95% CI 0.26-8.94) per 100,000 males respectively. The incidence of DMD ranged from 10.71 to 27.78 per 100,000. This is the first meta-analysis of worldwide prevalence estimates for muscular dystrophies. There is a need for more epidemiological studies addressing global estimates on incidence and prevalence of muscular dystrophies, utilizing standardized diagnostic criteria as well as multiple sources of case ascertainment., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The worldwide burden of diabetes and its complications in children continues to increase due to the rise in type 1 and type 2 diabetes. Although overt diabetic neuropathy is rarely present in children and adolescents with diabetes, subclinical diabetic neuropathy has been estimated to occur in approximately half of all children with type 1 diabetes with a duration of 5 years or longer and up to 25% of pediatric patients with newly diagnosed diabetes have abnormal findings on nerve conduction studies. The present review on the state of pediatric diabetic neuropathy covers the definition, prevalence, pathogenesis, diagnosis, risk factors, and possible treatment approaches specific to children and adolescents with diabetes. It also highlights the many unknowns in this field. Nonetheless, new emerging interventions that can either prevent or delay the progression of diabetic microvascular and macrovascular complications may become available in the near future. Until specific interventions for diabetic neuropathy are available for use in children, it will be hard to justify screening for neuropathy other than through clinical assessment. Meanwhile, the search for quicker, easily administered, and quantifiable tests for diabetic neuropathy and efforts to establish valid pediatric norms for well-established measures used in adults will need to continue.

Angio-Seal is a vascular closure device designed for repairing arterial puncture sites used for various endovascular procedures. It has a better safety and efficacy profile compared to manual compression in the previous studies. However, there are significant complications that may arise from the use of Angio-Seal like infections, aneurysm formation, and vessel occlusion. Our case is a demonstration of one such complication. We conclude with a discussion of the present literature available with regards to the Angio-Seal device.

Despite an increase in the number of nurse practitioners (NPs) practising within the realm of cardiovascular care, roles and responsibilities of cardiovascular NPs in similar areas appear to be vast and variable. With the recent changes in certification and regulation of the NP role by the Canadian Nurses Association, there has been an attempt to standardize patient care practices. In the spring of 2005, the University of Alberta Hospital-based cardiovascular NPs conducted a national survey. This survey was the first formalized attempt to gather information on the practice patterns of cardiovascular NPs and determine if similarities in roles, responsibilities, manpower and patient workload existed across Canada. A survey was mailed out to all centres that were known to have cardiovascular NPs in their employ. An impressive response rate of 63% was obtained. As predicted, survey results reveal that roles and responsibilities of cardiovascular NPs are diverse and unique. One hundred per cent of respondents were Masters-prepared with 88% of cardiovascular NPs practising in a ward and/or outpatient setting. However, reporting structure, patient workload, clinical, educational, administrative, and research responsibilities were more diversified. The results of the survey may facilitate a better understanding of the NP role within the health care setting and in cardiovascular care. In turn, the findings may provide a basis by which to establish a template for developing future NP roles or enhancing existing NP roles in cardiovascular centres across Canada.

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