Implementation of Transgender/Gender Nonbinary Care in a Family Medicine Teaching Practice.

PURPOSE: Numerous studies have shown that transgender or gender nonbinary (TGNB) individuals encounter significantly more health care barriers, including overall lack of access to gender-affirming care providers. This study describes 2 assessments of transgender care services at a large family medicine teaching practice. METHODS: Staff and providers were invited to attend an optional, practice-wide, hourlong free training session on gender-affirming care offered on 3 different dates in 2019. A structured protocol was used to collect observational data from which key takeaways from the training sessions were developed. Separately, a retrospective chart review of patients with a gender dysphoria diagnosis was completed. Charts were reviewed for adherence to regional and international organization recommendations for comprehensive transgender care. RESULTS: Three main takeaways from the training sessions included lack of knowledge or familiarity with gender terminology and expression, fear of offending patients, and employee hesitation to change behaviors when interacting with patients. On chart review, the most common interventions identified were need to schedule a follow-up visit (61.5%), need for health maintenance screenings (osteoporosis screening, 50%; Papanicolaou smear, 56.3%; mammogram, 66.7%), need for mental health screening (41.5%), need for laboratory monitoring of testosterone therapy (20%), and corrected gender markers/names listed in the appropriate place in the patient chart (16.9%). CONCLUSIONS: This study highlighted hesitation to provide and lack of familiarity with transgender care among practice staff. Although some aspects of comprehensive transgender care are well implemented, maintaining follow-up, completing health maintenance and mental health screenings, and appropriate laboratory monitoring are areas for improvement.

The evolution of function in strictosidine synthase-like proteins.

The exponential growth of sequence data provides abundant information for the discovery of new enzyme reactions. Correctly annotating the functions of highly diverse proteins can be difficult, however, hindering use of this information. Global analysis of large superfamilies of related proteins is a powerful strategy for understanding the evolution of reactions by identifying catalytic commonalities and differences in reaction and substrate specificity, even when only a few members have been biochemically or structurally characterized. A comparison of >2500 sequences sharing the six-bladed ß-propeller fold establishes sequence, structural, and functional links among the three subgroups of the functionally diverse N6P superfamily: the arylesterase-like and senescence marker protein-30/gluconolactonase/luciferin-regenerating enzyme-like (SGL) subgroups, representing enzymes that catalyze lactonase and related hydrolytic reactions, and the so-called strictosidine synthase-like (SSL) subgroup. Metal-coordinating residues were identified as broadly conserved in the active sites of all three subgroups except for a few proteins from the SSL subgroup, which have been experimentally determined to catalyze the quite different strictosidine synthase (SS) reaction, a metal-independent condensation reaction. Despite these differences, comparison of conserved catalytic features of the arylesterase-like and SGL enzymes with the SSs identified similar structural and mechanistic attributes between the hydrolytic reactions catalyzed by the former and the condensation reaction catalyzed by SS. The results also suggest that despite their annotations, the great majority of these >500 SSL sequences do not catalyze the SS reaction; rather, they likely catalyze hydrolytic reactions typical of the other two subgroups instead. This prediction was confirmed experimentally for one of these proteins.

Inter-domain dynamics drive cholesterol transport by NPC1 and NPC1L1 proteins.

Transport of LDL-derived cholesterol from lysosomes into the cytoplasm requires NPC1 protein; NPC1L1 mediates uptake of dietary cholesterol. We introduced single disulfide bonds into NPC1 and NPC1L1 to explore the importance of inter-domain dynamics in cholesterol transport. Using a sensitive method to monitor lysosomal cholesterol efflux, we found that NPC1's N-terminal domain need not release from the rest of the protein for efficient cholesterol export. Either introducing single disulfide bonds to constrain lumenal/extracellular domains or shortening a cytoplasmic loop abolishes transport activity by both NPC1 and NPC1L1. The widely prescribed cholesterol uptake inhibitor, ezetimibe, blocks NPC1L1; we show that residues that lie at the interface between NPC1L1's three extracellular domains comprise the drug's binding site. These data support a model in which cholesterol passes through the cores of NPC1/NPC1L1 proteins; concerted movement of various domains is needed for transfer and ezetimibe blocks transport by binding to multiple domains simultaneously.