101 research outputs found
Duchenne muscular dystrophy: Canadian paediatric neuromuscular physicians survey
Background: Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy in childhood. Method: To assess the current care of paediatric DMD patients in Canada, a questionnaire was mailed to 17 physicians who were members of the Canadian paediatric neuromuscular group. Areas of enquiry included; 1) multidisciplinary team composition; 2) means of DMD diagnosis; 3) corticosteroid use; surveillance and management for: 4) orthopaedic, 5) respiratory and 6) cardiac complications and 7) health maintenance (nutrition & immunizations). Results: Completed surveys were returned by 14/17 (82%) of physicians. Twelve respondents followed DMD patients. All centres had multidisciplinary teams, including respirology (11/12), child neurology or physiatry (11), physiotherapy (9), occupational therapy (9) and orthopaedic surgery (7). Deflazacort 0.9mg/kg/d was used at all centres, which was continued after loss of independent ambulation (11), along with routine calcium and vitamin D supplementation (10). Night splints were prescribed at all centres. Routine surveillance studies included pulmonary function testing (11), sleep studies (10), EKG/echocardiogram (10), bone density (DEXA) scans (10), spine radiography (9), and dietician referral (4). Conclusion: Paediatric DMD patients are receiving relatively consistent care in multidisciplinary clinics across Canada, in accordance with recommended guidelines for DMD
Π’ΡΡΠΏΠΎΡΠΏΠ°Π»Π΅Π½Π½Ρ ΡΠ΅ΡΠ½Π΅Π»ΡΠ²-ΡΡΡΡΠΊΠΎΠ³ΠΎ ΡΠ΅ΡΠ½ΡΡ ΡΠ²ΡΡΠΊΠΎΠ³ΠΎ ΠΌΠΎΠ³ΠΈΠ»ΡΠ½ΠΈΠΊΠ°
Π ΠΎΠ·Π³Π»ΡΠ½ΡΡΠΎ ΠΌΠ°ΡΠ΅ΡΡΠ°Π»ΠΈ ΠΊΠΎΠΌΠΏΠ»Π΅ΠΊΡΡΠ² ΡΠ· ΠΊΡΠ΅ΠΌΠ°ΡΡΡΠΌΠΈ ΡΠ΅ΡΠ½Π΅Π»ΡΠ²-ΡΡΡΡΠΊΠΎΠ³ΠΎ ΠΌΠΎΠ³ΠΈΠ»ΡΠ½ΠΈΠΊΠ° ΡΠ΅ΡΠ½ΡΡ
ΡΠ²ΡΡΠΊΠΎΡ ΠΊΡΠ»ΡΡΡΡΠΈ.Π ΡΡΠ°ΡΡΠ΅ ΡΠ°ΡΡΠΌΠΎΡΡΠ΅Π½Ρ ΠΌΠ°ΡΠ΅ΡΠΈΠ°Π»Ρ ΠΊΠΎΠΌΠΏΠ»Π΅ΠΊΡΠΎΠ² Ρ ΠΊΡΠ΅ΠΌΠ°ΡΠΈΡΠΌΠΈ ΡΠ΅ΡΠ½Π΅Π»ΠΈΠ²-ΡΡΡΡΠΊΠΎΠ³ΠΎ ΠΌΠΎΠ³ΠΈΠ»ΡΠ½ΠΈΠΊΠ° ΡΠ΅ΡΠ½ΡΡ
ΠΎΠ²ΡΠΊΠΎΠΉ ΠΊΡΠ»ΡΡΡΡΡ (ΠΠ°ΠΏΠ°Π΄Π½ΠΎΠ΅ ΠΠΎΠ΄ΠΎΠ»ΡΠ΅), ΠΊΠΎΡΠΎΡΡΠΉ ΠΎΡΠ½ΠΎΡΠΈΡΡΡ ΠΊ ΠΊΠ°ΡΠ΅Π³ΠΎΡΠΈΠΈ ΠΌΠΎΠ³ΠΈΠ»ΡΠ½ΠΈΠΊΠΎΠ² Ρ Π΄ΠΎΠΌΠΈΠ½ΠΈΡΠΎΠ²Π°Π½ΠΈΠ΅ΠΌ ΠΈΠ½Π³ΡΠΌΠ°ΡΠΈΠΉ, ΡΡΠΎ Π²ΡΠ΄Π΅Π»ΡΠ΅Ρ Π΅Π³ΠΎ ΡΡΠ΅Π΄ΠΈ Π±ΠΈΡΠΈΡΡΠ°Π»ΡΠ½ΡΡ
ΠΌΠΎΠ³ΠΈΠ»ΡΠ½ΠΈΠΊΠΎΠ² ΡΠ΅ΡΠ½ΡΡ
ΠΎΠ²ΡΠΊΠΎΠΉ ΠΊΡΠ»ΡΡΡΡΡ. ΠΠ· 288 ΠΈΡΡΠ»Π΅Π΄ΠΎΠ²Π°Π½Π½ΡΡ
ΠΏΠΎΠ³ΡΠ΅Π±Π΅Π½ΠΈΠΉ ΡΠ΅ΡΠ½ΡΡ
ΠΎΠ²ΡΠΊΠΎΠΉ ΠΊΡΠ»ΡΡΡΡΡ β ΡΠΎΠ»ΡΠΊΠΎ Π΄Π²Π΅ ΠΊΡΠ΅ΠΌΠ°ΡΠΈΠΈ (ΠΏΠΎΠ³ΡΠ΅Π±Π΅Π½ΠΈΡ 44 ΠΈ 240), ΡΡΠΎ ΡΠΎΡΡΠ°Π²Π»ΡΠ΅Ρ ΠΌΠ΅Π½Π΅Π΅ 1 % ΠΏΠΎΠ³ΡΠ΅Π±Π΅Π½ΠΈΠΉ ΠΌΠΎΠ³ΠΈΠ»ΡΠ½ΠΈΠΊΠ°. ΠΡΠΎΠΌΠ΅ ΡΠΎΠ³ΠΎ, Π² ΠΌΠΎΠ³ΠΈΠ»ΡΠ½ΠΈΠΊΠ΅ Π²ΡΡΠ²Π»Π΅Π½Ρ ΡΠΈΡΡΠ°Π»ΡΠ½ΠΎ Π½Π°ΡΡΡΠ΅Π½Π½ΡΠ΅ ΠΈΠ½Π³ΡΠΌΠ°ΡΠΈΠΈ, Π² Π·Π°ΠΏΠΎΠ»Π½Π΅Π½ΠΈΠΈ ΠΌΠΎΠ³ΠΈΠ»ΡΠ½ΡΡ
ΡΠΌ ΠΊΠΎΡΠΎΡΡΡ
Π·Π°ΡΠΈΠΊΡΠΈΡΠΎΠ²Π°Π½Ρ ΠΎΡΡΠ°ΡΠΊΠΈ ΠΊΡΠ΅ΠΌΠ°ΡΠΈΠΉ, ΡΡΠΎ, Π²ΠΎΠ·ΠΌΠΎΠΆΠ½ΠΎ, ΡΠ²ΡΠ·Π°Π½ΠΎ Ρ ΡΠΎΠΆΠΆΠ΅Π½ΠΈΠ΅ΠΌ ΡΠΊΡΠ³ΡΠΌΠΈΡΠΎΠ²Π°Π½Π½ΡΡ
ΡΠ°ΡΡΠ΅ΠΉ ΡΡΠΈΡ
ΠΈΠ½Π³ΡΠΌΠ°ΡΠΈΠΉ.The article views the materials from the assemblages with cremations in the burial ground Cherneliv-Rus of Chernyakhivska culture (Western Podillya). Cherneliv-Rus burial ground belongs to the category of burial grounds with inhumation prevailed and stands out against the biritual burial grounds of Chernyakhivska culture. There are only two cremations among 288 excavated burials of Chernyakhivska culture (burials 44 and 240). It comprises less than 1% of burials on the burial ground. The latter includes also ritually disturbed inhumations with the remains of cremations in the fi ll of burial pits, which could be related with the burning of exhumated parts of these inhumations
Efficacy and Safety of Viltolarsen in Boys With Duchenne Muscular Dystrophy: Results From the Phase 2, Open-Label, 4-Year Extension Study
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 ofβ\u3eβ4 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 toβ\u3cβ10 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
Dual-energy X-ray absorptiometry measures of lean body mass as a biomarker for progression in boys with Duchenne muscular dystrophy
We evaluated whether whole-body dual-energy X-ray absorptiometry (DXA) measures of lean body mass can be used as biomarkers for disease progression and treatment effects in patients with Duchenne muscular dystrophy. This post hoc analysis utilized data from a randomized, 2-period study of domagrozumab versus placebo in 120 ambulatory boys with DMD. DXA measures of lean body mass were obtained from the whole body (excluding head), arms, legs and appendicular skeleton at baseline and every 16Β weeks. Treatment effects on DXA measures for domagrozumab versus placebo were assessed at Week 49. At Week 49, domagrozumab statistically significantly increased lean body mass versus placebo in the appendicular skeleton (pβ=β0.050) and arms (pβ<β0.001). The relationship between lean body mass at Week 49 and functional endpoints at Week 97 was evaluated. Changes in lean body mass at Week 49 in all regions except arms were significantly correlated with percent change from baseline in 4-stair climb (4SC) at Week 97. DXA-derived percent lean mass at Week 49 also correlated with 4SC and North Star Ambulatory Assessment at Week 97. These data indicate that whole-body DXA measures can be used as biomarkers for treatment effects and disease progression in patients with DMD, and warrant further investigation.Trial registration: ClinicalTrials.gov, NCT02310763; registered 8 December 2014
Novel approaches to analysis of the North Star Ambulatory Assessment (NSAA) in Duchenne muscular dystrophy (DMD): Observations from a phase 2 trial
Introduction:
The North Star Ambulatory Assessment (NSAA) tool is a key instrument for measuring clinical outcomes in patients with Duchenne muscular dystrophy (DMD). To gain a better understanding of the longitudinal utility of the NSAA, we evaluated NSAA data from a phase II trial of 120 patients with DMD treated with domagrozumab or placebo.
Methods:
The NSAA exploratory analyses included assessment of individual skills gained/lost, total skills gained/lost, cumulative loss of function, and the impact of transient loss of function due to a temporary disability on NSAA total score (temporary zero score).
Results:
There was no significant difference in the total number of NSAA skills gained (mean 1.41 and 1.04, respectively; p = 0.3314) or lost (3.90 vs. 5.0; p = 0.0998) between domagrozumab- vs. placebo-treated patients at week 49. However, domagrozumab-treated patients were less likely to lose the ability to perform a NSAA item (hazard ratio 0.80, 95% confidence interval [CI]: 0.65β0.98, p = 0.029) over 48-weeks vs. placebo-treated patients. When temporary zero scores were changed to βnot obtainableβ (8 values from 7 patients), domagrozumab-treated patients scored higher on the NSAA total score versus placebo-treated patients (difference at week 49: 2.0, 95% CI: 0.1β3.9, p = 0.0359).
Conclusions:
These exploratory analyses reveal additional approaches to interpreting the NSAA data beyond just change in NSAA total score. These observations also highlight the importance of reporting items as βnot obtainableβ for a patient with a temporary/transient physical disability that impacts their ability to perform the NSAA test
Early onset facioscapulohumeral dystrophy - a systematic review using individual patient data
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
The Canadian Neuromuscular Disease Registry: Connecting Patients to National and International Research Opportunities
Introduction
Patient registries serve an important role in rare disease research, particularly for the recruitment and planning of clinical trials. The Canadian Neuromuscular Disease Registry was established with the primary objective of improving the future for neuromuscular (NM) patients through the enablement and support of research into potential treatments.
Methods
In this report, we discuss design and utilization of the Canadian Neuromuscular Disease Registry with special reference to the paediatric cohort currently enrolled in the registry.
Results
As of July 25, 2017, there are 658 paediatric participants enrolled in the registry, 249 are dystrophinopathies (229 are Duchenne muscular dystrophy), 57 are myotonic dystrophy participants, 98 spinal muscular atrophy participants and 65 are limb girdle muscular dystrophy. A total of 175 patients have another NM diagnosis. The registry has facilitated 20 clinical trial inquiries, 5 mail-out survey studies and 5 other studies in the paediatric population.
Discussion
The strengths of the registry are discussed. The registry has proven to be an invaluable tool to NM disease research and has increased Canadaβs visibility as a competitive location for the conduct of clinical trials for NM therapies
Quantitative magnetic resonance imaging measures as biomarkers of disease progression in boys with Duchenne muscular dystrophy: a phase 2 trial of domagrozumab
Duchenne muscular dystrophy (DMD) is a progressive, neuromuscular disorder caused by mutations in the DMD gene that results in a lack of functional dystrophin protein. Herein, we report the use of quantitative magnetic resonance imaging (MRI) measures as biomarkers in the context of a multicenter phase 2, randomized, placebo-controlled clinical trial evaluating the myostatin inhibitor domagrozumab in ambulatory boys with DMD (nβ=β120 aged 6 toβ<β16Β years). MRI scans of the thigh to measure muscle volume, muscle volume index (MVI), fat fraction, and T2 relaxation time were obtained at baseline and at weeks 17, 33, 49, and 97 as per protocol. These quantitative MRI measurements appeared to be sensitive and objective biomarkers for evaluating disease progression, with significant changes observed in muscle volume, MVI, and T2 mapping measures over time. To further explore the utility of quantitative MRI measures as biomarkers to inform longer term functional changes in this cohort, a regression analysis was performed and demonstrated that muscle volume, MVI, T2 mapping measures, and fat fraction assessment were significantly correlated with longer term changes in four-stair climb times and North Star Ambulatory Assessment functional scores. Finally, less favorable baseline measures of MVI, fat fraction of the muscle bundle, and fat fraction of lean muscle were significant risk factors for loss of ambulation over a 2-year monitoring period. These analyses suggest that MRI can be a valuable tool for use in clinical trials and may help inform future functional changes in DMD.Trial registration: ClinicalTrials.gov identifier, NCT02310763; registered December 2014
Large-scale serum protein biomarker discovery in Duchenne muscular dystrophy.
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 age-matched 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
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