Mechanism-based inhibition of gut microbial tryptophanases reduces serum indoxyl sulfate.

Indoxyl sulfate is a microbially derived uremic toxin that accumulates in late-stage chronic kidney disease and contributes to both renal and cardiovascular toxicity. Indoxyl sulfate is generated by the metabolism of indole, a compound created solely by gut microbial tryptophanases. Here, we characterize the landscape of tryptophanase enzymes in the human gut microbiome and find remarkable structural and functional similarities across diverse taxa. We leverage this homology through a medicinal chemistry campaign to create a potent pan-inhibitor, (3S) ALG-05, and validate its action as a transition-state analog. (3S) ALG-05 successfully reduces indole production in microbial culture and displays minimal toxicity against microbial and mammalian cells. Mice treated with (3S) ALG-05 show reduced cecal indole and serum indoxyl sulfate levels with minimal changes in other tryptophan-metabolizing pathways. These studies present a non-bactericidal pan-inhibitor of gut microbial tryptophanases with potential promise for reducing indoxyl sulfate in chronic kidney disease.

Leveraging School Infection Data to Address Community COVID-19 Data Gaps.

BACKGROUND: At-home COVID-19 tests became available in the USA in April 2021 with widespread use by January 2022; however, the lack of infrastructure to report test results to public health agencies created a gap in public health data. Kindergarten through grade 12 (K-12) schools often tracked COVID-19 cases among students and staff; leveraging school data may have helped bridge data gaps. METHODS: We examined infection rates reported by school districts to ABC Science Collaborative with corresponding community rates from March 15, 2021 to June 3, 2022. We computed weekly ratios of community-to-district-reported rates (reporting ratios) across 3 study periods (spring 2021, fall 2021, and spring 2022) and estimated the difference and 95% confidence intervals (CIs) in the average reporting ratio between study periods. RESULTS: In spring 2021, before approval or widespread use of at-home testing, the community-reported infection rate was higher than the school-reported infection rate (reporting ratio: 1.40). In fall 2021 and spring 2022, as at-home testing rapidly increased, school-reported rates were higher than community-reported rates (reporting ratios: 0.82 and 0.66). Average reporting ratios decreased between spring 2021 and fall 2021 (-0.58, 95% CI -0.84, -0.32) and spring 2021 and spring 2022 (-0.73, 95% CI -0.96, -0.48); there was no significant change between fall 2021 and spring 2022 (-0.15, 95% CI -0.36, 0.06). CONCLUSIONS: At-home COVID-19 testing resulted in significant data gaps; K-12 data could have supplemented community data. In future public health emergencies, reporting of school data could minimize data gaps, but requires additional resources including funding to track infections and standardized data reporting methods.

Equal access.

As nurse coordinator at Manchester's Chinese Health Information Centre, Mary Tso Kam Ha believes permanent mainstream funding is essential if she is to achieve her goal of a stable, well orientated service for this long established community.