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Aims: To develop a clinical risk model to identify individuals at higher risk of developing new‐onset diabetes and who might benefit more from weight loss pharmacotherapy. Materials and Methods: A total of 21 143 patients without type 2 diabetes at baseline from two TIMI clinical trials of stable cardiovascular patients were divided into a derivation (~2/3) and validation (~1/3) cohort. The primary outcome was new‐onset diabetes. Twenty‐seven candidate risk variables were considered, and variable selection was performed using multivariable Cox regression. The final model was evaluated for discrimination and calibration, and for its ability to identify patients who experienced a larger benefit from the weight loss medication lorcaserin in terms of risk of new‐onset diabetes. Results: During a median (interquartile range) follow‐up of 2.3 (1.8–2.7) years, new‐onset diabetes occurred in 1013 patients (7.7%). The final model included five independent predictors (glycated haemoglobin, fasting glucose, age, body mass index, and triglycerides/high‐density lipoprotein). The clinical risk model showed good discrimination (Harrell's C‐indices 0.802, 95% confidence interval [CI] 0.788–0.817 and 0.807, 95% CI 0.788–0.826) in the derivation and validation cohorts. The calibration plot demonstrated adequate calibration (2.5‐year area under the curve was 81.2 [79.1–83.5]). While hazard ratios for new‐onset diabetes with a weight‐loss therapy were comparable across risk groups (annual risks of <1%, 1%–5%, and >5%), there was a sixfold gradient in absolute risk reduction from lowest to highest risk group (p = 0.027). Conclusions: The developed clinical risk model effectively predicts new‐onset diabetes, with potential implications for personalized patient care and therapeutic decision making. [ABSTRACT FROM AUTHOR]

Simian immunodeficiency virus (SIV) vaccines based upon 68-1 Rhesus Cytomegalovirus (RhCMV) vectors show remarkable protection against pathogenic SIVmac239 challenge. Across multiple independent rhesus macaque (RM) challenge studies, nearly 60% of vaccinated RM show early, complete arrest of SIVmac239 replication after effective challenge, whereas the remainder show progressive infection similar to controls. Here, we performed viral sequencing to determine whether the failure to control viral replication in non-protected RMs is associated with the acquisition of viral escape mutations. While low level viral mutations accumulated in all animals by 28 days-post-challenge, which is after the establishment of viral control in protected animals, the dominant circulating virus in virtually all unprotected RMs was nearly identical to the challenge stock, and there was no difference in mutation patterns between this cohort and unvaccinated controls. These data definitively demonstrate that viral mutation does not explain lack of viral control in RMs not protected by RhCMV/SIV vaccination. We further demonstrate that during chronic infection RhCMV/SIV vaccinated RMs do not acquire escape mutation in epitopes targeted by RhCMV/SIV, but instead display mutation in canonical MHC-Ia epitopes similar to unvaccinated RMs. This suggests that after the initial failure of viral control, unconventional T cell responses induced by 68-1 RhCMV/SIV vaccination do not exert strong selective pressure on systemically replicating SIV. [ABSTRACT FROM AUTHOR]

BACKGROUND: Sex disparities exist in the management and outcomes of various cardiovascular diseases. However, little is known about sex differences in cardiogenic shock (CS). We sought to assess sex-related differences in the characteristics, resource utilization, and outcomes of patients with CS. METHODS: The Critical Care Cardiology Trials Network is a multicenter registry of advanced cardiac intensive care units (CICUs) in North America. Between 2018 and 2022, each center (N=35) contributed annual 2-month snapshots of consecutive CICU admissions. Patients with CS were stratified as either CS after acute myocardial infarction or heart failure-related CS (HF-CS). Multivariable logistic regression was used for analyses. RESULTS: Of the 22 869 admissions in the overall population, 4505 (20%) had CS. Among 3923 patients with CS due to ventricular failure (32% female), 1235 (31%) had CS after acute myocardial infarction and 2688 (69%) had HF-CS. Median sequential organ failure assessment scores did not differ by sex. Women with HF-CS had shorter CICU lengths of stay (4.5 versus 5.4 days; P<0.0001) and shorter overall lengths of hospital stay (10.9 versus 12.8 days; P<0.0001) than men. Women with HF-CS were less likely to receive pulmonary artery catheters (50% versus 55%; P<0.01) and mechanical circulatory support (26% versus 34%; P<0.0001) compared with men. Women with HF-CS had higher in-hospital mortality than men, even after adjusting for age, illness severity, and comorbidities (34% versus 23%; odds ratio, 1.76 [95% CI, 1.42-2.17]). In contrast, there were no significant sex differences in utilization of advanced CICU monitoring and interventions, or mortality, among patients with CS after acute myocardial infarction. CONCLUSIONS: Women with HF-CS had lower use of pulmonary artery catheters and mechanical circulatory support, shorter CICU lengths of stay, and higher in-hospital mortality than men, even after accounting for age, illness severity, and comorbidities. These data highlight the need to identify underlying reasons driving the differences in treatment decisions, so outcomes gaps in HF-CS can be understood and eliminated. [ABSTRACT FROM AUTHOR]

BACKGROUND: Cardiogenic shock is a morbid complication of heart disease that claims the lives of more than 1 in 3 patients presenting with this syndrome. Supporting a unique collaboration across clinical specialties, federal regulators, payors, and industry, the American Heart Association volunteers and staff have launched a quality improvement registry to better understand the clinical manifestations of shock phenotypes, and to benchmark the management patterns, and outcomes of patients presenting with cardiogenic shock to hospitals across the United States. METHODS: Participating hospitals will enroll consecutive hospitalized patients with cardiogenic shock, regardless of etiology or severity. Data are collected through individual reviews of medical records of sequential adult patients with cardiogenic shock. The electronic case record form was collaboratively designed with a core minimum data structure and aligned with Shock Academic Research Consortium definitions. This registry will allow participating health systems to evaluate patientlevel data including diagnostic approaches, therapeutics, use of advanced monitoring and circulatory support, processes of care, complications, and in-hospital survival. Participating sites can leverage these data for onsite monitoring of outcomes and benchmarking versus other institutions. The registry was concomitantly designed to provide a high-quality longitudinal research infrastructure for pragmatic randomized trials as well as translational, clinical, and implementation research. An aggregate deidentified data set will be made available to the research community on the American Heart Association's Precision Medicine Platform. On March 31, 2022, the American Heart Association Cardiogenic Shock Registry received its first clinical records. At the time of this submission, 100 centers are participating. CONCLUSIONS: The American Heart Association Cardiogenic Shock Registry will serve as a resource using consistent data structure and definitions for the medical and research community to accelerate scientific advancement through shared learning and research resulting in improved quality of care and outcomes of shock patients. [ABSTRACT FROM AUTHOR]

The glossiphoniid leech, Helobdella austinensis, is an experimentally tractable member of the superphylum, Lophotrochozoa. Its large embryonic cells, stereotyped asymmetric cell divisions and ex vivo development capabilities makes it a favorable model for studying the molecular and cellular events of a representative spiralian. In this study, we focused on a narrow developmental time window of ~6–8 h, comprising stages just prior to and immediately following zygote deposition. Employing RNA-Seq methodology, we identified differentially expressed transcripts at this fundamental ontogenic boundary, known as the maternal-to-zygotic transition (MZT). Gene expression changes were characterized by the massive degradation of maternal RNAs (~45%) coupled with the rapid transcription of ~5000 zygotic genes (~20% of the genome) in the first mitotic cell cycle. The latter transcripts encoded a mixture of cell maintenance and regulatory proteins that predictably influence downstream developmental events. [ABSTRACT FROM AUTHOR]

Aim: N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) concentrations are lower in patients with obesity. The interaction between body mass index (BMI) and NT‐proBNP with respect to heart failure risk remains incompletely defined. Methods and results: Data were pooled across three randomized clinical trials enrolling predominantly patients who were overweight or obese with established cardiometabolic disease: SAVOR‐TIMI 53, DECLARE‐TIMI 58 and CAMELLIA‐TIMI 61. Hospitalization for heart failure (HHF) was examined across strata of baseline BMI and NT‐proBNP. The effect of dapagliflozin versus placebo was assessed for a treatment interaction across BMI categories in patients with or without an elevated baseline NT‐proBNP (≥125 pg/ml). Among 24 455 patients, the median NT‐proBNP was 96 (interquartile range [IQR]: 43–225) pg/ml and the median BMI was 33 (IQR 29–37) kg/m2, with 68% of patients having a BMI ≥30 kg/m2. There was a significant inverse association between NT‐proBNP and BMI which persisted after adjustment for all clinical variables (p < 0.001). Within any range of NT‐proBNP, those at higher BMI had higher risk of HHF at 2 years (comparing BMI <30 vs. ≥40 kg/m2 for NT‐proBNP ranges of <125, 125–<450 and ≥450 pg/ml: 0.0% vs. 0.6%, 1.3% vs. 4.0%, and 8.1% vs. 13.8%, respectively), which persisted after multivariable adjustment (adjusted hazard ratio [HRadj] 7.47, 95% confidence interval [CI] 3.16–17.66, HRadj 3.22 [95% CI 2.13–4.86], and HRadj 1.87 [95% CI 1.35–2.60], respectively). In DECLARE‐TIMI 58, dapagliflozin versus placebo consistently reduced HHF across BMI categories in those with an elevated NT‐proBNP (p‐trend for HR across BMI = 0.60), with a pattern of greater absolute risk reduction (ARR) at higher BMI (ARR for BMI <30 to ≥40 kg/m2: 2.2% to 4.7%; p‐trend = 0.059). Conclusions: The risk of HHF varies across BMI categories for any given range of circulating NT‐proBNP. These findings showcase the importance of considering BMI when applying NT‐proBNP for heart failure risk stratification, particularly for patients with low‐level elevations in NT‐proBNP (125–<450 pg/ml) where there appears to be a clinically meaningful absolute and relative risk gradient. [ABSTRACT FROM AUTHOR]