Significance Our results demonstrate that connexin 43 hemichannels are the conduits for amyotrophic lateral sclerosis (ALS) astrocyte-mediated motor neuron toxicity and disease spread, acting as a common mechanism that can target both familial ALS and sporadic ALS populations. Furthermore, our present work provides proof of principle that tonabersat, as a drug already studied in clinical trials for other indications, could serve as a potential ALS therapeutic.

Objective To determine the clinical and molecular features in patients with amyotrophic lateral sclerosis 4 (ALS4) due to mutations in the senataxin (SETX) gene and to develop tools for evaluating SETX variants. Methods Our study involved 32 patients, including 31 with mutation in SETX at c.1166 T>C (p.Leu389Ser) and 1 with mutation at c.1153 G>A (p.Glu385Lys). Clinical characterization of the patients included neurological examination, blood tests, magnetic resonance imaging (MRI), and dual‐energy x‐ray absorptiometry (DEXA). Fibroblasts and motor neurons were obtained to model the disease and characterize the molecular alteration in senataxin function. Results We report key clinical features of ALS4. Laboratory analysis showed alteration of serum creatine kinase and creatinine in the Leu389Ser ALS4 cohort. MRI showed increased muscle fat fraction in the lower extremities, which correlates with disease duration (thigh fat fraction R2 = 0.35, p = 0.01; lower leg fat fraction R2 = 0.49, p < 0.01). DEXA measurements showed lower extremities are more affected than upper extremities (average fat z scores of 2.1 and 0.6, respectively). A cellular assay for SETX function confirmed that like the Leu389Ser mutation, the Glu385Lys variant leads to a decrease in R loops, likely from a gain of function. Interpretation We identified clinical laboratory and radiological features of ALS4, and hence they should be monitored for disease progression. The molecular characterization of R‐loop levels in patient‐derived cells provides insight into the disease pathology and assays to evaluate the pathogenicity of candidate mutations in the SETX gene. ANN NEUROL 2020;87:547–555

Background: With the expanding accessibility of online health-care information, patients frequently report visiting physician rating websites before choosing a surgeon. As such, it is important to analyze patients' perception of arthroplasty surgeons as reflected on physician rating websites. Methods: A total of 6402 online reviews of arthroplasty surgeons were extracted for analysis. Each review rated less than 5 on a 5-point scale was deemed a "negative" review and was subsequently assigned to an appropriate category. Reviews were stratified by practice type, years in practice, gender, and low (<3) vs high (> 3) ratings. Results: A total of 6402 reviews comprising 315 physicians were included in the analysis. The average rating for all surgeons was 4.35. The average rating for physicians in private practice was 4.3, compared to 4.5 for those in an academic setting. The average rating for physicians in practice for 1-10 years was 4.46, compared to 4.03 for those with >10 years of experience (P < .001). The most common factors contributing to negative reviews were bedside manner, wait time, poor outcome, and surgeon proficiency. Surgeon-dependent factors were more commonly associated with lower rated reviews (P < .001). Conclusions: Arthroplasty surgeons typically receive high online ratings, with a mean of 4.35 on a 5-point scale. Physicians in academic practice received higher ratings than those in private practice, and physicians who have been in practice for 1-10 years received higher ratings than those with more than 10 years in practice. The most common factors contributing to negative reviews are surgeon-dependent, including bedside manner, poor outcome, and surgeon proficiency.