Aims While most patients with myocardial infarction (MI) have underlying coronary atherosclerosis, not all patients with coronary artery disease (CAD) develop MI. We sought to address the hypothesis that some of the genetic factors which establish atherosclerosis may be distinct from those that predispose to vulnerable plaques and thrombus formation. Methods and results We carried out a genome-wide association study for MI in the UK Biobank (n∼472 000), followed by a meta-analysis with summary statistics from the CARDIoGRAMplusC4D Consortium (n∼167 000). Multiple independent replication analyses and functional approaches were used to prioritize loci and evaluate positional candidate genes. Eight novel regions were identified for MI at the genome wide significance level, of which effect sizes at six loci were more robust for MI than for CAD without the presence of MI. Confirmatory evidence for association of a locus on chromosome 1p21.3 harbouring choline-like transporter 3 (SLC44A3) with MI in the context of CAD, but not with coronary atherosclerosis itself, was obtained in Biobank Japan (n∼165 000) and 16 independent angiography-based cohorts (n∼27 000). Follow-up analyses did not reveal association of the SLC44A3 locus with CAD risk factors, biomarkers of coagulation, other thrombotic diseases, or plasma levels of a broad array of metabolites, including choline, trimethylamine N-oxide, and betaine. However, aortic expression of SLC44A3 was increased in carriers of the MI risk allele at chromosome 1p21.3, increased in ischaemic (vs. non-diseased) coronary arteries, up-regulated in human aortic endothelial cells treated with interleukin-1β (vs. vehicle), and associated with smooth muscle cell migration in vitro. Conclusions A large-scale analysis comprising ∼831 000 subjects revealed novel genetic determinants of MI and implicated SLC44A3 in the pathophysiology of vulnerable plaques.
Background The pathophysiology of COVID-19 includes immune-mediated hyperinflammation, which could potentially lead to respiratory failure and death. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is among cytokines that contribute to the inflammatory processes. Lenzilumab, a GM-CSF neutralising monoclonal antibody, was investigated in the LIVE-AIR trial to assess its efficacy and safety in treating COVID-19 beyond available treatments. Methods In LIVE-AIR, a phase 3, randomised, double-blind, placebo-controlled trial, hospitalised adult patients with COVID-19 pneumonia not requiring invasive mechanical ventilation were recruited from 29 sites in the USA and Brazil and were randomly assigned (1:1) to receive three intravenous doses of lenzilumab (600 mg per dose) or placebo delivered 8 h apart. All patients received standard supportive care, including the use of remdesivir and corticosteroids. Patients were stratified at randomisation by age and disease severity. The primary endpoint was survival without invasive mechanical ventilation to day 28 in the modified intention-to-treat population (mITT), comprising all randomised participants who received at least one dose of study drug under the documented supervision of the principal investigator or sub-investigator. Adverse events were assessed in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov , NCT04351152 , and is completed. Findings Patients were enrolled from May 5, 2020, until Jan 27, 2021. 528 patients were screened, of whom 520 were randomly assigned and included in the intention-to-treat population. 479 of these patients (n=236, lenzilumab; n=243, placebo) were included in the mITT analysis for the primary outcome. Baseline demographics were similar between groups. 311 (65%) participants were males, mean age was 61 (SD 14) years at baseline, and median C-reactive protein concentration was 79 (IQR 41–137) mg/L. Steroids were administered to 449 (94%) patients and remdesivir to 347 (72%) patients; 331 (69%) patients received both treatments. Survival without invasive mechanical ventilation to day 28 was achieved in 198 (84%; 95% CI 79–89) participants in the lenzilumab group and in 190 (78%; 72–83) patients in the placebo group, and the likelihood of survival was greater with lenzilumab than placebo (hazard ratio 1·54; 95% CI 1·02–2·32; p=0·040). 68 (27%) of 255 patients in the lenzilumab group and 84 (33%) of 257 patients in the placebo group experienced at least one adverse event that was at least grade 3 in severity based on CTCAE criteria. The most common treatment-emergent adverse events of grade 3 or higher were related to respiratory disorders (26%) and cardiac disorders (6%) and none led to death. Interpretation Lenzilumab significantly improved survival without invasive mechanical ventilation in hospitalised patients with CO...
Background The optimal timing of VTE prophylaxis initiation after blunt solid organ injury is controversial. Retrospective studies suggest initiation ≤48 h is safe. This prospective study examined the safety and efficacy of early VTE prophylaxis initiation after nonoperative blunt solid organ injury. Methods All patients >15 years of age presenting after blunt trauma (12/01/16–11/30/17) were prospectively screened. Patients were included if solid organ injury (liver, spleen, kidney) was diagnosed on admission CT scan and nonoperative management was planned. ED deaths, transfers, patients with pre‐existing bleeding disorders or home antiplatelet/anticoagulant medications, and those who did not receive VTE prophylaxis were excluded. Demographics, injury/clinical data, type/timing of VTE prophylaxis initiation, and outcomes were collected. Patients were dichotomized into study groups based on VTE prophylaxis initiation time: Early (≤48 h) vs Late (>48 h after admission). Prophylaxis initiation was at the discretion of the attending trauma surgeon. The primary study outcome was VTE event rate. Secondary outcomes included hospital length of stay (LOS), intensive care unit (ICU) LOS, need for and volume of post‐prophylaxis blood transfusion, need for delayed (post‐prophylaxis) interventional radiology (IR) or operative intervention, failure of nonoperative management, and mortality. Outcomes were compared with univariate analysis. Multivariate analysis with logistic regression determined independent predictors of late VTE prophylaxis initiation. Results After exclusions, 118 patients were identified. Median ISS was 22 [IQR 14–26]. Median AAST grade of injury was 2 [IQR 2–3] for liver, 2 [IQR 1–3] for spleen, and 3 [IQR 2–3] for kidney. Compared to late prophylaxis patients (n = 57, 48%), early prophylaxis patients (n = 61, 52%) had significantly fewer DVTs (n = 0, 0% vs n = 5, 9%, p = 0.024) but similar rates of PE (n = 2, 3% vs n = 3, 5%, p = 0.672). TBI was the only significant risk factor for late prophylaxis (OR 0.22, p = 0.015). No patient in either group required delayed intervention (operative or IR) for bleeding. There was no difference in volume of post‐prophylaxis blood transfusion. Conclusions In this prospective study of patients with nonoperative blunt solid organ injuries, early (≤48 h) initiation of VTE prophylaxis resulted in a lower incidence of DVTs without an associated increase in bleeding or need for intervention. Early initiation of VTE prophylaxis is likely to be safe and beneficial for patients with blunt solid organ injury.
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