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The use of a validated tool for risk assessment to inform hospital discharge, combined with rapid follow-up, led to a lower risk of death or hospitalization for cardiovascular causes within 30 days among patients with acute heart failure.

Background Although acetylsalicylic acid is the most commonly used antithrombotic agent for the secondary prevention of cardiovascular events, residual atherothrombotic risk has prompted a guideline recommendation for the addition of dual antiplatelet therapy (DAPT) or dual pathway inhibition (DPI) in high vascular risk patients. Accordingly, the CONNECT CVD quality enhancement initiative provides a contemporary “snapshot” of the clinical features and antithrombotic management of atherosclerotic cardiovascular disease (ASCVD) patients in Canada. Methods Canadian cardiologists (49 cardiologists from six provinces) undertook a retrospective chart audit of 10 ASCVD patients in their outpatient practice who met the Cardiovascular Outcomes for People Using Anticoagulation Strategy‐like criteria from May 2018 to April 2019. Results Of the 492 (two cardiologists provided 11 patients) enroled, average age was 70 years, 25% were female, 39% had diabetes and 20% had atrial fibrillation. Prior revascularisation was common (percutaneous coronary artery intervention 61%, coronary artery bypass graft 39%), with 31% having multivessel disease. A total of 47% of patients had a Reduction of Atherothrombosis for Continued Health bleeding score of ≥11 (~2.8% risk of serious bleeding at 2 years). Single antiplatelet therapy (SAPT) alone was most commonly used (62%), while 22% were on DAPT alone. In total, 22% were on oral anticoagulation (OAC), with 16% being on non‐vitamin K oral anticoagulant alone, 5% on DPI and 1% received triple therapy. Conclusions In contemporary Canadian clinical practice of stable ASCVD patients, a large number of patients receive antithrombotic therapy other than SAPT. Further efforts are required to guide the appropriate selection of patients in whom more potent antithrombotic therapies may safely reduce residual risk.

Semaglutide, a GLP-1 receptor agonist, reduces the risk of major adverse cardiovascular events (MACE) in people with overweight or obesity, but the effects of this drug on outcomes in patients with atherosclerotic cardiovascular disease and heart failure are unknown. We report a prespecified analysis of the effect of once-weekly subcutaneous semaglutide 2·4 mg on ischaemic and heart failure cardiovascular outcomes. We aimed to investigate if semaglutide was beneficial in patients with atherosclerotic cardiovascular disease with a history of heart failure compared with placebo; if there was a difference in outcome in patients designated as having heart failure with preserved ejection fraction compared with heart failure with reduced ejection fraction; and if the efficacy and safety of semaglutide in patients with heart failure was related to baseline characteristics or subtype of heart failure. The SELECT trial was a randomised, double-blind, multicentre, placebo-controlled, event-driven phase 3 trial in 41 countries. Adults aged 45 years and older, with a BMI of 27 kg/m2 or greater and established cardiovascular disease were eligible for the study. Patients were randomly assigned (1:1) with a block size of four using an interactive web response system in a double-blind manner to escalating doses of once-weekly subcutaneous semaglutide over 16 weeks to a target dose of 2·4 mg, or placebo. In a prespecified analysis, we examined the effect of semaglutide compared with placebo in patients with and without a history of heart failure at enrolment, subclassified as heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, or unclassified heart failure. Endpoints comprised MACE (a composite of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death); a composite heart failure outcome (cardiovascular death or hospitalisation or urgent hospital visit for heart failure); cardiovascular death; and all-cause death. The study is registered with ClinicalTrials.gov, NCT03574597. Between Oct 31, 2018, and March 31, 2021, 17 604 patients with a mean age of 61·6 years (SD 8·9) and a mean BMI of 33·4 kg/m2 (5·0) were randomly assigned to receive semaglutide (8803 [50·0%] patients) or placebo (8801 [50·0%] patients). 4286 (24·3%) of 17 604 patients had a history of investigator-defined heart failure at enrolment: 2273 (53·0%) of 4286 patients had heart failure with preserved ejection fraction, 1347 (31·4%) had heart failure with reduced ejection fraction, and 666 (15·5%) had unclassified heart failure. Baseline characteristics were similar between patients with and without heart failure. Patients with heart failure had a higher incidence of clinical events. Semaglutide improved all outcome measures in patients with heart failure at random assignment compared with those without heart failure (hazard ratio [HR] 0·72, 95% CI 0·60–0·87 for MACE; 0·79, 0·64–0·98 for the heart failure composite endpoint; 0·76, 0·59–0·97 for cardiovascular death; and 0·81, 0·66–1·00 for all-cause death; all pinteraction>0·19). Treatment with semaglutide resulted in improved outcomes in both the heart failure with reduced ejection fraction (HR 0·65, 95% CI 0·49–0·87 for MACE; 0·79, 0·58–1·08 for the composite heart failure endpoint) and heart failure with preserved ejection fraction groups (0·69, 0·51–0·91 for MACE; 0·75, 0·52–1·07 for the composite heart failure endpoint), although patients with heart failure with reduced ejection fraction had higher absolute event rates than those with heart failure with preserved ejection fraction. For MACE and the heart failure composite, there were no significant differences in benefits across baseline age, sex, BMI, New York Heart Association status, and diuretic use. Serious adverse events were less frequent with semaglutide versus placebo, regardless of heart failure subtype. In patients with atherosclerotic cardiovascular diease and overweight or obesity, treatment with semaglutide 2·4 mg reduced MACE and composite heart failure endpoints compared with placebo in those with and without clinical heart failure, regardless of heart failure subtype. Our findings could facilitate prescribing and result in improved clinical outcomes for this patient group. Novo Nordisk.

Vericiguat is indicated to reduce the risk of cardiovascular death and hospitalisation for heart failure in patients with heart failure and reduced ejection fraction (HFrEF) following a recent worsening event. The aim of the VICTOR trial was to assess the effect of vericiguat in patients with HFrEF without recent heart failure worsening. In this double-blind, placebo-controlled, phase 3 trial, conducted at 482 sites across 36 countries, patients aged 18 years or older with HFrEF (left ventricular ejection fraction of ≤40%) without heart failure hospitalisation within 6 months or outpatient intravenous diuretic use within 3 months before randomisation were randomly assigned (1:1) using an intervention randomisation system with interactive response technology to oral vericiguat (target 10 mg dose) or matching placebo. The primary composite endpoint was time to cardiovascular death or heart failure hospitalisation. Efficacy endpoints were assessed in the intention-to-treat population. Adverse events were assessed in all randomly assigned patients who received at least one dose of study drug (safety population). This trial is registered with ClinicalTrials.gov, NCT05093933, and is complete. Between Nov 2, 2021, and Dec 21, 2023, 10 921 patients were screened and 6105 were randomly assigned: 3053 to vericiguat and 3052 to placebo. The median age was 68·0 years (IQR 61·0–75·0), 1440 (23·6%) patients were women, 4665 (76·4%) were men, 3934 (64·4%) were White, and 2899 (47·5%) had no previous hospitalisation for heart failure. During a median follow-up of 18·5 months (IQR 13·6–24·7), primary outcome events occurred in 549 (18·0%) patients in the vericiguat group and 584 (19·1%) patients in the placebo group (hazard ratio [HR] 0·93 [95% CI 0·83–1·04]; p=0·22). As prespecified in the protocol, because the primary endpoint was not statistically significant, all analyses of secondary and exploratory endpoints are considered nominal. Cardiovascular death occurred in 292 (9·6%) patients in the vericiguat group and 346 (11·3%) patients in the placebo group (HR 0·83 [95% CI 0·71–0·97]). Hospitalisation for heart failure occurred in 348 (11·4%) patients in the vericiguat group and in 362 (11·9%) patients in the placebo group (HR 0·95 [95% CI 0·82–1·10]). Serious adverse events occurred in 717 (23·5%) of 3049 patients in the vericiguat group and 751 (24·6%) of 3049 patients in the placebo group. The most common adverse event was symptomatic hypotension (345 [11·3%] patients in the vericiguat group and 281 [9·2%] in the placebo group). All-cause death occurred in 377 (12·3%) patients in the vericiguat group and 440 (14·4%) patients in the placebo group (HR 0·84 [95% CI 0·74–0·97]). Among patients with HFrEF and no recent worsening, vericiguat did not reduce the risk of a composite endpoint of time to cardiovascular death or heart failure hospitalisation. Fewer cardiovascular deaths were observed in the vericiguat group than in the placebo group. Merck Sharp & Dohme (a subsidiary of Merck) and Bayer.

Following completion of the VICTORIA trial, vericiguat was approved for the treatment of worsening heart failure with reduced ejection fraction (HFrEF) and received a class IIb recommendation in European and North American guidelines. The subsequent VICTOR trial evaluated the use of vericiguat in patients with HFrEF and no recent worsening. We aimed to assess the effect of vericiguat on clinical endpoints through pooled analyses of patient-level data from the VICTORIA and VICTOR trials. This prespecified, pooled individual participant-level analysis was conducted on data from two trials: VICTORIA, which was active from Sept 25, 2016, to Sept 2, 2019 in 42 countries, and VICTOR, which was active from Nov 2, 2021, to Feb 5, 2025 in 36 countries. The VICTORIA trial enrolled adult (aged ≥18 years) participants with HFrEF with recent worsening (defined as either hospitalisation for heart failure within the previous 6 months or outpatient use of intravenous diuretics within the previous 3 months) and increased NT-proBNP concentrations; the VICTOR trial had similar eligibility criteria but participants had no recent worsening of heart failure. Participants in both trials received contemporary background guideline-directed heart failure therapy as appropriate. The primary endpoint was a composite endpoint of cardiovascular death or hospitalisation for heart failure (also assessed individually). This study is registered with PROSPERO, CRD420251065636. Data from 11 155 patients (5050 in the VICTORIA trial and 6105 in the VICTOR trial) were included in the pooled analysis. The primary endpoint of cardiovascular death or hospitalisation for heart failure occurred in 1446 (25·9%) of 5579 patients in the vericiguat group and 1556 (27·9%) of 5576 patients in the placebo group (hazard ratio [HR] 0·91 [95% CI 0·85–0·98]; p=0·0088), with similar reductions in its individual components of cardiovascular death (0·89 [0·80–0·98]; p=0·020) and hospitalisation for heart failure (0·92 [0·84–1·00]; p=0·043) as first events. Vericiguat reduced the risk of hospitalisation for heart failure and cardiovascular death in patients with HFrEF across a broad range of clinical severity, including those receiving contemporary guideline-directed medical therapy. Vericiguat might be suitable as an additional treatment option for selected patients with HFrEF. Merck Sharp & Dohme (a subsidiary of Merck) and Bayer.

The expression of the two gene products (M1 and M2) for the two subunits of the heterodimeric deoxynucleotide biosynthetic enzyme ribonucleoside diphosphate reductase (RNR) is not induced, as in the normal cell cycle, following exposure of animals to 2-AAF and partial hepatectomy. We have proposed two possible mechanisms to explain the seemingly specific effects of 2-AAF on the induction of RNR. The catalylitically essential tyrosyl free radical of RNR is susceptible to attack by hydroxylamines, such as hydroxyurea (HU). This interaction results in a quenching of the radical and inhibition of catalytic activity. It is possible that a hydroxylamine metabolite of 2-AAF might interact with RNR in a manner analogous to hydroxyurea. This may well result in an inhibition of enzyme activity with some secondary feedback control of transcription of the genes for both subunits of the enzyme. The other possibility suggests that the induction of RNR activity in hepatocytes is sensitive to the alkylative damage, ostensibly with DNA as a target, caused by metabolites of 2-AAF. The findings of this study (i.e. ribonucleotide reductase purification, in vitro enzyme inhibition studies, enzyme expression following exposure of animals to various mitoinhibitors, including Northern analysis) do not support the hypothesis that the seemingly specific inhibition of induction of RNR in the livers of animals pre-exposed to 2-AAF can be accounted for solely by an interaction between a metabolite of 2-AAF and RNR. Rather, the hypothesis that the induction of ribonucleotide reductase is sensitive to the levels of DNA damage, caused by alkylating agents, can best explain the results obtained.

The spike (S) protein of severe acute respiratory syndrome coronavirus (SARS-CoV) mediates viral entry into target cells. Cleavage and activation of SARS S by a host cell protease is essential for infectious viral entry and the responsible enzymes are potential targets for antiviral intervention. The type II transmembrane serine protease TMPRSS2 cleaves and activates SARS S in cell culture and potentially also in the infected host. Here, we investigated which determinants in SARS S control cleavage and activation by TMPRSS2. We found that SARS S residue R667, a previously identified trypsin cleavage site, is also required for S protein cleavage by TMPRSS2. The cleavage fragments produced by trypsin and TMPRSS2 differed in their decoration with N-glycans, suggesting that these proteases cleave different SARS S glycoforms. Although R667 was required for SARS S cleavage by TMPRSS2, this residue was dispensable for TMPRSS2-mediated S protein activation. Conversely, residue R797, previously reported to be required for SARS S activation by trypsin, was dispensable for S protein cleavage but required for S protein activation by TMPRSS2. Collectively, these results show that different residues in SARS S control cleavage and activation by TMPRSS2, suggesting that these processes are more complex than initially appreciated.

FloraGREIF presents an internet-based information tool on the vascular plant flora of Mongolia combining taxon- and record-specific information, text and image information with map information and digitized plant specimens with images of living species and their habitats. Based on an updated checklist as taxonomic backbone, information is split into the \"taxon\" and the \"record\" level. At the taxon level the user finds taxonomic diagnoses, habitat information, and species distribution within the floristic regions of Mongolia. The latter is visualized in a Web GIS application. The record level offers information for all records assigned to one taxon, which may include locality data only or additional, high-resolution scans of herbarium specimens combined with images from living species and their habitats. Several query masks allow a flexible search and display of species lists. The interactive Web GIS application links taxon or record information with various map layers, comprising administrative units, topography and orography, floristic regions and vegetation zones of Mongolia. They present background information for the display of species distribution or record localities. FloraGREIF offers a virtual research environment to make the substantial information on Mongolia's flora mainly published in Russian accessible to the public.