The Importance of Measuring Competency-Based Outcomes: Standard Evaluation Measures Are Not Surrogates for Clinical Performance of Internal Medicine Residents

Background: Despite recent emphasis on educational outcomes, program directors still rely on standard evaluation techniques such as tests of knowledge and subjective ratings. Purposes: To assess the correlation of standard internal medicine (IM) residency evaluation scores (attending global evaluations, In-Training examination, and Mini-Clinical Examination Exercise) with documented performance of preventive measures for continuity clinic patients. Methods: Cross-sectional study of 132 IM residents attending an IM teaching clinic, July 2000 to June 2003, comparing standard evaluations with chart audit. Results: Mean resident performance ranged from 53% (SD = 24) through 89% (SD = 20) across the 6 preventive measures abstracted from 1,102 patient charts. We found weak and mostly not significant correlations between standard measures and performance of preventive services. Conclusions: Standard measures are not adequate surrogates for measuring clinical outcomes. This supports the Accreditation Council for Graduate Medical Education's recommendations to incorporate novel Toolbox measures, like chart audit, into residency evaluations.     

SARS-CoV-2 Spike Protein Disrupts Blood–Brain Barrier Integrity via RhoA Activation

The SARS-CoV-2 spike protein has been shown to disrupt blood–brain barrier (BBB) function, but its pathogenic mechanism of action is unknown. Whether angiotensin converting enzyme 2 (ACE2), the viral binding site for SARS-CoV-2, contributes to the spike protein-induced barrier disruption also remains unclear. Here, a 3D-BBB microfluidic model was used to interrogate mechanisms by which the spike protein may facilitate barrier dysfunction. The spike protein upregulated the expression of ACE2 in response to laminar shear stress. Moreover, interrogating the role of ACE2 showed that knock-down affected endothelial barrier properties. These results identify a possible role of ACE2 in barrier homeostasis. Analysis of RhoA, a key molecule in regulating endothelial cytoskeleton and tight junction complex dynamics, reveals that the spike protein triggers RhoA activation. Inhibition of RhoA with C3 transferase rescues its effect on tight junction disassembly. Overall, these results indicate a possible means by which the engagement of SARS-CoV-2 with ACE2 facilitates disruption of the BBB via RhoA activation. Understanding how SARS-CoV-2 dysregulates the BBB may lead to strategies to prevent the neurological deficits seen in COVID-19 patients.

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Nitrate in Drinking Water during Pregnancy and Spontaneous Preterm Birth: A Retrospective Within-Mother Analysis in California

Background: Nitrate is a widespread groundwater contaminant and a leading cause of drinking water quality violations in California. Associations between nitrate exposure and select adverse birth outcomes have been suggested, but few studies have examined gestational exposures to nitrate and risk of preterm birth (before 37 wk gestation).Objective: We investigated the association between elevated nitrate in drinking water and spontaneous preterm birth through a within-mother retrospective cohort study of births in California.Methods: We acquired over 6 million birth certificate records linked with Office of Statewide Health Planning and Development hospital discharge data for California births from 2000–2011. We used public water system monitoring records to estimate nitrate concentrations in drinking water for each woman’s residence during gestation. After exclusions, we constructed a sample of 1,443,318 consecutive sibling births in order to conduct a within-mother analysis. We used separate conditional logistic regression models to estimate the odds of preterm birth at 20–31 and 32–36 wk, respectively, among women whose nitrate exposure changed between consecutive pregnancies.Results: Spontaneous preterm birth at 20–31 wk was increased in association with tap water nitrate concentrations during pregnancy of 5 to <10mg/L [odds ratio (OR)=1.47; 95% confidence interval (CI): 1.29, 1.67] and ≥10mg/L (OR=2.52; 95% CI: 1.49, 4.26) compared with <5mg/L (as nitrogen). Corresponding estimates for spontaneous preterm birth at 32–36 wk were positive but close to the null for 5 to <10mg/L nitrate (OR=1.08; 95% CI: 1.02, 1.15) and for ≥10mg/L nitrate (OR=1.05; 95% CI: 0.85, 1.31) vs. <5mg/L nitrate. Our findings were similar in several secondary and sensitivity analyses, including in a conventional individual-level design.Discussion: The results suggest that nitrate in drinking water is associated with increased odds of spontaneous preterm birth. Notably, we estimated modestly increased odds associated with tap water nitrate concentrations of 5 to <10mg/L (below the federal drinking water standard of 10mg/L) relative to <5mg/L. https://doi.org/10.1289/EHP8205     

Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities

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Abnormalities in nitric oxide and its derivatives in lung cancer

RATIONALE: A cellular prooxidant state promotes cells to neoplastic growth, in part because of modification of proteins and their functions. Reactive nitrogen species formed from nitric oxide (NO) or its metabolites, can lead to protein tyrosine nitration, which is elevated in lung cancer. OBJECTIVE: To determine the alteration in these NO derivatives and the role they may play in contributing to lung carcinogenesis. METHODS: We analyzed levels of NO, nitrite (NO2-), nitrate (NO3-), and the location of the protein nitration and identified the proteins that are modified. MEASUREMENTS AND MAIN RESULTS: Although exhaled NO and NO2- were increased, endothelial NO synthase or inducible NO synthase expression was similar in the tumor and tumor-free regions. However, immunohistochemistry showed that nitrotyrosine was increased in the tumor relative to non-tumor-bearing sections. We used proteomics to identify the modified proteins (two-dimensional polyacrylamide gel electrophoresis; mass spectrometry). Both the degree of nitration and the protein nitration profile were altered. We identified more than 25 nitrated proteins, including metabolic enzymes, structural proteins, and proteins involved in prevention of oxidative damage. Alterations of the biology of NO metabolites and nitration of proteins may contribute to the mutagenic processes and promote carcinogenesis. CONCLUSIONS: This study provides evidence in favor of a role for reactive nitrogen and oxygen species in lung cancer.