Acinetobacter baumannii is an opportunistic Gram‐negative bacterial pathogen, associated mostly with hospital‐acquired infections. The emergence of drug resistance strains made it necessary to explore new pathways for the development of more effective antibiotics. Enoyl CoA reductase (FabI), a key enzyme in the fatty acid biosynthesis (FAS) pathway, has emerged as a potential target for antibacterial drug development. Earlier reports show that the lead SaFabI inhibitor AFN‐1252 can inhibit FabI from other organisms including Escherichia coli and Burkholderia pseudomallei, but with differential potency. In the present work, we show that AFN‐1252 is a moderate inhibitor of AbFabI with an IC50 of 216 nM. AFN‐1252 stabilized AbFabI with a 4.2°C increase in the melting temperature (Tm) and, interestingly, the stabilization effect was significantly increased in presence of the cofactor NADH (∆Tm = 17°C), suggesting the formation of a ternary complex AbFabI: AFN‐1252: NADH. X‐ray crystallography studies of AbFabI co‐crystalized with AFN‐1252 and NADH confirmed the ternary complex formation. The critical interactions of AFN‐1252 with AbFabI and NADH identified from the co‐crystal structure may facilitate the design and development of new drugs against A. baumannii infections by targeting the FAS pathway.
Purpose: Ruxolitinib (Jakafi) is a Janus kinase 1 and 2 small molecule inhibitor that the Food and Drug Administration approved for myelofibrosis and polycythemia vera. It has been expanded to off-label treatment for a variety of dermatologic conditions, with several clinical trials ongoing. A review of available studies and cases of off-label uses was performed to guide clinicians seeking evidence on the efficacy of this Janus kinase inhibitor for dermatologic disorders.Materials and Methods: PubMed/MEDLINE, EMBASE, Scopus, and ClinicalTrials.gov databases were searched with the term "ruxolitinib," and results were manually reviewed to identify published data on off-label uses of ruxolitinib. Studies included are structured by quality of evidence available.Results: Ruxolitinib may have utility in the treatment of atopic dermatitis, psoriasis, and vitiligo, with data from open-label and randomized trials supporting efficacy of topical formulations. Evidence of utility for alopecia areata is mixed and differs depending on topical versus oral form. Evidence for numerous other conditions is available through case reports and case series.Conclusions: There is growing evidence supporting potential off-label use of oral and topical ruxolitinib for a wide range of skin conditions. There are several ongoing investigations of ruxolitinib use in dermatology that will undoubtedly better define its efficacy and appropriate use in dermatology.
Objective: To assess public response to cancellations of elective surgeries following the American College of Surgeons' (ACS) recommendation on March 13. Methods: We queried text comments from Reddit, a social media platform and the fifth most popular website in the United States. Comments were manually reviewed to assess for relevance to elective surgery in the United States during the global coronavirus outbreak, whether the text was written by a healthcare worker (HCW), whether the user was based in the United States, and whether the text documented cancellations of surgery, expected cancellations of surgery, or surgery ongoing after the ACS announcement. Analysis of overall sentiment and negativity in comment text was performed using the Valence Aware Dictionary for sEntiment Reasoning (VADER), a validated natural language processing tool previously used in studies of health behaviors using social media. Non-parametric tests were used for subgroup comparisons based on posting date and characteristics identified during manual review. Results: Following manual review, 1272 comments were included for analysis. Overall sentiment among non-HCWs became significantly more negative following the ACS announcement (P ¼ 0.037). Overall sentiment did not significantly differ between HCWs and non-HCWs prior to the ACS announcement (P ¼ 0.98), but non-HCW sentiment became significantly more negative than HCW sentiment after the announcement (P ¼ 0.027). Negativity scores in posts describing cancellations were significantly higher among posts written by non-HCWs than HCWs (P ¼ 0.028). Conclusions: Cancellation of elective surgeries had an adverse emotional impact on non-HCWs. This finding highlights the importance of access to elective surgery to patients' emotional well-being.
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