Niemann-Pick disease type C1 (NPC1) is a rare autosomal recessive lysosomal storage disease primarily caused by mutations in NPC1. NPC1 is characterized by abnormal accumulation of unesterified cholesterol and glycolipids in late endosomes and lysosomes. Common signs include neonatal jaundice, hepatosplenomegaly, cerebellar ataxia, seizures and cognitive decline. Both mouse and feline models of NPC1 mimic the disease progression in humans and have been used in preclinical studies of 2-hydroxypropyl-β-cyclodextrin (2HPβCD; VTS-270), a drug that appeared to slow neurological progression in a Phase 1/2 clinical trial. However, there remains a need to identify additional therapeutic agents. High-throughput drug screens have been useful in identifying potential therapeutic compounds; however, current preclinical testing is time and labor intensive. Thus, development of a high-capacity in vivo platform suitable for screening candidate drugs/compounds would be valuable for compound optimization and prioritizing subsequent in vivo testing. Here, we generated and characterize two zebrafish npc1-null mutants using CRISPR/Cas9-mediated gene targeting. The npc1 mutants model both the early liver and later neurological disease phenotypes of NPC1. LysoTracker staining of npc1 mutant larvae was notable for intense staining of lateral line neuromasts, thus providing a robust in vivo screen for lysosomal storage. As a proof of principle, we were able to show that treatment of the npc1 mutant larvae with 2HPβCD significantly reduced neuromast LysoTracker staining. These data demonstrate the potential value of using this zebrafish NPC1 model for efficient and rapid in vivo optimization and screening of potential therapeutic compounds..

Background In addition to systemic gender disparities, women in surgery encounter interpersonal microaggressions. The objective of this study is to describe the most common forms of microaggressions reported by women in surgery. Methods We conducted a scoping review using PubMed/MEDLINE, Ovid, and Web of Science to describe the international, indexed English‐language literature on gender‐based microaggressions experienced by female surgeons, surgical trainees, and medical students in surgery. After screening by title, abstract, and full‐text, 37 articles were retained for data extraction and analysis. Microaggressions were analyzed using the Sexist Microaggression Experience and Stress Scale (MESS) framework and stratified by country of origin. Results Gender‐based microaggression publications most commonly originated from the United States (n = 27 articles), Canada (n = 3), and India (n = 2). Gender‐based microaggressions were classified into environmental invalidations (n = 20), being treated like a second‐class citizen (n = 18), assumptions of traditional gender roles (n = 12), sexual objectification (n = 11), assumptions of inferiority (n = 10), being forced to leave gender at the door (n = 8), and experiencing sexist language (n = 6). Additionally, attendings were more frequently reported to experience microaggressions than surgical trainees and medical students, but more articles reported data on attendings (n = 16) than surgical trainees (n = 10) or students (n = 4). Conclusion While recent advancements have opened the field of surgery to women, there is still a lack of female representation, and persistent microaggressions may perpetuate this gender disparity. Addressing microaggressions against female surgeons is essential to achieving gender equity in surgical practice.