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Immune checkpoint inhibitors (ICI) targeting CTLA4 or PD-1/PD-L1 have transformed cancer therapy but are associated with immune-related adverse events, including myocarditis. Here, we report a robust preclinical mouse model of ICI-associated myocarditis in which monoallelic loss of Ctla4 in the context of complete genetic absence of Pdcd1 leads to premature death in approximately half of mice. Premature death results from myocardial infiltration by T cells and macrophages and severe ECG abnormalities, closely recapitulating the clinical and pathologic hallmarks of ICI-associated myocarditis observed in patients. Using this model, we show that Ctla4 and Pdcd1 functionally interact in a gene dosage-dependent manner, providing a mechanism by which myocarditis arises with increased frequency in the setting of combination ICI therapy. We demonstrate that intervention with CTLA4-Ig (abatacept) is sufficient to ameliorate disease progression and additionally provide a case series of patients in which abatacept mitigates the fulminant course of ICI myocarditis. SIGNIFICANCE: We provide a preclinical model of ICI-associated myocarditis which recapitulates this clinical syndrome. Using this model, we demonstrate that CTLA4 and PD-1 (ICI targets) functionally interact for myocarditis development and that intervention with CTLA4-Ig (abatacept) attenuates myocarditis, providing mechanistic rationale and preclinical support for therapeutic clinical studies.See related commentary by Young and Bluestone, p. 537.This article is highlighted in the In This Issue feature, p. 521.

Immune checkpoint therapies (ICT) improve overall survival of patients with cancer but may cause immune-related adverse events (irAEs) such as myocarditis. Cytotoxic T lymphocyte-associated antigen 4 immunoglobulin fusion protein (CTLA-4 Ig), an inhibitor of T cell costimulation through CD28, reverses irAEs in animal models. However, concerns exist about potentially compromising antitumor response of ICT. In mouse tumor models, we administered CTLA-4 Ig 1) concomitantly with ICT or 2) after ICT completion. Concomitant treatment reduced antitumor efficacy, while post-ICT administration improved efficacy without affecting frequency and function of CD8 T cells. The improved response was independent of the ICT used, whether CTLA-4 or PD-1 blockade. The frequency of Tregs was significantly decreased with CTLA-4 Ig. The resulting increased CD8/Treg ratio potentially underlies the enhanced efficacy of ICT followed by CTLA-4 Ig. This paradoxical mechanism shows that a CTLA-4 Ig regimen shown to reduce irAE severity does not compromise antitumor efficacy. [ABSTRACT FROM AUTHOR]

This article discusses the results of a post-hoc analysis of the VERTIS CV trial, which examined the effects of the medication ertugliflozin on the risk of hospitalization for heart failure (HHF) in patients with type 2 diabetes mellitus (T2DM) and atherosclerotic cardiovascular disease. The study found that ertugliflozin significantly reduced the risk of first HHF in the overall cohort of participants. However, the treatment effect was more pronounced in individuals with a pre-trial ejection fraction (EF) of less than 45% and attenuated in those with an EF greater than 60%. These findings contribute to the understanding of the efficacy of SGLT2 inhibitors in reducing the risk of HHF across different EF ranges. [Extracted from the article]

Purpose: This paper investigates the association between self-reported perceived health status and doctor-informed medical conditions among US active duty service members (ADSM).Methods: Data are from the 2018 Health-Related Behaviors Survey – a cross-sectional survey weighted to represent the US military (N = 17166). Perceived good health status was defined as having a response choice of "good", "very good", or "excellent" to the question: Would you say your overall physical health is ___? Medical conditions were based on self-reported presence of nine clinical conditions. Analysis included weighted prevalence and log-binomial regression models to explore relationships between ADSM characteristics with perceived good health status as well as concordance between perceived status and medical conditions.Results: ADSM rated their health to be excellent (14.6%), very good (37.7%), good (36.2%), fair (9.7%) and poor (1.7%). About 88.5% perceived a good (to excellent) health status. Perceived good health status was negatively associated with the number of medical conditions present (adjusted odds ratio (aOR): ranging from 0.78 to 0.92) as well as several health behaviors (aOR): ranging from 0.86 to 0.98) and other sociodemographic factors. Among all ADSMs, 51% perceived good health in the absence of medical conditions, while 8% perceived poor health status in the presence of medical conditions. Concordance between perceived health status and medical conditions was significantly lower among ADSM who were older (aOR: 0.61; 95% CI: 0.54– 0.69), with dependent children (aOR: 0.89; 95% CI: 0.84– 0.95), or had been deployed (aOR: 0.89, 95% CI: 0.84-0.95).Conclusion: The prevalence of perceived good health status among ADSMs was consistent with those documented in the general US population. The interrelationships between ADSM's perceptions, medical conditions and sociodemographic characteristics may have implications for their health literacy and utilization of health services. Study findings suggest that interventions promoting healthy behaviors, health literacy and treatment-seeking may influence perceived health status and mitigate medical conditions among ADSM, thus improving the US Military readiness, resilience and mission success. [ABSTRACT FROM AUTHOR]

Eliminating health disparities and achieving health equity are central to US national health objectives and the Military Health System's "quadruple aim," which has readiness as its core aim. Because military service members enjoy universal eligibility for health care, it is sometimes assumed that health disparities do not exist in the Department of Defense (DoD). However, while some studies have shown that disparities have been attenuated or eliminated in the DoD, others suggest that significant disparities remain. Reasons these disparities may remain include that universal eligibility for care does not necessarily result in equal to access to care, and that equal access to care does not necessarily result in health equity. Priority groups for DoD health equity research and advocacy efforts should include: racial and ethnic minorities, sexual and gender minorities, women, and enlisted ranks. The DoD can advance health equity by improving data quality, increasing relevant population health research, targeting interventions towards the social determinants of health, improving the health care experience, and integrating DoD health equity efforts with those in the US society at large. [ABSTRACT FROM AUTHOR]