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To evaluate the impact of age and COVID-19 variant time period on morbidity and mortality among those hospitalized with COVID-19.Patients from the American Heart Association's Get With The Guidelines COVID-19 cardiovascular disease registry (January 20, 2020-February 14, 2022) were divided into groups based on whether they presented during periods of wild type/alpha, delta, or omicron predominance. They were further subdivided by age (young: 18-40 years; older: more than 40 years), and characteristics and outcomes were compared.The cohort consisted of 45,421 hospitalized COVID-19 patients (wild type/alpha period: 41,426, delta period: 3349, and omicron period: 646). Among young patients (18-40 years), presentation during delta was associated with increased odds of severe COVID-19 (OR, 1.6; 95% CI, 1.3-2.1), major adverse cardiovascular events (MACE) (OR, 1.8; 95% CI, 1.3-2.5), and in-hospital mortality (OR, 2.2; 95% CI, 1.5-3.3) when compared with presentation during wild type/alpha. Among older patients (more than 40 years), presentation during delta was associated with increased odds of severe COVID-19 (OR, 1.2; 95% CI, 1.1-1.3), MACE (OR, 1.5; 95% CI, 1.4-1.7), and in-hospital mortality (OR, 1.4; 95% CI, 1.3-1.6) when compared with wild type/alpha. Among older patients (more than 40 years), presentation during omicron associated with decreased odds of severe COVID-19 (OR, 0.7; 95% CI, 0.5-0.9) and in-hospital mortality (OR, 0.6; 95% CI, 0.5-0.9) when compared with wild type/alpha.Among hospitalized adults with COVID-19, presentation during a time of delta predominance was associated with increased odds of severe COVID-19, MACE, and in-hospital mortality compared with presentation during wild type/alpha. Among older patients (aged more than 40 years), presentation during omicron was associated with decreased odds of severe COVID-19 and in-hospital mortality compared with wild type/alpha.

Proteinaceous cysteines function as essential sensors of cellular redox state. Consequently, defining the cysteine redoxome is a key challenge for functional proteomic studies. While proteome-wide inventories of cysteine oxidation state are readily achieved using established, widely adopted proteomic methods such as OxICAT, Biotin Switch, and SP3-Rox, these methods typically assay bulk proteomes and therefore fail to capture protein localization-dependent oxidative modifications. Here we establish the local cysteine capture (Cys-LoC) and local cysteine oxidation (Cys-LOx) methods, which together yield compartment-specific cysteine capture and quantitation of cysteine oxidation state. Benchmarking of the Cys-LoC method across a panel of subcellular compartments revealed more than 3,500 cysteines not previously captured by whole-cell proteomic analysis. Application of the Cys-LOx method to LPS-stimulated immortalized murine bone marrow-derived macrophages (iBMDM), revealed previously unidentified, mitochondrially localized cysteine oxidative modifications upon pro-inflammatory activation, including those associated with oxidative mitochondrial metabolism.

Career selection in medicine is a complex and underexplored process. Most medical career studies performed in the U.S. focused on the effect of demographic variables and medical education debt on career choice. Considering ongoing U.S. physician workforce shortages and the trilateral adaptive model of career decision making, a robust assessment of professional attitudes and work-life preferences is necessary. The objective of this study was to explore and define the dominant viewpoints related to career choice selection in a cohort of U.S. IM residents. We administered an electronic Q-sort in which 218 IM residents sorted 50 statements reflecting the spectrum of opinions that influence postgraduate career choice decisions. Participants provided comments that explained the reasoning behind their individual responses. In the final year of residency training, we ascertained participating residents' chosen career. Factor analysis grouped similar sorts and revealed four distinct viewpoints. We characterized the viewpoints as "Fellowship-Bound-Academic," "Altruistic-Longitudinal-Generalist," "Inpatient-Burnout-Aware," and "Lifestyle-Focused-Consultant." There is concordance between residents who loaded significantly onto a viewpoint and their ultimate career choice. Four dominant career choice viewpoints were found among contemporary U.S. IM residents. These viewpoints reflect the intersection of competing priorities, personal interests, professional identity, socio-economic factors, and work/life satisfaction. Better appreciation of determinants of IM residents' career choices may help address workforce shortages and enhance professional satisfaction.

Introduction: The COVID-19 pandemic has caused significant cardiovascular (CV) morbidity and mortality. Using a national registry, we evaluate the impact of age and variant on CV outcomes across the three main coronavirus waves. Methods: Using the AHA’s COVID-19 CV Disease Registry, we divided patients hospitalized with COVID-19 into three groups based on dominant variant at the time of admission (Alpha, Delta, Omicron). We further stratified patients based on age (young: 18-40, older: >40 years). Using adjusted logistic regression, we compared rates of major adverse cardiovascular events (MACE: new onset heart failure, myocardial infarction, stroke, or death) and in-patient mortality between the groups. Results: There were 41,426 patients in the alpha wave (young: 5,585, older: 35,841), 3,349 patients in the delta wave (young: 690, older: 2,659), and 646 patients in the omicron wave (young: 213, older: 433). The cohort’s median (25 th -75 th %ile) age was 63 (50-75) years. 46.8% of the patients were female. Rates of MACE in the Alpha, Delta, and Omicron waves were 20.8%, 23.6%, and 15.5%. Rates of death were 14.0%, 14.8% and 6.0%, respectively. Compared to alpha, patients presenting during delta had increased odds of MACE and death (OR: 1.57 [1.42-1.73] and OR: 1.49 [1.34-1.66]). Patients presenting during omicron had decreased odds of death (OR: 0.6 [0.43-0.84]) and similar odds of MACE compared to alpha. When stratifying by age, both young and older patients presenting during delta had increased odds of MACE and death when compared to alpha (Fig 1A). When compared to young patients, older patients had increased odds of MACE in all three waves (Fig 1B). Conclusions: Patients had increased odds of MACE and death during delta compared to alpha. Compared to young patients, older patients had increased odds of MACE across all three waves. These findings help elucidate the differential impact of age and variant on cardiovascular outcomes among those hospitalized with COVID-19.

BackgroundInflammatory bowel disease (IBD) has been implicated as a risk factor for prostate cancer, however, the mechanism of how IBD leads to prostate tumorigenesis is not known. Here, we investigated whether chronic intestinal inflammation leads to pro-inflammatory changes associated with tumorigenesis in the prostate.MethodsUsing clinical samples of men with IBD who underwent prostatectomy, we analyzed whether prostate tumors had differences in lymphocyte infiltrate compared to non-IBD controls. In a mouse model of chemically-induced intestinal inflammation, we investigated whether chronic intestinal inflammation could be transferred to the wild-type mouse prostate. In addition, mouse prostates were evaluated for activation of pro-oncogenic signaling and genomic instability.ResultsA higher proportion of men with IBD had T and B lymphocyte infiltration within prostate tumors. Mice with chronic colitis showed significant increases in prostatic CD45 + leukocyte infiltration and elevation of three pro-inflammatory cytokines-TIMP-1, CCL5, and CXCL1 and activation of AKT and NF-kB signaling pathways. Lastly, mice with chronic colitis had greater prostatic oxidative stress/DNA damage, and prostate epithelial cells had undergone cell cycle arrest.ConclusionsThese data suggest chronic intestinal inflammation is associated with an inflammatory-rich, pro-tumorigenic prostatic phenotype which may explain how gut inflammation fosters prostate cancer development in men with IBD.

Proteinaceous cysteine residues act as privileged sensors of oxidative stress. As reactive oxygen and nitrogen species have been implicated in numerous pathophysiological processes, deciphering which cysteines are sensitive to oxidative modification and the specific nature of these modifications is essential to understanding protein and cellular function in health and disease. While established mass spectrometry-based proteomic platforms have improved our understanding of the redox proteome, the widespread adoption of these methods is often hindered by complex sample preparation workflows, prohibitive cost of isotopic labeling reagents, and requirements for custom data analysis workflows. Here, we present the SP3-Rox redox proteomics method that combines tailored low cost isotopically labeled capture reagents with SP3 sample cleanup to achieve high throughput and high coverage proteome-wide identification of redox-sensitive cysteines. By implementing a customized workflow in the free FragPipe computational pipeline, we achieve accurate MS1-based quantitation, including for peptides containing multiple cysteine residues. Application of the SP3-Rox method to cellular proteomes identified cysteines sensitive to the oxidative stressor GSNO and cysteine oxidation state changes that occur during T cell activation.