Characteristics differentiating problem representation synthesis between novices and experts.

BACKGROUND: Formulating a thoughtful problem representation (PR) is fundamental to sound clinical reasoning and an essential component of medical education. Aside from basic structural recommendations, little consensus exists on what characterizes high-quality PRs. OBJECTIVES: To elucidate characteristics that distinguish PRs created by experts and novices. METHODS: Early internal medicine residents (novices) and inpatient teaching faculty (experts) from two academic medical centers were given two written clinical vignettes and were instructed to write a PR and three-item differential diagnosis for each. Deductive content analysis described the characteristics comprising PRs. An initial codebook of characteristics was refined iteratively. The primary outcome was differences in characteristic frequencies between groups. The secondary outcome was characteristics correlating with diagnostic accuracy. Mixed-effects regression with random effects modeling compared case-level outcomes by group. RESULTS: Overall, 167 PRs were analyzed from 30 novices and 54 experts. Experts included 0.8 fewer comorbidities (p < .01) and 0.6 more examination findings (p = .01) than novices on average. Experts were less likely to include irrelevant comorbidities (odds ratio [OR] = 0.4, 95% confidence interval [CI] = 0.2-0.8) or a diagnosis (OR = 0.3, 95% CI = 0.1-0.8) compared with novices. Experts encapsulated clinical data into higher-order terms (e.g., sepsis) than novices (p < .01) while including similar numbers of semantic qualifiers (SQs). Regardless of expertise level, PRs following a three-part structure (e.g., demographics, temporal course, and clinical syndrome) and including temporal SQs were associated with diagnostic accuracy (p < .01). CONCLUSIONS: Compared with novices, expert PRs include less irrelevant data and synthesize information into higher-order concepts. Future studies should determine whether targeted educational interventions for PRs improve diagnostic accuracy.

Design, synthesis, and evaluation of substituted nicotinamide adenine dinucleotide (NAD+) synthetase inhibitors as potential antitubercular agents.

Nicotinamide adenine dinucleotide (NAD+) synthetase catalyzes the last step in NAD+ biosynthesis. Depletion of NAD+ is bactericidal for both active and dormant Mycobacterium tuberculosis (Mtb). By inhibiting NAD+ synthetase (NadE) from Mtb, we expect to eliminate NAD+ production which will result in cell death in both growing and nonreplicating Mtb. NadE inhibitors have been investigated against various pathogens, but few have been tested against Mtb. Here, we report on the expansion of a series of urea-sulfonamides, previously reported by Brouillette et al. Guided by docking studies, substituents on a terminal phenyl ring were varied to understand the structure-activity-relationships of substituents on this position. Compounds were tested as inhibitors of both recombinant Mtb NadE and Mtb whole cells. While the parent compound displayed very weak inhibition against Mtb NadE (IC50=1000µM), we observed up to a 10-fold enhancement in potency after optimization. Replacement of the 3,4-dichloro group on the phenyl ring of the parent compound with 4-nitro yielded 4f, the most potent compound of the series with an IC50 value of 90µM against Mtb NadE. Our modeling results show that these urea-sulfonamides potentially bind to the intramolecular ammonia tunnel, which transports ammonia from the glutaminase domain to the active site of the enzyme. This hypothesis is supported by data showing that, even when treated with potent inhibitors, NadE catalysis is restored when treated with exogenous ammonia. Most of these compounds also inhibited Mtb cell growth with MIC values of 19-100µg/mL. These results improve our understanding of the SAR of the urea-sulfonamides, their mechanism of binding to the enzyme, and of Mtb NadE as a potential antitubercular drug target.