Sociodemographic disadvantage in the burden of stress and academic performance in medical school: implications for diversity in medicine.

BACKGROUND: Nontraditional students bring to medicine inherent characteristics and perspectives that enrich the learning environment and contribute to expanding diversity in medicine. However, research has shown that these students, by virtue of their sociodemographic backgrounds, face unique challenges in medical education, which ultimately place them at a disadvantage compared to their peers. The purpose of this study is to explore relationships between sociodemographic characteristics, stress, and academic performance, in the context of outcomes that may be undermining efforts to diversify the physician workforce. METHODS: Using a retrospective observational cohort methodology, we examined institutional and USMLE exam performance data in conjunction with Perceived Stress Scale-4 survey results from six cohorts of students at Kirk Kerkorian School of Medicine at UNLV (n = 358). Using independent samples t-test, mean stress and academic performance were compared between four sociodemographic groups: first-generation college students, underrepresented in medicine (URM), socioeconomically disadvantaged, and age 30 + at matriculation. Results were considered significant where P ≤ .05. RESULTS: First-generation college students had significantly higher stress at the end of third year clerkships (mean 7.8 vs. 6.8, P* = .03). URM students had significantly lower scores on preclinical exams (mean 81.37 vs. 83.07, P* = .02). The students who were age 30 + at matriculation had significantly lower exam scores on all academic performance measures. CONCLUSION: Our results echo historic trends in academic performance for racial and ethnic minority students, and we present recent evidence of academic performance disparities based on age at matriculation. Residency program directors continue to use test scores as a primary metric to screen applicants and thus, poor academic performance has profound consequences on career trajectory. Finally, significantly higher stress in the first-generation students may be evidence of underlying psychological distress. Expanding the sociodemographic diversity among physicians, and by extension, medical students, has long been recognized as fundamental to addressing inequities in healthcare. However, results from our study suggest that aspects of medical education are unfavorable and disadvantageous for first-generation, URM, and older medical students. A deeper understanding of the interplay between sociodemographic characteristics and success in medical school is paramount as we pursue diversity in medicine.

Data supporting a saturation mutagenesis assay for Tat-driven transcription with the GigaAssay.

The data in this article are associated with the research paper "GigaAssay - an adaptable high-throughput saturation mutagenesis assay" [1]. The raw data are sequence reads of HIV-1 Tat cDNA amplified from cellular genomic DNA in a new single-pot saturation mutagenesis assay designated the "GigaAssay". A bioinformatic pipeline and parameters used to analyze the data. Raw, processed, analyzed, and filtered data are reported. The data is processed to calculate the Tat-driven transcription activity for cells with each possible single amino acid substitution in Tat. This data can be reused to interpret Tat intermolecular interactions and HIV latency. This is one of the largest and most complete datasets regarding the impact of amino acid substitutions within a single protein on a molecular function.

GigaAssay - An adaptable high-throughput saturation mutagenesis assay platform.

High-throughput assay systems have had a large impact on understanding the mechanisms of basic cell functions. However, high-throughput assays that directly assess molecular functions are limited. Herein, we describe the "GigaAssay", a modular high-throughput one-pot assay system for measuring molecular functions of thousands of genetic variants at once. In this system, each cell was infected with one virus from a library encoding thousands of Tat mutant proteins, with each viral particle encoding a random unique molecular identifier (UMI). We demonstrate proof of concept by measuring transcription of a GFP reporter in an engineered reporter cell line driven by binding of the HIV Tat transcription factor to the HIV long terminal repeat. Infected cells were flow-sorted into 3 bins based on their GFP fluorescence readout. The transcriptional activity of each Tat mutant was calculated from the ratio of signals from each bin. The use of UMIs in the GigaAssay produced a high average accuracy (95%) and positive predictive value (98%) determined by comparison to literature benchmark data, known C-terminal truncations, and blinded independent mutant tests. Including the substitution tolerance with structure/function analysis shows restricted substitution types spatially concentrated in the Cys-rich region. Tat has abundant intragenic epistasis (10%) when single and double mutants are compared.

XRCC4 and MRE11 Roles and Transcriptional Response to Repair of TALEN-Induced Double-Strand DNA Breaks.

Double-strand breaks (DSB) are one of the most lethal forms of DNA damage that, if left unrepaired, can lead to genomic instability, cellular transformation, and cell death. In this work, we examined how repair of transcription activator-like effector nuclease (TALEN)-induced DNA damage was altered when knocking out, or inhibiting a function of, two DNA repair proteins, XRCC4 and MRE11, respectively. We developed a fluorescent reporter assay that uses TALENs to introduce DSB and detected repair by the presence of GFP fluorescence. We observed repair of TALEN-induced breaks in the XRCC4 knockout cells treated with mirin (a pharmacological inhibitor of MRE11 exonuclease activity), albeit with ~40% reduced efficiency compared to normal cells. Editing in the absence of XRCC4 or MRE11 exonuclease was robust, with little difference between the indel profiles amongst any of the groups. Reviewing the transcriptional profiles of the mirin-treated XRCC4 knockout cells showed 307 uniquely differentially expressed genes, a number far greater than for either of the other cell lines (the HeLa XRCC4 knockout sample had 83 genes, and the mirin-treated HeLa cells had 30 genes uniquely differentially expressed). Pathways unique to the XRCC4 knockout+mirin group included differential expression of p53 downstream pathways, and metabolic pathways indicating cell adaptation for energy regulation and stress response. In conclusion, our study showed that TALEN-induced DSBs are repaired, even when a key DSB repair protein or protein function is not operational, without a change in indel profiles. However, transcriptional profiles indicate the induction of unique cellular responses dependent upon the DNA repair protein(s) hampered.