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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]

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]

OBJECTIVE: To develop a risk assessment tool to identify patients with type 2 diabetes (T2D) at higher risk for kidney disease progression and who might benefit more from sodium–glucose cotransporter 2 (SGLT2) inhibition. RESEARCH DESIGN AND METHODS: A total of 41,204 patients with T2D from four Thrombolysis In Myocardial Infarction (TIMI) clinical trials were divided into derivation (70%) and validation cohorts (30%). Candidate predictors of kidney disease progression (composite of sustained ≥40% decline in estimated glomerular filtration rate [eGFR], end-stage kidney disease, or kidney death) were selected with multivariable Cox regression. Efficacy of dapagliflozin was assessed by risk categories (low: <0.5%; intermediate: 0.5 to <2%; high: ≥2%) in Dapagliflozin Effect on Cardiovascular Events (DECLARE)-TIMI 58. RESULTS: There were 695 events over a median follow-up of 2.4 years. The final model comprised eight independent predictors of kidney disease progression: atherosclerotic cardiovascular disease, heart failure, systolic blood pressure, T2D duration, glycated hemoglobin, eGFR, urine albumin-to-creatinine ratio, and hemoglobin. The c-indices were 0.798 (95% CI, 0.774–0.821) and 0.798 (95% CI, 0.765–0.831) in the derivation and validation cohort, respectively. The calibration plot slope (deciles of predicted vs. observed risk) was 0.98 (95% CI, 0.93–1.04) in the validation cohort. Whereas relative risk reductions with dapagliflozin did not differ across risk categories, there was greater absolute risk reduction in patients with higher baseline risk, with a 3.5% absolute risk reduction in kidney disease progression at 4 years in the highest risk group (≥1%/year). Results were similar with the 2022 Chronic Kidney Disease Prognosis Consortium risk prediction model. CONCLUSIONS: Risk models for kidney disease progression can be applied in patients with T2D to stratify risk and identify those who experience a greater magnitude of benefit from SGLT2 inhibition. [ABSTRACT FROM AUTHOR]

Key Points: Question: How does risk prediction based on proteomics data compare with clinical risk factors and polygenic risk scores? Findings: In a retrospective analysis using measurements of thousands of plasma proteins in primary- and secondary-event populations, a protein risk score, developed using more than 4900 plasma protein levels to predict major atherosclerotic cardiovascular disease events, stratified risk as well as a risk factor score and was slightly better than polygenic risk scores for coronary artery disease and stroke. The protein score modestly improved discriminative accuracy (measured by C index) and risk classification (measured by category-free net reclassification improvement and integrated discrimination improvement) when added to a model using clinical risk factors. Meaning: A protein risk score, derived from large-scale proteomics, yielded a modest improvement in discrimination when added to models based on clinical risk factors. Importance: Whether protein risk scores derived from a single plasma sample could be useful for risk assessment for atherosclerotic cardiovascular disease (ASCVD), in conjunction with clinical risk factors and polygenic risk scores, is uncertain. Objective: To develop protein risk scores for ASCVD risk prediction and compare them to clinical risk factors and polygenic risk scores in primary and secondary event populations. Design, Setting, and Participants: The primary analysis was a retrospective study of primary events among 13 540 individuals in Iceland (aged 40-75 years) with proteomics data and no history of major ASCVD events at recruitment (study duration, August 23, 2000 until October 26, 2006; follow-up through 2018). We also analyzed a secondary event population from a randomized, double-blind lipid-lowering clinical trial (2013-2016), consisting of individuals with stable ASCVD receiving statin therapy and for whom proteomic data were available for 6791 individuals. Exposures: Protein risk scores (based on 4963 plasma protein levels and developed in a training set in the primary event population); polygenic risk scores for coronary artery disease and stroke; and clinical risk factors that included age, sex, statin use, hypertension treatment, type 2 diabetes, body mass index, and smoking status at the time of plasma sampling. Main Outcomes and Measures: Outcomes were composites of myocardial infarction, stroke, and coronary heart disease death or cardiovascular death. Performance was evaluated using Cox survival models and measures of discrimination and reclassification that accounted for the competing risk of non-ASCVD death. Results: In the primary event population test set (4018 individuals [59.0% women]; 465 events; median follow-up, 15.8 years), the protein risk score had a hazard ratio (HR) of 1.93 per SD (95% CI, 1.75 to 2.13). Addition of protein risk score and polygenic risk scores significantly increased the C index when added to a clinical risk factor model (C index change, 0.022 [95% CI, 0.007 to 0.038]). Addition of the protein risk score alone to a clinical risk factor model also led to a significantly increased C index (difference, 0.014 [95% CI, 0.002 to 0.028]). Among White individuals in the secondary event population (6307 participants; 432 events; median follow-up, 2.2 years), the protein risk score had an HR of 1.62 per SD (95% CI, 1.48 to 1.79) and significantly increased C index when added to a clinical risk factor model (C index change, 0.026 [95% CI, 0.011 to 0.042]). The protein risk score was significantly associated with major adverse cardiovascular events among individuals of African and Asian ancestries in the secondary event population. Conclusions and Relevance: A protein risk score was significantly associated with ASCVD events in primary and secondary event populations. When added to clinical risk factors, the protein risk score and polygenic risk score both provided statistically significant but modest improvement in discrimination. This study of 13 540 individuals in Iceland (aged 40-75 years) evaluated the utility of protein risk scores for prediction of atherosclerotic cardiovascular disease events compared to risk prediction using polygenic risk scores in addition to risk scores based on clinical risk factors [ABSTRACT FROM AUTHOR]

Aims The PARAGLIDE-HF trial demonstrated reductions in natriuretic peptides with sacubitril/valsartan compared with valsartan in patients with heart failure (HF) with mildly reduced or preserved ejection fraction who had a recent worsening HF event, but was not adequately powered to examine clinical outcomes. PARAGON-HF included a subset of PARAGLIDE-HF-like patients who were recently hospitalized for HF. Participant-level data from PARAGLIDE-HF and PARAGON-HF were pooled to better estimate the efficacy and safety of sacubitril/valsartan in reducing cardiovascular and renal events in HF with mildly reduced or preserved ejection fraction. Methods and results Both PARAGLIDE-HF and PARAGON-HF were multicentre, double-blind, randomized, active-controlled trials of sacubitril/valsartan vs. valsartan in patients with HF with mildly reduced or preserved left ventricular ejection fraction (LVEF >40% in PARAGLIDE-HF and ≥45% in PARAGON-HF). In the pre-specified primary analysis, we pooled participants in PARAGLIDE-HF (all of whom were enrolled during or within 30 days of a worsening HF event) with a 'PARAGLIDE-like' subset of PARAGON-HF (those hospitalized for HF within 30 days). We also pooled the entire PARAGLIDE-HF and PARAGON-HF populations for a broader context. The primary endpoint for this analysis was the composite of total worsening HF events (including first and recurrent HF hospitalizations and urgent visits) and cardiovascular death. The secondary endpoint was the pre-specified renal composite endpoint for both studies (≥50% decline in estimated glomerular filtration rate from baseline, end-stage renal disease, or renal death). Compared with valsartan, sacubitril/valsartan significantly reduced total worsening HF events and cardiovascular death in both the primary pooled analysis of participants with recent worsening HF [ n = 1088; rate ratio (RR) 0.78; 95% confidence interval (CI) 0.61–0.99; P = 0.042] and in the pooled analysis of all participants (n = 5262; RR 0.86; 95% CI: 0.75–0.98; P = 0.027). In the pooled analysis of all participants, first nominal statistical significance was reached by Day 9 after randomization, and treatment benefits were larger in those with LVEF ≤60% (RR 0.78; 95% CI 0.66–0.91) compared with those with LVEF >60% (RR 1.09; 95% CI 0.86–1.40; P interaction = 0.021). Sacubitril/valsartan was also associated with lower rates of the renal composite endpoint in the primary pooled analysis [hazard ratio (HR) 0.67; 95% CI 0.43–1.05; P = 0.080] and the pooled analysis of all participants (HR 0.60; 95% CI 0.44–0.83; P = 0.002). Conclusion In pooled analyses of PARAGLIDE-HF and PARAGON-HF, sacubitril/valsartan reduced cardiovascular and renal events among patients with HF with mildly reduced or preserved ejection fraction. These data provide support for use of sacubitril/valsartan in patients with HF with mildly reduced or preserved ejection fraction, particularly among those with an LVEF below normal, regardless of care setting. [ABSTRACT FROM AUTHOR]

Keywords: Lipids; imaging; biomarkers; CT angiography; calcium score; Hs-CRP; Troponin; risk assesment EN Lipids imaging biomarkers CT angiography calcium score Hs-CRP Troponin risk assesment 2292 2304 13 07/04/23 20230701 NES 230701 Graph: Graphical Abstract Advantages of tailoring lipid lowering therapy with biomarkers versus imaging. The following debate will focus on whether biomarkers or imaging can help us answer the following questions better: How can we better identify the seemingly low-moderate risk patient who will benefit from lipid lowering therapy and the high risk patient who needs treatment intensification? The fact that acute ischemic events result from either rupture or erosion of an atherosclerotic plaque and the clear relationship between atherosclerotic disease burden and cardiovascular risk from multiple studies, including autopsy, invasive coronary angiography, intravascular imaging, and most recently computed tomography coronary angiography (CTCA),[[5], [7], [9], [11]] all support the argument that vascular imaging has the potential to play an important role in triaging patients to more intensive lipid lowering ( I Figure 1 i ). [Extracted from the article]

Aims: Cardiac functional and structural remodelling in patients with atrial fibrillation (AF) contributes to development of heart failure (HF) as their major cardiovascular comorbidity. Circulating biomarkers may reflect these cardiac alterations. Methods and results: ENGAGE AF‐TIMI 48 was a randomized trial of edoxaban versus warfarin in 21 105 patients with AF. We performed a nested biomarker study, analysing high‐sensitivity troponin T (hsTnT, n = 8705), N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP, n = 8765), and growth differentiation factor‐15 (GDF‐15, n = 8705) at baseline and 12 months. Of the biomarker cohort, 5207 had a history of HF, among whom 3996 had known ejection fraction (EF): 926 with reduced EF (HFrEF; ≤40%), 1043 with mildly reduced EF (HFmrEF; 40–49%), and 2027 with preserved EF (HFpEF; ≥50%). Elevated baseline hsTnT, NT‐proBNP, and GDF‐15 were associated with higher risk of hospitalization for HF (HHF) or HF death overall and in subpopulations defined by HF history and EF (p < 0.001 for each). These associations of outcome with each biomarker were consistent regardless of a history of HF or EF (p‐interaction >0.05 for each). Patients who had an increase in or had persistently elevated values in any of the three biomarkers over 12 months were at higher risk for HHF or HF death in the overall population (p < 0.001 for each biomarker and category). Conclusion: Serial measurement of hsTnT, NT‐proBNP, and GDF‐15 revealed that higher baseline values, and increasing or persistently elevated values over 1 year are associated with higher risk of HF outcomes in patients with AF regardless of HF history or HF phenotype based on EF. Clinical Trial Registration: ClinicalTrials.gov unique identifier NCT00781391. [ABSTRACT FROM AUTHOR]

Aims The prognosis of patients with atrial fibrillation (AF) and ischemic stroke while taking oral anticoagulation is poorly understood. This study aimed to characterize the outcomes of patients following a stroke event while on oral anticoagulation. Methods and results Individual participant data from five pivotal randomized trials of antithrombotic therapy in AF were used to assess the outcomes of patients with a post-randomization ischemic stroke while on study medication (warfarin, standard-, or lower-dose direct oral anticoagulant regimen) during trial follow-up. The primary outcome was recurrent ischemic stroke after the first post-randomization ischemic stroke. The primary analysis included 1163 patients with a first post-randomization ischemic stroke while on study medication (median age 73 years, 39.3% female, 35.4% history of stroke before trial enrollment). During a median continued follow-up of 337 days, 74 patients had a recurrent ischemic stroke [cumulative incidence at 1 year: 7.0%, 95% confidence interval (CI) 5.2%–8.7%]. The cumulative incidence of mortality at 3 months after stroke was 12.4% (95% CI 10.5%–14.4%). Consistent results for the incidence of recurrent ischemic stroke at 1 year were obtained in an analysis accounting for the competing risk of death (6.2%, 95% CI 4.8%–7.9%) and in a landmark analysis excluding the first 2 weeks after the index stroke and only including patients without permanent study drug discontinuation since then (6.8%, 95% CI 4.6%–8.9%). Conclusion Patients with AF and ischemic stroke while on oral anticoagulation are at increased risk of recurrent ischemic stroke and death. These patients currently have an unmet medical need. [ABSTRACT FROM AUTHOR]

Administration of the ChAdOx1 nCoV-19 (AstraZeneca) vaccination has recently been associated with rare, unusual cases of thrombotic events. We report a case of a 55-year-old woman who presented to hospital with headaches, petechial rashes and bruising—7 days after receiving her first vaccine dose. Blood tests showed low platelets, a markedly high d-dimer and positive anti-platelet factor 4 antibodies. Computed tomography (CT) of head and venogram showed features consistent with venous sinus thrombosis. She was immediately started on IV pooled immunoglobulin therapy, high-dose prednisolone and full anticoagulation. Subsequent magnetic resonance imaging of head and venogram supported the initial CT findings, with features suggestive of a small-volume venous sinus thrombosis. Additionally, CT pulmonary angiogram revealed a right-sided segmental pulmonary embolism. Our case highlights the importance of increased awareness of this complication after covid vaccination and how searching for distal thrombotic events and liaison with tertiary centres influence clinical outcomes. [ABSTRACT FROM AUTHOR]

Aims: To describe outcomes associated with bridging strategies in patients with acute decompensated heart failure‐related cardiogenic shock (ADHF‐CS) bridged to durable left ventricular assist device (LVAD) or heart transplantation (HTx). Methods and results: Durable LVAD or HTx recipients from 2014 to 2019 with pre‐operative ADHF‐CS were identified in the Society of Thoracic Surgeons Adult Cardiac Surgery Database and stratified by bridging strategy. The primary outcome was operative or 30‐day post‐operative mortality. Secondary outcomes included post‐operative major bleeding. Exploratory comparisons between bridging strategies and outcomes were performed using overlap weighting with and without covariate adjustment. Among 9783 patients with pre‐operative CS, 8777 (89.7%) had ADHF‐CS. Medical therapy (n = 5013) was the most common bridging strategy, followed by intra‐aortic balloon pump (IABP; n = 2816), catheter‐based temporary mechanical circulatory support (TMCS; n = 417), and veno‐arterial extracorporeal membrane oxygenation (VA‐ECMO; n = 465). Mortality was highest in patients bridged with VA‐ECMO (22%), followed by catheter‐based TMCS (10%), IABP (9%), and medical therapy (7%). Adverse post‐operative outcomes were more frequent in LVAD recipients compared with HTx recipients. Conclusion: Among patients with ADHF‐CS bridged to HTx or durable LVAD, the highest rates of death and adverse events during index hospitalization were observed in those bridged with VA‐ECMO, followed by catheter‐based TMCS, IABP, and medical therapy. Patients who received durable LVAD had higher rates of post‐operative complications compared with HTx recipients. Prospective trials are needed to define optimal bridging strategies in patients with ADHF‐CS. [ABSTRACT FROM AUTHOR]

This paper introduces GCAM-CDR 1.0, an integrated assessment model for climate policy based on the open-source Global Change Analysis Model (GCAM). GCAM-CDR extends GCAM v5.4 by enabling users to model additional carbon dioxide removal (CDR) technologies and additional policies and controls related to CDR. New CDR technologies include terrestrial enhanced weathering with basalt, ocean liming, and additional versions of direct air capture. New CDR policies and controls include integration of bioenergy with carbon capture and storage (BECCS) into the CDR market, interregional trade in CDR, exogenous control over the rate of growth of CDR, the ability to set independent targets for emissions abatement and CDR, and a variety of mechanisms for setting demand for CDR at the regional and/or global level. These extensions enhance users' ability to study the potential roles of CDR in climate policy. [ABSTRACT FROM AUTHOR]

Aims Levels of growth differentiation factor 15 (GDF-15), a cytokine secreted in response to cellular stress and inflammation, have been associated with multiple types of cardiovascular (CV) events. However, its comparative prognostic performance across different presentations of atherosclerotic cardiovascular disease (ASCVD) remains unknown. Methods and results An individual patient meta-analysis was performed using data pooled from eight trials including 53 486 patients. Baseline GDF-15 concentration was analyzed as a continuous variable and using established cutpoints (<1200 ng/L, 1200–1800 ng/L, > 1800 ng/L) to evaluate its prognostic performance for CV death/hospitalization for heart failure (HHF), major adverse cardiovascular events (MACE), and their components using Cox models adjusted for clinical variables and established CV biomarkers. Analyses were further stratified on ASCVD status: acute coronary syndrome (ACS), stabilized after recent ACS, and stable ASCVD. Overall, higher GDF-15 concentration was significantly and independently associated with an increased rate of CV death/HHF and MACE (P < 0.001 for each). However, while GDF-15 showed a robust and consistent independent association with CV death and HHF across all presentations of ASCVD, its prognostic association with future myocardial infarction (MI) and stroke only remained significant in patients stabilized after recent ACS or with stable ASCVD [hazard ratio (HR): 1.24, 95% confidence interval (CI): 1.17–1.31 and HR: 1.16, 95% CI: 1.05–1.28 for MI and stroke, respectively] and not in ACS (HR: 0.98, 95% CI: 0.90–1.06 and HR: 0.87, 95% CI: 0.39–1.92, respectively). Conclusion Growth differentiation factor 15 consistently adds prognostic information for CV death and HHF across the spectrum of ASCVD. GDF-15 also adds prognostic information for MI and stroke beyond clinical risk factors and cardiac biomarkers but not in the setting of ACS. [ABSTRACT FROM AUTHOR]

Aims Interest in targeted screening programmes for atrial fibrillation (AF) has increased, yet the role of genetics in identifying patients at highest risk of developing AF is unclear. Methods and results A total of 36,662 subjects without prior AF were analyzed from four TIMI trials. Subjects were divided into quintiles using a validated polygenic risk score (PRS) for AF. Clinical risk for AF was calculated using the CHARGE-AF model. Kaplan–Meier event rates, adjusted hazard ratios (HRs), C -indices, and net reclassification improvement were used to determine if the addition of the PRS improved prediction compared with clinical risk and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Over 2.3 years, 1018 new AF cases developed. AF PRS predicted a significant risk gradient for AF with a 40% increased risk per 1-SD increase in PRS [HR: 1.40 (1.32–1.49); P < 0.001]. Those with high AF PRS (top 20%) were more than two-fold more likely to develop AF [HR 2.45 (1.99–3.03), P < 0.001] compared with low PRS (bottom 20%). Furthermore, PRS provided an additional gradient of risk stratification on top of the CHARGE-AF clinical risk score, ranging from a 3-year incidence of 1.3% in patients with low clinical and genetic risk to 8.7% in patients with high clinical and genetic risk. The subgroup of patients with high clinical risk, high PRS, and elevated NT-proBNP had an AF risk of 16.7% over 3 years. The C -index with the CHARGE-AF clinical risk score alone was 0.65, which improved to 0.67 (P < 0.001) with the addition of NT-proBNP, and increased further to 0.70 (P < 0.001) with the addition of the PRS. Conclusion In patients with cardiovascular conditions, AF PRS is a strong independent predictor of incident AF that provides complementary predictive value when added to a validated clinical risk score and NT-proBNP. [ABSTRACT FROM AUTHOR]

Background: Heart failure (HF) is a growing public health problem and ischemic heart disease is an important risk factor. Understanding the epidemiology of HF in patients with atherosclerosis may help identify subgroups at greater risk who have the potential to derive greater benefit from preventive strategies. Methods and Results: The TRA 2°P‐TIMI 50 trial randomized 26,449 patients with stable atherosclerosis to the antiplatelet agent vorapaxar versus placebo. Hospitalization for HF (HHF) endpoints were adjudicated from serious adverse events by blinded structured review using established definitions. HHF incidence was estimated using Kaplan–Meier analysis. Independent predictors of HHF risk were identified using multivariable logistic regression. The effect of vorapaxar on HHF risk was explored using Cox regression. The estimated incidence of HHF at 3 years was 1.6%. Independent predictors of HHF included prior HF (adjusted odds ratio [adj‐OR]: 8.31; 95% confidence interval [CI]: 6.56–10.54), age (adj‐OR [per 10 years]: 1.67; 95% CI: 1.47–1.89), type 2 diabetes mellitus (T2DM; adj‐OR: 2.55; 95% CI: 2.01–3.24), polyvascular disease (two‐territory disease, adj‐OR: 1.89; 95% CI: 1.46–2.44; three‐territory disease, adj‐OR: 2.68; 95% CI: 1.94–3.70), chronic kidney disease (CKD; adj‐OR: 1.65; 95% CI: 1.30–2.11), body mass index (BMI; adj‐OR [per 5 kg/m2]: 1.15; 95% CI: 1.03–1.27), prior myocardial infarction (MI) (adj‐OR: 1.35; 95% CI: 1.03–1.78), and hypertension (adj‐OR: 1.44; 95% CI: 1.02–2.04). Patients who experienced HHF during follow‐up had higher rates of subsequent rehospitalization and death. Vorapaxar did not modify the risk of HHF. Conclusions: In patients with stable atherosclerosis, prior HF, age, T2DM, polyvascular disease, CKD, BMI, prior MI, and hypertension are important predictors of HHF risk. [ABSTRACT FROM AUTHOR]

Aims: Blood uric acid (UA) levels are frequently elevated in patients with heart failure and reduced ejection fraction (HFrEF), may lead to gout and are associated with worse outcomes. Reduction in UA is desirable in HFrEF and sodium–glucose cotransporter 2 inhibitors may have this effect. We aimed to examine the association between UA and outcomes, the effect of dapagliflozin according to baseline UA level, and the effect of dapagliflozin on UA in patients with HFrEF in the DAPA‐HF trial. Methods and results: The association between UA and the primary composite outcome of cardiovascular death or worsening heart failure, its components, and all‐cause mortality was examined using Cox regression analyses among 3119 patients using tertiles of UA, after adjustment for other prognostic variables. Change in UA from baseline over 12 months was also evaluated. Patients in tertile 3 (UA ≥6.8 mg/dl) versus tertile 1 (<5.4 mg/dl) were younger (66.3 ± 10.8 vs. 68 ± 10.2 years), more often male (83.1% vs. 71.5%), had lower estimated glomerular filtration rate (58.2 ± 17.4 vs. 70.6 ± 18.7 ml/min/1.73 m2), and more often treated with diuretics. Higher UA was associated with a greater risk of the primary outcome (adjusted hazard ratio tertile 3 vs. tertile 1: 1.32, 95% confidence interval [CI] 1.06–1.66; p = 0.01). The risk of heart failure hospitalization and cardiovascular death increased by 7% and 6%, respectively per 1 mg/dl unit increase of UA (p = 0.04 and p = 0.07). Spline analysis revealed a linear increase in risk above a cut‐off UA value of 7.09 mg/dl. Compared with placebo, dapagliflozin reduced UA by 0.84 mg/dl (95% CI −0.93 to −0.74) over 12 months (p < 0.001). Dapagliflozin improved outcomes, irrespective of baseline UA concentration. Conclusion: Uric acid remains an independent predictor of worse outcomes in a well‐treated contemporary HFrEF population. Compared with placebo, dapagliflozin reduced UA and improved outcomes irrespective of UA concentration. [ABSTRACT FROM AUTHOR]

The strain 68-1 rhesus cytomegalovirus (RhCMV)–based vaccine for simian immunodeficiency virus (SIV) can stringently protect rhesus macaques (RMs) from SIV challenge by arresting viral replication early in primary infection. This vaccine elicits unconventional SIV-specific CD8+ T cells that recognize epitopes presented by major histocompatibility complex (MHC)–II and MHC-E instead of MHC-Ia. Although RhCMV/SIV vaccines based on strains that only elicit MHC-II– and/or MHC-Ia–restricted CD8+ T cells do not protect against SIV, it remains unclear whether MHC-E–restricted T cells are directly responsible for protection and whether these responses can be separated from the MHC-II–restricted component. Using host microRNA (miR)–mediated vector tropism restriction, we show that the priming of MHC-II and MHC-E epitope–targeted responses depended on vector infection of different nonoverlapping cell types in RMs. Selective inhibition of RhCMV infection in myeloid cells with miR-142–mediated tropism restriction eliminated MHC-E epitope–targeted CD8+ T cell priming, yielding an exclusively MHC-II epitope–targeted response. Inhibition with the endothelial cell–selective miR-126 eliminated MHC-II epitope–targeted CD8+ T cell priming, yielding an exclusively MHC-E epitope–targeted response. Dual miR-142 + miR-126–mediated tropism restriction reverted CD8+ T cell responses back to conventional MHC-Ia epitope targeting. Although the magnitude and differentiation state of these CD8+ T cell responses were generally similar, only the vectors programmed to elicit MHC-E–restricted CD8+ T cell responses provided protection against SIV challenge, directly demonstrating the essential role of these responses in RhCMV/SIV vaccine efficacy. RhCMV tropism determines unconventional response: CMV-based vaccine vectors for simian immunodeficiency virus (RhCMV/SIV) lead to profound protection against SIV in rhesus macaques (RMs). This protection is related to the induction of MHC-II– and MHC-E–targeting CD8+ T cells, but it is unclear how these unconventional cells are primed and which are needed for protection. Here, Hansen et al. used microRNAs to limit the ability of RhCMV/SIV vectors to replicate in various cell types. They found that limiting RhCMV/SIV vaccine replication in myeloid cells abrogated the induction of MHC-E–restricted T cells and protection against SIV of in RMs. These data suggest that the unconventional, MHC-E–restricted CD8+ T cells induced by RhCMV/SIV are critical for protection against SIV. [ABSTRACT FROM AUTHOR]

This paper introduces GCAM-CDR 1.0, an integrated assessment model for climate policy based on the open-source Global Change Analysis Model (GCAM). GCAM-CDR extends GCAM v5.4 by enabling users to model additional carbon dioxide removal (CDR) technologies and additional policies and controls related to CDR. New CDR technologies include terrestrial enhanced weathering with basalt, ocean liming, and additional versions of direct air capture. New CDR policies and controls include integration of bioenergy with carbon capture and storage (BECCS) into the CDR market, interregional trade in CDR, exogenous control over the rate of growth of CDR, the ability to set independent targets for emissions abatement and CDR, and a variety of mechanisms for setting demand for CDR at the regional and/or global level. These extensions enhance users' ability to study the potential roles of CDR in climate policy. [ABSTRACT FROM AUTHOR]

Only 57% of patients with an elevated hsTnT at both time points in Pareek's study had a final diagnosis of MI. The mortality rates reported in the study also presumably reflect standard management for ACS in those patients, including hospitalization in all patients and revascularization in a sizable proportion. [Extracted from the article]