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Background and Purpose: Inhibitors of voltage‐gated sodium channels (NaVs) are important anti‐epileptic drugs, but the contribution of specific channel isoforms is unknown since available inhibitors are non‐selective. We aimed to create novel, isoform selective inhibitors of Nav channels as a means of informing the development of improved antiseizure drugs. Experimental Approach: We created a series of compounds with diverse selectivity profiles enabling block of NaV1.6 alone or together with NaV1.2. These novel NaV inhibitors were evaluated for their ability to inhibit electrically evoked seizures in mice with a heterozygous gain‐of‐function mutation (N1768D/+) in Scn8a (encoding NaV1.6) and in wild‐type mice. Key Results: Pharmacologic inhibition of NaV1.6 in Scn8aN1768D/+ mice prevented seizures evoked by a 6‐Hz shock. Inhibitors were also effective in a direct current maximal electroshock seizure assay in wild‐type mice. NaV1.6 inhibition correlated with efficacy in both models, even without inhibition of other CNS NaV isoforms. Conclusions and Implications: Our data suggest NaV1.6 inhibition is a driver of efficacy for NaV inhibitor anti‐seizure medicines. Sparing the NaV1.1 channels of inhibitory interneurons did not compromise efficacy. Selective NaV1.6 inhibitors may provide targeted therapies for human Scn8a developmental and epileptic encephalopathies and improved treatments for idiopathic epilepsies. [ABSTRACT FROM AUTHOR]

Objective: The authors determined the prevalence of stress, depression, and burnout in medical students and the resources used by students in one school to alleviate psychological distress. Methods: A survey was administered to 526 students in the first 3 years of medical school (336 responders; response rate: 70%) at one institution, using a modified Maslach Burnout Inventory Human Services Survey (MBI-HSS), the two-question PRIME-MD depression screening survey, the Perceived Medical School Stress Scale, along with questions on demographics and helpful programs to cope with stress. Results: The percentage of respondents scoring in the High Burnout range was approximately 55% for all three subscales. Depressive symptoms were reported by 60% of respondents. The most helpful coping mechanisms reported were social support from peers and faculty, counseling services, and extracurricular activities. Conclusions: The prevalences of burnout, depression, and stress were higher in this sample of first- through third-year medical students when compared with other medical student groups previously studied. Important limitations of this research included the fact that it was cross-sectional in design and that the PRIME-MD tool is simply a screening tool and does not diagnose major depression. Medical educators, deans, and administrators should appreciate the possibility of higher levels of psychological distress among their own students than those previously reported. (Contains 1 table.)

This article discusses the role of upfront cytoreductive nephrectomy (CN) in the treatment of metastatic renal cell carcinoma. The authors present the results of their pooled analysis of three clinical trials, which showed that CN prior to systemic treatment with immune checkpoint inhibitors and anti-angiogenic therapy was associated with improved progression-free survival (PFS) and overall survival (OS). These findings support the use of CN as a first-line therapeutic option for metastatic renal cell carcinoma. The authors note that further research and data sharing are needed to fully understand the benefits of CN in this context. [Extracted from the article]

After previously discovering that the ion channel TRPA1 is used as an internal temperature sensor in Drosophila to control the slow response of flies to shallow thermal gradients, the authors show here that the rapid response of flies to steep warming gradients relies on a different protein, GR28B, providing the first example of a thermosensory role for a gustatory receptor. A novel thermosensor in Drosophila Flies use the TRPA1 ion channel as an internal temperature sensor to slowly adjust their response to shallow thermal gradients. Now Paul Garrity and colleagues show that the rapid response of flies exposed to steep warmth gradients does not require TRPA1, but instead relies on the gustatory receptor GR28B(D), acting in peripheral thermosensing cells. Gustatory receptors have been implicated in taste, olfaction and host-seeking by disease-vector insects, but have not previously been linked with thermosensation. Behavioural responses to temperature are critical for survival, and animals from insects to humans show strong preferences for specific temperatures.sup.1,2. Preferred temperature selection promotes avoidance of adverse thermal environments in the short term and maintenance of optimal body temperatures over the long term.sup.1,2, but its molecular and cellular basis is largely unknown. Recent studies have generated conflicting views of thermal preference in Drosophila, attributing importance to either internal.sup.3 or peripheral.sup.4 warmth sensors. Here we reconcile these views by showing that thermal preference is not a singular response, but involves multiple systems relevant in different contexts. We found previously that the transient receptor potential channel TRPA1 acts internally to control the slowly developing preference response of flies exposed to a shallow thermal gradient.sup.3. We now find that the rapid response of flies exposed to a steep warmth gradient does not require TRPA1; rather, the gustatory receptor GR28B(D) drives this behaviour through peripheral thermosensors. Gustatory receptors are a large gene family, widely studied in insect gustation and olfaction, and are implicated in host-seeking by insect disease vectors.sup.5,6,7, but have not previously been implicated in thermosensation. At the molecular level, GR28B(D) misexpression confers thermosensitivity upon diverse cell types, suggesting that it is a warmth sensor. These data reveal a new type of thermosensory molecule and uncover a functional distinction between peripheral and internal warmth sensors in this tiny ectotherm reminiscent of thermoregulatory systems in larger, endothermic animals.sup.2. The use of multiple, distinct molecules to respond to a given temperature, as observed here, may facilitate independent tuning of an animal's distinct thermosensory responses., Author(s): Lina Ni [sup.1] [sup.2] , Peter Bronk [sup.1] [sup.2] , Elaine C. Chang [sup.1] [sup.2] , April M. Lowell [sup.1] [sup.2] , Juliette O. Flam [sup.1] [sup.2] , Vincent [...]