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Axon loss underlies symptom onset and progression in many neurodegenerative disorders. Axon degeneration in injury and disease is promoted by activation of the NAD-consuming enzyme SARM1. Here, we report a novel activator of SARM1, a metabolite of the pesticide and neurotoxin vacor. Removal of SARM1 completely rescues mouse neurons from vacor-induced neuron and axon death in vitro and in vivo. We present the crystal structure of the Drosophila SARM1 regulatory domain complexed with this activator, the vacor metabolite VMN, which as the most potent activator yet known is likely to support drug development for human SARM1 and NMNAT2 disorders. This study indicates the mechanism of neurotoxicity and pesticide action by vacor, raises important questions about other pyridines in wider use today, provides important new tools for drug discovery, and demonstrates that removing SARM1 can robustly block programmed axon death induced by toxicity as well as genetic mutation.

Background Many trainees plan pregnancy during fellowship training. A study of internal medicine program directors (PDs) demonstrated frequent misinterpretation of American Board of Internal Medicine (ABIM) leave policies when applied to parental leave. The ABIM has since attempted to clarify its leave and deficits in training policies. The primary aim of this study was to investigate how infectious disease (ID) program directors interpret the current ABIM leave policies in crafting parental leave for trainees. Methods We surveyed 155 ID program directors in an online, anonymous questionnaire regarding their knowledge of ABIM leave policies and application toward trainees’ leaves of absence. Results 75/155 (48%) of program directors responded to the survey. Most respondents incorrectly identified the leave limits permitted by ABIM policies, and a majority mistakenly chose to extend training when a clinically competent fellow was within their allowed duration of leave.(Figure 1) Most respondents correctly identified that equal time is permitted for both birth and non-birth parent parental leave, however, reported leave durations did not reflect this equity. PDs reported the majority (60.4%) of ID trainee maternity/birth parent leaves at their programs were ≤7weeks and 4.6% were≤3 weeks, while only 7% were≥12 weeks. In contrast, 50% of paternity/non birth parent leaves were ≤3weeks and none were ≥12 weeks. (Figure 2) PDs utilize various strategies to prevent extending training for fellows taking parental leaves that exceed the limits allowed by ABIM policies, including creating “home electives,” though 34% counsel trainees to take “a shorter maternity leave.” Conclusion Fellowship program directors often misinterpret ABIM leave policies, and misapply them when given example scenarios. These findings have clear implications for trainees’ family planning and may lead to shortened parental leaves and inappropriate fellowship training extensions. Disclosures All Authors: No reported disclosures