Windebank, Anthony J.

Abstract Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disorder with complex biology and significant clinical heterogeneity. Many preclinical and early phase ALS clinical trials have yielded promising results that could not be replicated in larger phase 3 confirmatory trials. One reason for the lack of reproducibility may be ALS biological and clinical heterogeneity. Therefore, in this review, we explore sources of ALS heterogeneity that may reduce statistical power to evaluate efficacy in ALS trials. We also review efforts to manage clinical heterogeneity, including use of validated disease outcome measures, predictive biomarkers of disease progression, and individual clinical risk stratification. We propose that personalized prognostic models with use of predictive biomarkers may identify patients with ALS for whom a specific therapeutic strategy may be expected to be more successful. Finally, the rapid application of emerging clinical and biomarker strategies may reduce heterogeneity, increase trial efficiency, and, in turn, accelerate ALS drug development.

Problem Case-based learning is an established means of educating students in law, business, and medicine; however, this methodology is not often applied to educating translational biomedical researchers. The application of case-based learning to translational biomedical research education allows scholars to actively engage with real-world material and apply their newfound knowledge as it is acquired. Approach Through the Mayo Clinic Center for Clinical and Translational Science (CCaTS), three courses were delivered in 2009–2017 which emphasized case-based learning in clinical and translational science, entrepreneurship, and individualized medicine. Quantitative measures collected in student course reviews upon course completion were analyzed. Additionally, products arising from each course were identified, including publications and startups pitched. Outcomes Analyses demonstrate that case-based learning techniques are well suited to graduate biomedical research education. Furthermore, case studies can be employed throughout the entire clinical and translational spectrum, from basic and preclinical work through to clinical and population-based learning. Next Steps Within CCaTS, next steps include creating case-based courses in regulatory and team science to continue to allow scholars to learn and apply these critical skills to real-world material. The goal is to continue to provide immersive training opportunities in areas of clinical and translational science that cannot be readily learned in a traditional lecture-based class setting.

ABSTRACTIntroduction: Multifocal motor neuropathy (MMN) is a motor only, asymmetric onset neuropathy that is relatively treatment‐refractory compared with classic chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and multifocal acquired demyelinating sensory and motor (MADSAM) neuropathy. Methods: We reviewed 35 patients seropositive for GM1 (monosialo‐asialo [immunoglobulin M, IgM; immunoglobulin G, IgG]) and/or GD1b (disialo [IgG, IgM]) autoantibodies having MMN, classic CIDP, or MADSAM. Immune‐treatment responsiveness and clinical course was compared with antibody negative disease controls. Results: Seventy‐nine percent of seropositives with an initial diagnosis of MMN were immunotherapy responsive compared with 46% of seronegatives (P = 0.045). Eight ganglioside antibody positive MMN patients of 19 (42%) developed sensory findings consistent with MADSAM compared with 3 of 41 (7%) seronegative MMN patients (P = 0.003). MMN and MADSAM patients with ganglioside antibody positivity had more sustained treatment responses (P = 0.03). Discussion: Patients initially diagnosed with MMN seropositive for diverse GM1 autoantibodies appear more likely to have sustained treatment response and evolution to MADSAM. Muscle Nerve 57: 1000–1005, 2018