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

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

Facilitators and Barriers for Implementing an Internet Clinic for the Treatment of Pressure Injuries.

Background: Pressure injuries (PIs) represent a frequent, often preventable, secondary complication of spinal cord injury (SCI) with serious consequences to health, societal participation, and quality of life. Specialized knowledge and service delivery related to treatment and prevention are typically located within major health centers.Introduction: For persons with SCI living at home, it can be challenging to access specialized PI care. A telehealth approach could help mitigate this challenge. This multisite pilot investigation assessed the feasibility of integrating information technologies within the management of PIs.Materials and Methods: Each study site formed a specialized interdisciplinary care team that identified components of their standard clinical care pathway and examined how they could be integrated with study technologies. A monitoring system was utilized to enable patients and caregivers to exchange clinical information with the care team.Results: Clinician and patient focus groups were completed to identify facilitators and barriers for long-term implementation. Findings demonstrate that this method of service delivery is feasible but requires further development.Discussion: This model of care requires refinement to address technological, regulatory, and clinician acceptance barriers; however, increased access to these services has the potential for improving PI healing or prevention rates in comparison with those not able to access specialized services.Conclusions: This project demonstrates that PI treatment services can be delivered effectively through the internet. Future trials can investigate efficacy and cost-effectiveness of this model of care to inform sustained implementation.

Provincial Differences in the Diagnosis and Care of Amyotrophic Lateral Sclerosis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease resulting in muscle weakness, dysarthria and dysphagia, and ultimately respiratory failure leading to death. Half of the ALS patients survive less than 3 years, and 80% of the patients survive less than 5 years. Riluzole is the only approved medication in Canada with randomized controlled clinical trial evidence to slow the progression of ALS, albeit only to a modest degree. The Canadian Neuromuscular Disease Registry (CNDR) collects data on over 140 different neuromuscular diseases including ALS across ten academic institutions and 28 clinics including ten multidisciplinary ALS clinics. METHODS: In this study, CNDR registry data were analyzed to examine potential differences in ALS care among provinces in time to diagnosis, riluzole and feeding tube use. RESULTS: Significant differences were found among provinces, in time to diagnosis from symptom onset, in the use of riluzole and in feeding tube use. CONCLUSIONS: Future investigations should be undertaken to identify factors contributing to such differences, and to propose potential interventions to address the provincial differences reported.

Dalteparin vs low-dose unfractionated heparin for prophylaxis against clinically evident venous thromboembolism in acute traumatic spinal cord injury: a retrospective cohort study.

BACKGROUND: When venous thromboembolism (VTE) includes deep-vein thrombosis (DVT) and pulmonary embolism (PE), patients with acute traumatic spinal cord injury (SCI) have the highest incidence of VTE among all hospitalized groups, with PE the third most common cause of death. Although low-molecular-weight heparin (LMWH) outperforms low-dose unfractionated heparin (LDUH) in other patient populations, the evidence in SCI remains less robust. OBJECTIVE: To determine whether the efficacy for LMWH shown in previous SCI surveillance studies (eg, routine Doppler ultrasound) would translate into real-world effectiveness in which only clinically evident VTE is investigated (ie, after symptoms or signs present). METHODS: A retrospective cohort study was conducted of 90 patients receiving LMWH dalteparin (5,000 U daily) or LDUH (5,000 U twice daily) for VTE prophylaxis after acute traumatic SCI. The incidence of radiographically confirmed VTE was primarily analyzed, and secondary outcomes included complications of bleeding and heparin-induced thrombocytopenia. RESULTS: There was no statistically significant association (p = 0.7054) between the incidence of VTE (7.78% overall) and the type of prophylaxis received (LDUH 3/47 vs dalteparin 4/43). There was no significant differences in complications, location of VTE, and incidence of fatal PE. Paraplegia (as opposed to tetraplegia) was the only risk factor identified for VTE. CONCLUSIONS: There continues to be an absence of definitive evidence for dalteparin (or other LMWH) over LDUH as the choice for VTE prophylaxis in patients with SCI. Novel approaches to VTE prophylaxis are urgently required for this population, whose risk of fatal PE has not decreased over the last 25 years.

Wheeling à petit pas: Parkinsonism detected by observation of wheelchair propulsion.

We present a man with parkinsonism detected by the observation of wheelchair propulsion. His manual wheelchair propulsion technique was observed to include rapid, brief, low-power strokes resembling the marche à petit pas (walking with tiny steps) phenomenon of parkinsonism. We videotaped his wheelchair propulsion and compared him with ten age-, gender-, and diagnosis-matched controls. The patient had a propulsion velocity of 0.14 m/sec compared with a mean (+/- standard deviation) of 0.73 (+/- 0.16) m/sec for the controls, a cadence of 209 strokes/min vs. 60 (+/- 12) strokes/min for the controls, and a mechanical efficiency of 0.04 m/stroke compared with 0.75 (+/- 0.25) m/stroke for the controls. This observation shifted the course of his medical investigations and management as well as his rehabilitation care. This is the first detailed report of how parkinsonian features may affect manual wheelchair propulsion. It suggests that observation of wheelchair mobility should be a routine component of the physical examination of wheelchair users.

Structure and cooperativity of a T-state mutant of histidine decarboxylase from Lactobacillus 30a.

Histidine decarboxylase (HDC) from Lactobacillus 30a converts histidine to histamine, a process that enables the bacteria to maintain the optimum pH range for cell growth. HDC is regulated by pH; it is active at low pH and inactive at neutral to alkaline pH. The X-ray structure of HDC at pH 8 revealed that a helix was disordered, resulting in the disruption of the substrate-binding site. The HDC trimer has also been shown to exhibit cooperative kinetics at neutral pH, that is, histidine can trigger a T-state to R-state transition. The D53,54N mutant of HDC has an elevated Km, even at low pH, indicating that the enzyme assumes the low activity T-state. We have solved the structures of the D53,54N mutant at low pH, with and without the substrate analog histidine methyl ester (HME) bound. Structural analysis shows that the apo-D53,54N mutant is in the inactive or T-state and that binding of the substrate analog induces the enzyme to adopt the active or R-state. A mechanism for the cooperative transition is proposed.