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The article reports that The value of variant-adapted vaccines that are capable of inducing a higher and broader immune response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at booster vaccination is currently being evaluated.1-4 We conducted a multicenter, randomized, single-blind trial to assess the immunogenicity and safety of two adjuvanted recombinant vaccines and the messenger RNA (mRNA) vaccine BNT162b2 (Pfizer–BioNTech) administered as a booster.

Ticagrelor reduced major adverse cardiovascular events (MACE) and increased bleeding in patients with type 2 diabetes mellitus (T2DM) and coronary artery disease. Limb events including revascularization, acute limb ischemia (ALI), and amputation are major morbidities in patients with T2DM and atherosclerosis. This study sought to determine the effect of ticagrelor on limb events. Patients were randomized to ticagrelor or placebo on top of aspirin and followed for a median of 3 years. MACE (cardiovascular death, myocardial infarction, or stroke), limb events (ALI, amputation, revascularization), and bleeding were adjudicated by an independent and blinded clinical events committee. The presence of peripheral artery disease (PAD) was reported at baseline. Of 19,220 patients randomized, 1,687 (8.8%) had PAD at baseline. In patients receiving placebo, PAD was associated with higher MACE (10.7% vs 7.3%; HR: 1.48; P < 0.001) and limb (9.5% vs 0.8%; HR: 10.67; P < 0.001) risk. Ticagrelor reduced limb events (1.6% vs 1.3%; HR: 0.77; 95% CI: 0.61-0.96; P = 0.022) with significant reductions for revascularization (HR: 0.79; 95% CI: 0.62-0.99; P = 0.044) and ALI (HR: 0.24; 95% CI: 0.08-0.70; P = 0.009). The benefit was consistent with or without PAD (HR: 0.80; 95% CI: 0.58-1.11; and HR: 0.76; 95% CI: 0.55-1.05, respectively; P interaction = 0.81). There was no effect modification of ticagrelor vs placebo based on PAD for MACE (P interaction = 0.40) or TIMI major bleeding (P interaction = 0.3239). Patients with T2DM and atherosclerosis are at high risk of limb events. Ticagrelor decreased this risk, but increased bleeding. Future trials evaluating the combination of ticagrelor and aspirin would further elucidate the benefit/risk of such therapy in patients with PAD, including those without coronary artery disease. (A Study Comparing Cardiovascular Effects of Ticagrelor Versus Placebo in Patients With Type 2 Diabetes Mellitus [THEMIS]: NCT01991795) [Display omitted] [ABSTRACT FROM AUTHOR]

Background: ST-segment-elevation myocardial infarction (STEMI) and non-ST-segment-elevation myocardial infarction (NSTEMI) management has evolved considerably over the past 2 decades. Little information on mortality trends in the most recent years is available. We assessed trends in characteristics, treatments, and outcomes for acute myocardial infarction in France between 1995 and 2015.Methods: We used data from 5 one-month registries, conducted 5 years apart, from 1995 to 2015, including 14 423 patients with acute myocardial infarction (59% STEMI) admitted to cardiac intensive care units in metropolitan France.Results: From 1995 to 2015, mean age decreased from 66±14 to 63±14 years in patients with STEMI; it remained stable (68±14 years) in patients with NSTEMI, whereas diabetes mellitus, obesity, and hypertension increased. At the acute stage, intended primary percutaneous coronary intervention increased from 12% (1995) to 76% (2015) in patients with STEMI. In patients with NSTEMI, percutaneous coronary intervention ≤72 hours from admission increased from 9% (1995) to 60% (2015). Six-month mortality consistently decreased in patients with STEMI from 17.2% in 1995 to 6.9% in 2010 and 5.3% in 2015; it decreased from 17.2% to 6.9% in 2010 and 6.3% in 2015 in patients with NSTEMI. Mortality still decreased after 2010 in patients with STEMI without reperfusion therapy, whereas no further mortality gain was found in patients with STEMI with reperfusion therapy or in patients with NSTEMI, whether or not they were treated with percutaneous coronary intervention.Conclusions: Over the past 20 years, 6-month mortality after acute myocardial infarction has decreased considerably for patients with STEMI and NSTEMI. Mortality figures continued to decline in patients with STEMI until 2015, whereas mortality in patients with NSTEMI appears stable since 2010. [ABSTRACT FROM AUTHOR]

The authors comment on the clinical impact of pharmacogenomics of clopidogrel in the treatment of stroke. They explain the increasing incidence of stroke despite progress in its diagnosis and treatment. They discuss a study which examined the effectiveness of clopidogrel, in addition to aspirin therapy, in reducing the risk of stroke. The relationship between the effect of clopidogrel, vascular mortality, nonfatal myocardial infarction, and stroke, and CYP2C19 polymorphisms is also discussed.

Antithrombotic drugs, which include antiplatelet and anticoagulant therapies, prevent and treat many cardiovascular disorders and, as such, are some of the most commonly prescribed drugs worldwide. The first drugs designed to inhibit platelets or coagulation factors, such as the antiplatelet clopidogrel and the anticoagulant warfarin, significantly reduced the risk of thrombotic events at the cost of increased bleeding in patients. However, both clopidogrel and warfarin have some pharmacological limitations including interpatient variability in antithrombotic effects in part due to the metabolism, interactions (eg, drug, environment, and genetic), or targets of the drugs. Increased knowledge of the pharmacology of antithrombotic drugs and the mechanisms underlying thrombosis has led to the development of newer drugs with faster onset of action, fewer interactions, and less interpatient variability in their antithrombotic effects than previous antithrombotic drugs. Treatment options now include the next-generation antiplatelet drugs prasugrel and ticagrelor, and, in terms of anticoagulants, inhibitors that directly target factor IIa (dabigatran) or Xa (rivaroxaban, apixaban, edoxaban) are available. In this Series paper we review the pharmacological properties of these most commonly used oral antithrombotic drugs, and explore the development of antiplatelet and anticoagulant therapies. [ABSTRACT FROM AUTHOR]

Objectives: This study sought to investigate the role of secretory phospholipase A2 (sPLA2)-IIA in cardiovascular disease.Background: Higher circulating levels of sPLA2-IIA mass or sPLA2 enzyme activity have been associated with increased risk of cardiovascular events. However, it is not clear if this association is causal. A recent phase III clinical trial of an sPLA2 inhibitor (varespladib) was stopped prematurely for lack of efficacy.Methods: We conducted a Mendelian randomization meta-analysis of 19 general population studies (8,021 incident, 7,513 prevalent major vascular events [MVE] in 74,683 individuals) and 10 acute coronary syndrome (ACS) cohorts (2,520 recurrent MVE in 18,355 individuals) using rs11573156, a variant in PLA2G2A encoding the sPLA2-IIA isoenzyme, as an instrumental variable.Results: PLA2G2A rs11573156 C allele associated with lower circulating sPLA2-IIA mass (38% to 44%) and sPLA2 enzyme activity (3% to 23%) per C allele. The odds ratio (OR) for MVE per rs11573156 C allele was 1.02 (95% confidence interval [CI]: 0.98 to 1.06) in general populations and 0.96 (95% CI: 0.90 to 1.03) in ACS cohorts. In the general population studies, the OR derived from the genetic instrumental variable analysis for MVE for a 1-log unit lower sPLA2-IIA mass was 1.04 (95% CI: 0.96 to 1.13), and differed from the non-genetic observational estimate (OR: 0.69; 95% CI: 0.61 to 0.79). In the ACS cohorts, both the genetic instrumental variable and observational ORs showed a null association with MVE. Instrumental variable analysis failed to show associations between sPLA2 enzyme activity and MVE.Conclusions: Reducing sPLA2-IIA mass is unlikely to be a useful therapeutic goal for preventing cardiovascular events. [ABSTRACT FROM AUTHOR]

Objectives: This study sought to investigate the role of secretory phospholipase A2 (sPLA2)-IIA in cardiovascular disease. Background: Higher circulating levels of sPLA2-IIA mass or sPLA2 enzyme activity have been associated with increased risk of cardiovascular events. However, it is not clear if this association is causal. A recent phase III clinical trial of an sPLA2 inhibitor (varespladib) was stopped prematurely for lack of efficacy. Methods: We conducted a Mendelian randomization meta-analysis of 19 general population studies (8,021 incident, 7,513 prevalent major vascular events [MVE] in 74,683 individuals) and 10 acute coronary syndrome (ACS) cohorts (2,520 recurrent MVE in 18,355 individuals) using rs11573156, a variant in PLA2G2A encoding the sPLA2-IIA isoenzyme, as an instrumental variable. Results: PLA2G2A rs11573156 C allele associated with lower circulating sPLA2-IIA mass (38% to 44%) and sPLA2 enzyme activity (3% to 23%) per C allele. The odds ratio (OR) for MVE per rs11573156 C allele was 1.02 (95% confidence interval [CI]: 0.98 to 1.06) in general populations and 0.96 (95% CI: 0.90 to 1.03) in ACS cohorts. In the general population studies, the OR derived from the genetic instrumental variable analysis for MVE for a 1-log unit lower sPLA2-IIA mass was 1.04 (95% CI: 0.96 to 1.13), and differed from the non-genetic observational estimate (OR: 0.69; 95% CI: 0.61 to 0.79). In the ACS cohorts, both the genetic instrumental variable and observational ORs showed a null association with MVE. Instrumental variable analysis failed to show associations between sPLA2 enzyme activity and MVE. Conclusions: Reducing sPLA2-IIA mass is unlikely to be a useful therapeutic goal for preventing cardiovascular events. [Copyright &y& Elsevier]

The article presents a research which aims to assess the association between changes in mortality and patient management with ST-segment elevation myocardial infarction (STEMI) by analyzing French surveys conducted between 1995 and 2010. It is concluded that the overall rate of patients with STEMI has decreased in France followed by an increase in the proportion of STEMI women younger than 60 years. The main findings of this study are nine percent decrease in STEMI mortality in 15 years.

The article provides information on a study which examined the risk of major adverse cardiovascular outcomes among carriers of reduced-function CYP2C19 genetic variants in patients treated with clopidogrel for percutaneous coronary intervention (PCI). An overview of the mechanism of action and metabolism of clopidogrel is given. Data reviewed were from MEDLINE, Cochrane Database of Systematic Reviews and EMBASE. A discussion on the research findings is detailed. The increased risk of major adverse cardiovascular events, specifically stent thrombosis, was observed among patients given with clopidogrel for PCI.

Background: Pharmacogenetic determinants of the response of patients to clopidogrel contribute to variability in the biologic antiplatelet activity of the drug. The effect of these determinants on clinical outcomes after an acute myocardial infarction is unknown. Methods: We consecutively enrolled 2208 patients presenting with an acute myocardial infarction in a nationwide French registry and receiving clopidogrel therapy. We then assessed the relation of allelic variants of genes modulating clopidogrel absorption (ABCB1), metabolic activation (CYP3A5 and CYP2C19), and biologic activity (P2RY12 and ITGB3) to the risk of death from any cause, nonfatal stroke, or myocardial infarction during 1 year of follow-up. Results: Death occurred in 225 patients, and nonfatal myocardial infarction or stroke in 94 patients, during the follow-up period. None of the selected single-nucleotide polymorphisms (SNPs) in CYP3A5, P2RY12, or ITGB3 were associated with a risk of an adverse outcome. Patients with two variant alleles of ABCB1 (TT at nucleotide 3435) had a higher rate of cardiovascular events at 1 year than those with the ABCB1 wild-type genotype (CC at nucleotide 3435) (15.5% vs. 10.7%; adjusted hazard ratio, 1.72; 95% confidence interval [CI], 1.20 to 2.47). Patients carrying any two CYP2C19 loss-of-function alleles (*2, *3, *4, or *5), had a higher event rate than patients with none (21.5% vs. 13.3%; adjusted hazard ratio, 1.98; 95% CI, 1.10 to 3.58). Among the 1535 patients who underwent percutaneous coronary intervention during hospitalization, the rate of cardiovascular events among patients with two CYP2C19 loss-of-function alleles was 3.58 times the rate among those with none (95% CI, 1.71 to 7.51). Conclusions: Among patients with an acute myocardial infarction who were receiving clopidogrel, those carrying CYP2C19 loss-of-function alleles had a higher rate of subsequent cardiovascular events than those who were not. This effect was particularly marked among the patients undergoing percutaneous coronary intervention. (ClinicalTrials.gov number, NCT00673036.) N Engl J Med 2009;360:363-75. [ABSTRACT FROM AUTHOR]

ABSTRACT Aims Methods and results Conclusion Burst steroid therapy, effective in acute respiratory diseases, may benefit patients with acute heart failure (AHF) in whom inflammatory activation is associated with adverse outcomes.CORTAHF assessed whether burst steroid therapy reduces inflammation and results in better quality of life and clinical outcomes in AHF. Patients with AHF, N‐terminal pro‐B‐type natriuretic peptide >1500 pg/ml, and high‐sensitivity C‐reactive protein (hsCRP) >20 mg/L were randomized 1:1 to oral, once daily 40 mg prednisone for 7 days or usual care, without blinding. Patients were followed for 90 days. A total of 101 patients were randomized. At day 7 the primary endpoint, hsCRP decreased in both arms – adjusted geometric mean ratios (GMRs) were 0.30 and 0.40 in the prednisone and usual care arms (ratio of GMRs 0.75, 95% confidence interval [CI] 0.56–1.00, p = 0.0498). The 90‐day risk of worsening heart failure (HF), HF readmission or death as reported by the unblinded investigators was significantly lower in the prednisone group (10.4%) than in usual care (30.8%) (hazard ratio 0.31, 95% CI 0.11–0.86, p = 0.016). The EQ‐5D visual analogue scale score as reported by the unblinded patients increased more in the prednisone group on day 7 (least squares mean difference 2.57, 95% CI 0.12–5.01 points, p = 0.040). All effects were statistically significant in the pre‐specified subgroup with centrally‐measured interleukin‐6 >13 pg/ml. Adverse events, particularly hyperglycaemia, occurred more in the prednisone group with no difference in infection rate.In this small open‐label study of patients with AHF, burst steroid therapy was associated with reduced inflammation as measured by hsCRP levels at day 7 (primary endpoint). Secondary endpoints showed improved quality of life at day 7 and reduced 90‐day risk of death or worsening HF. Large prospective studies are needed to evaluate these findings. [ABSTRACT FROM AUTHOR]

COVID-19 is associated with heterogeneous outcome. Early identification of a severe progression of the disease is essential to properly manage the patients and improve their outcome. Biomarkers reflecting an increased inflammatory response, as well as individual features including advanced age, male gender, and pre-existing comorbidities, are risk factors of severe COVID-19. Yet, these features show limited accuracy for outcome prediction. The aim was to evaluate the prognostic value of whole blood transcriptome at an early stage of the disease. Blood transcriptome of patients with mild pneumonia was profiled. Patients with subsequent severe COVID-19 were compared to those with favourable outcome, and a molecular predictor based on gene expression was built. Unsupervised classification discriminated patients who would later develop a COVID-19-related severe pneumonia. The corresponding gene expression signature reflected the immune response to the viral infection dominated by a prominent type I interferon, with IFI27 among the most over-expressed genes. A 48-genes transcriptome signature predicting the risk of severe COVID-19 was built on a training cohort, then validated on an external independent cohort, showing an accuracy of 81% for predicting severe outcome. These results identify an early transcriptome signature of severe COVID-19 pneumonia, with a possible relevance to improve COVID-19 patient management. [ABSTRACT FROM AUTHOR]

BACKGROUND In patients with ST-elevation myocardial infarction (STEMI) who have multivessel disease, percutaneous coronary intervention (PCI) for nonculprit lesions (complete revascularization) is superior to treatment of the culprit lesion alone. However, whether complete revascularization that is guided by fractional flow reserve (FFR) is superior to an angiography-guided procedure is unclear. METHODS In this multicenter trial, we randomly assigned patients with STEMI and multivessel disease who had undergone successful PCI of the infarct-related artery to receive complete revascularization guided by either FFR or angiography. The primary outcome was a composite of death from any cause, nonfatal myocardial infarction, or unplanned hospitalization leading to urgent revascularization at 1 year. RESULTS The mean (±SD) number of stents that were placed per patient for nonculprit lesions was 1.01±0.99 in the FFR-guided group and 1.50±0.86 in the angiography-guided group. During follow-up, a primary outcome event occurred in 32 of 586 patients (5.5%) in the FFR-guided group and in 24 of 577 patients (4.2%) in the angiography-guided group (hazard ratio, 1.32; 95% confidence interval, 0.78 to 2.23; P=0.31). Death occurred in 9 patients (1.5%) in the FFR-guided group and in 10 (1.7%) in the angiography-guided group; nonfatal myocardial infarction in 18 (3.1%) and 10 (1.7%), respectively; and unplanned hospitalization leading to urgent revascularization in 15 (2.6%) and 11 (1.9%), respectively. CONCLUSIONS In patients with STEMI undergoing complete revascularization, an FFR-guided strategy did not have a significant benefit over an angiography-guided strategy with respect to the risk of death, myocardial infarction, or urgent revascularization at 1 year. However, given the wide confidence intervals for the estimate of effect, the findings do not allow for a conclusive interpretation. [ABSTRACT FROM AUTHOR]

The NICO (non-invasive airway management in comatose patients) randomized controlled trial found that withholding intubation in acute poisoned comatose patients with a Glasgow Coma Scale < 9 led to significant clinical improvement in terms of in-hospital death, length of stay in the intensive care unit (ICU), and length of hospital stay compared to routine practice. The trial also conducted an economic evaluation, which showed that withholding intubation was both cost-saving and event-reducing. The study suggests that policymakers should consider utilizing these monetary benefits in critical care. [Extracted from the article]

Background: Asymptomatic and paucisymptomatic infections account for a substantial portion of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) transmissions. The value of intensified screening strategies, especially in emergency departments (EDs), in reaching asymptomatic and paucisymptomatic patients and helping to improve detection and reduce transmission has not been documented. The objective of this study was to evaluate in EDs whether an intensified SARS-CoV-2 screening strategy combining nurse-driven screening for asymptomatic/paucisymptomatic patients with routine practice (intervention) could contribute to higher detection of SARS-CoV-2 infections compared to routine practice alone, including screening for symptomatic or hospitalized patients (control). Methods and findings: We conducted a cluster-randomized, two-period, crossover trial from February 2021 to June 2021 in 18 EDs in the Paris metropolitan area, France. All adults visiting the EDs were eligible. At the start of the first period, 18 EDs were randomized to the intervention or control strategy by balanced block randomization with stratification, with the alternative condition being applied in the second period. During the control period, routine screening for SARS-CoV-2 included screening for symptomatic or hospitalized patients. During the intervention period, in addition to routine screening practice, a questionnaire about risk exposure and symptoms and a SARS-CoV-2 screening test were offered by nurses to all remaining asymptomatic/paucisymptomatic patients. The primary outcome was the proportion of newly diagnosed SARS-CoV-2–positive patients among all adults visiting the 18 EDs. Primary analysis was by intention-to-treat. The primary outcome was analyzed using a generalized linear mixed model (Poisson distribution) with the center and center by period as random effects and the strategy (intervention versus control) and period (modeled as a weekly categorical variable) as fixed effects with additional adjustment for community incidence. During the intervention and control periods, 69,248 patients and 69,104 patients, respectively, were included for a total of 138,352 patients. Patients had a median age of 45.0 years [31.0, 63.0], and women represented 45.7% of the patients. During the intervention period, 6,332 asymptomatic/paucisymptomatic patients completed the questionnaire; 4,283 were screened for SARS-CoV-2 by nurses, leading to 224 new SARS-CoV-2 diagnoses. A total of 1,859 patients versus 2,084 patients were newly diagnosed during the intervention and control periods, respectively (adjusted analysis: 26.7/1,000 versus 26.2/1,000, adjusted relative risk: 1.02 (95% confidence interval (CI) [0.94, 1.11]; p = 0.634)). The main limitation of this study is that it was conducted in a rapidly evolving epidemiological context. Conclusions: The results of this study showed that intensified screening for SARS-CoV-2 in EDs was unlikely to identify a higher proportion of newly diagnosed patients. Trial registration: Trial registration number: ClinicalTrials.gov NCT04756609. Judith Leblanc and co-workers report a cluster-randomized trial evaluating intensive screening for SARS-CoV-2 infection in emergency departments. Author summary: Why was this study done?: Undetected asymptomatic Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infections or paucisymptomatic infections with mild symptoms are responsible for a substantial portion of transmissions, which has been a major challenge in managing the Coronavirus Disease 2019 (COVID-19) pandemic. Free and widely available screening has been offered in many countries to reach asymptomatic/paucisymptomatic infectious individuals and improve detection, reduce transmission, and help contain the pandemic. To our knowledge, the value of systematically offering screening during medical consultations, particularly in emergency departments (EDs), to identify asymptomatic/paucisymptomatic infectious individuals has not been evaluated. What did the researchers do and find?: The objective of this trial was to evaluate whether an intensified screening strategy involving screening for asymptomatic/paucisymptomatic patients and routine screening of symptomatic and hospitalized patients (intervention) could lead to a higher proportion of new diagnoses compared with routine screening (control) in 18 EDs in the Paris metropolitan region. During the intervention period, 4,283 asymptomatic/paucisymptomatic patients were screened, leading to 224 new diagnoses. Overall, 1,859 patients were newly diagnosed during the intervention period versus 2,084 during the control period, corresponding, after analysis, to 26.7 new diagnoses/1,000 patients versus 26.2/1,000. The proportion of new diagnoses among asymptomatic/paucisymptomatic patients in EDs was higher than that in community screenings in the region. Comparison with findings from a mathematical model indicated that ED data allowed the estimation of regional incidences for asymptomatic/paucisymptomatic infections. What do these findings mean?: The results of this study showed that the intensified screening strategy was unlikely to bring a substantial benefit to the detection of SARS-CoV-2 infections. The population screened in EDs appeared to be more affected by SARS-CoV-2 than the general population screened in the region. Intensified screening in EDs could allow access to individuals who are less likely to be reached by the general screening system. The main limitation of this study is that it was conducted in a changing epidemiological context, which encourages further exploration of screening strategies for asymptomatically transmitted respiratory viruses to better define the observatory role of EDs in emerging epidemics. [ABSTRACT FROM AUTHOR]

Background: The aim of this trial-based economic evaluation was to assess the incremental costs and cost-effectiveness of the modified diagnostic strategy combining the YEARS rule and age-adjusted D-dimer threshold compared with the control (which used the age-adjusted D-dimer threshold only) for the diagnosis of pulmonary embolism (PE) in the Emergency Department (ED). Methods: Economic evaluation from a healthcare system perspective alongside a non-inferiority, crossover, and cluster-randomized trial conducted in 16 EDs in France and two in Spain with three months of follow-up. The primary endpoint was the additional cost of a patient without failure of the diagnostic strategy, defined as venous thromboembolism (VTE) diagnosis at 3months after exclusion of PE during the initial ED visit. Mean differences in 3-month failure and costs were estimated using separate generalized linear-regression mixed models, adjusted for strategy type, period, and the interaction between strategy and period as fixed effects and the hospital as a random effect. The incremental cost-effectiveness ratio (ICER) was obtained by dividing the incremental costs by the incremental frequency of VTE. Results: Of the 1,414 included patients, 1,217 (86%) were analyzed in the per-protocol analysis (648 in the intervention group and 623 in the control group). At three months, there were no statistically significant differences in total costs (€-46; 95% CI: €-93 to €0.2), and the failure rate was non inferior in the intervention group (-0.64%, one-sided 97.5% CI: -∞ to 0.21%, non-inferiority margin 1.5%) between groups. The point estimate of the incremental cost-effectiveness ratio (ICER) indicating that each undetected VTE averted in the intervention group is associated with cost savings of €7,142 in comparison with the control group. There was a 93% probability that the intervention was dominant. Similar results were found in the as randomized population. Conclusions: Given the observed cost decrease of borderline significance, and according to the 95% confidence ellipses, the intervention strategy has a potential to lead to cost savings as a result of a reduction in the use of chest imaging and of the number of undetected VTE averted. Policy-makers should investigate how these monetary benefits can be distributed across stakeholders. Clinicaltrials: Trial registration number ClinicalTrials.gov Identifier: NCT04032769; July 25, 2019. [ABSTRACT FROM AUTHOR]

We aimed at assessing the efficacy and safety on antibiotic exposure of a strategy combining a respiratory multiplex PCR (mPCR) with enlarged panel and daily procalcitonin (PCT) measurements, as compared with a conventional strategy, in adult patients who were critically ill with laboratory-confirmed SARS-CoV-2 pneumonia. This multicentre, parallel-group, open-label, randomized controlled trial enrolled patients admitted to 13 intensive care units (ICUs) in France. Patients were assigned (1:1) to the control strategy, in which antibiotic streamlining remained at the discretion of the physicians, or interventional strategy, consisting of using mPCR and daily PCT measurements within the first 7 days of randomization to streamline initial antibiotic therapy, with antibiotic continuation encouraged when PCT was >1 ng/mL and discouraged if < 1 ng/mL or decreased by 80% from baseline. All patients underwent conventional microbiological tests and cultures. The primary end point was antibiotic-free days at day 28. Between April 20th and November 23rd 2020, 194 patients were randomized, of whom 191 were retained in the intention-to-treat analysis. Respiratory bacterial co-infection was detected in 48.4% (45/93) and 21.4% (21/98) in the interventional and control group, respectively. The number of antibiotic-free days was 12.0 (0.0; 25.0) and 14.0 (0.0; 24.0) days, respectively (difference, −2.0, (95% CI, −10.6 to 6.6), p=0.89). Superinfection rates were high (51.6% and 48.5%, respectively). Mortality rates and ICU lengths of stay did not differ between groups. In severe SARS-CoV-2 pneumonia, the mPCR/PCT algorithm strategy did not affect 28-day antibiotics exposure nor the major clinical outcomes, as compared with routine practice. [ABSTRACT FROM AUTHOR]

Importance: The high mortality rate in critically ill elderly patients has led to questioning of the beneficial effect of intensive care unit (ICU) admission and to a variable ICU use among this population.Objective: To determine whether a recommendation for systematic ICU admission in critically ill elderly patients reduces 6-month mortality compared with usual practice.Design, Setting, and Participants: Multicenter, cluster-randomized clinical trial of 3037 critically ill patients aged 75 years or older, free of cancer, with preserved functional status (Index of Independence in Activities of Daily Living ≥4) and nutritional status (absence of cachexia) who arrived at the emergency department of one of 24 hospitals in France between January 2012 and April 2015 and were followed up until November 2015.Interventions: Centers were randomly assigned either to use a program to promote systematic ICU admission of patients (n=1519 participants) or to follow standard practice (n=1518 participants).Main Outcomes and Measures: The primary outcome was death at 6 months. Secondary outcomes included ICU admission rate, in-hospital death, functional status, and quality of life (12-Item Short Form Health Survey, ranging from 0 to 100, with higher score representing better self-reported health) at 6 months.Results: One patient withdrew consent, leaving 3036 patients included in the trial (median age, 85 [interquartile range, 81-89] years; 1361 [45%] men). Patients in the systematic strategy group had an increased risk of death at 6 months (45% vs 39%; relative risk [RR], 1.16; 95% CI, 1.07-1.26) despite an increased ICU admission rate (61% vs 34%; RR, 1.80; 95% CI, 1.66-1.95). After adjustments for baseline characteristics, patients in the systematic strategy group were more likely to be admitted to an ICU (RR, 1.68; 95% CI, 1.54-1.82) and had a higher risk of in-hospital death (RR, 1.18; 95% CI, 1.03-1.33) but had no significant increase in risk of death at 6 months (RR, 1.05; 95% CI, 0.96-1.14). Functional status and physical quality of life at 6 months were not significantly different between groups.Conclusions and Relevance: Among critically ill elderly patients in France, a program to promote systematic ICU admission increased ICU use but did not reduce 6-month mortality. Additional research is needed to understand the decision to admit elderly patients to the ICU.Trial Registration: clinicaltrials.gov Identifier: NCT01508819. [ABSTRACT FROM AUTHOR]

THEMIS is a double-blind, randomized trial of 19,220 patients with diabetes mellitus and stable coronary artery disease (CAD) comparing ticagrelor to placebo, in addition to aspirin. The present study aimed to describe the proportion of patients eligible and reasons for ineligibility for THEMIS within a population of patients with diabetes and CAD included in the Reduction of Atherothrombosis for Continued Health (REACH) registry. The THEMIS eligibility criteria were applied to REACH patients. THEMIS included patients ≥50 years with type 2 diabetes and stable CAD as determined by either a history of previous percutaneous coronary intervention, coronary artery bypass grafting, or documentation of angiographic stenosis of ≥50% of at least one coronary artery. Patients with prior myocardial infarction or stroke were excluded. In REACH, 10,156 patients had stable CAD and diabetes. Of these, 6515 (64.1%) patients had at least one exclusion criteria. From the remaining population, 784 patients did not meet inclusion criteria (7.7%) mainly due to absence of aspirin treatment (7.2%), yielding a 'THEMIS-eligible population' of 2857 patients (28.1% of patients with diabetes and stable CAD). The main reasons for exclusion were a history of myocardial infarction (53.1%), use of oral anticoagulation (14.5%), or history of stroke (12.9%). Among the 4208 patients with diabetes and a previous PCI, 1196 patients (28.4%) were eligible for inclusion in the THEMIS-PCI substudy. In a population of patients with diabetes and stable coronary artery disease, a sizeable proportion appear to be 'THEMIS eligible.' http://www.clinicaltrials.gov identifier: NCT01991795 • Over 25% of patients with diabetes and stable CAD would have been eligible for THEMIS and THEMIS-PCI. • In REACH, over 50% of the patients with CAD and diabetes had a prior ischemic event. • REACH-like had higher event rates and may derive a greater absolute benefit from ticagrelor than those in THEMIS. [ABSTRACT FROM AUTHOR]

At the end of 2021, infections with the B.1.1.529 SARS-CoV-2 variant (Omicron) overtook those with the B.1.617.2 variant (Delta). This study compared baseline characteristics and in-hospital outcomes of patients who presented to 13 emergency departments in Paris late in 2021 and early in 2022. Visual Abstract. Patients With Delta Versus Omicron Variants in the Emergency Department.: At the end of 2021, SARS-CoV-2 infections with the B.1.1.529 variant (Omicron) overtook those with the B.1.617.2 variant (Delta). This study compared baseline characteristics and in-hospital outcomes of patients who presented to 13 emergency departments in Paris late in 2021 and early in 2022. Background: At the end of 2021, the B.1.1.529 SARS-CoV-2 variant (Omicron) wave superseded the B.1.617.2 variant (Delta) wave. Objective: To compare baseline characteristics and in-hospital outcomes of patients with SARS-CoV-2 infection with the Delta variant versus the Omicron variant in the emergency department (ED). Design: Retrospective chart reviews. Setting: 13 adult EDs in academic hospitals in the Paris area from 29 November 2021 to 10 January 2022. Patients: Patients with a positive reverse transcriptase polymerase chain reaction (RT-PCR) test result for SARS-CoV-2 and variant identification. Measurements: Main outcome measures were baseline clinical and biological characteristics at ED presentation, intensive care unit (ICU) admission, mechanical ventilation, and in-hospital mortality. Results: A total of 3728 patients had a positive RT-PCR test result for SARS-CoV-2 during the study period; 1716 patients who had a variant determination (818 Delta and 898 Omicron) were included. Median age was 58 years, and 49% were women. Patients infected with the Omicron variant were younger (54 vs. 62 years; difference, 8.0 years [95% CI, 4.6 to 11.4 years]), had a lower rate of obesity (8.0% vs. 12.5%; difference, 4.5 percentage points [CI, 1.5 to 7.5 percentage points]), were more vaccinated (65% vs. 39% for 1 dose and 22% vs. 11% for 3 doses), had a lower rate of dyspnea (26% vs. 50%; difference, 23.6 percentage points [CI, 19.0 to 28.2 percentage points]), and had a higher rate of discharge home from the ED (59% vs. 37%; difference, 21.9 percentage points [−26.5 to −17.1 percentage points]). Compared with Delta, Omicron infection was independently associated with a lower risk for ICU admission (adjusted difference, 11.4 percentage points [CI, 8.4 to 14.4 percentage points]), mechanical ventilation (adjusted difference, 3.6 percentage points [CI, 1.7 to 5.6 percentage points]), and in-hospital mortality (adjusted difference, 4.2 percentage points [CI, 2.0 to 6.5 percentage points]). Limitation: Patients with COVID-19 illness and no SARS-CoV-2 variant determination in the ED were excluded. Conclusion: Compared with the Delta variant, infection with the Omicron variant in patients in the ED had different clinical and biological patterns and was associated with better in-hospital outcomes, including higher survival. Primary Funding Source: None. [ABSTRACT FROM AUTHOR]

• DIGICOD est la première cohorte hospitalière française prospective observationnelle de patients atteints d'arthrose digitale (AD). • La proportion de patients présentant une AD érosive est élevée dans la cohorte DIGICOD (45,8 %). • La cohorte DIGICOD permettra d'élaborer de nombreux projets de recherche sur l'AD. Malgré la prévalence de l'arthrose digitale (AD), les cohortes prospectives de patients ayant une AD sont rares. Le principal objectif de la cohorte DIGICOD (DIGItal COhort Design) est d'étudier les facteurs cliniques, biologiques, génétiques et d'imagerie prédictifs d'une aggravation après six ans de suivi. DIGICOD est une cohorte prospective hospitalière qui inclut des patients > 35 ans présentant une AD symptomatique selon l'une des deux définitions suivantes : i) AD symptomatique selon les critères ACR pour au moins deux articulations parmi les interphalangiennes proximales et distales ou l'articulation interphalangienne du pouce avec un score de Kellgren-Lawrence (KL) ≥ 2 ; ou ii) AD symptomatique de la base du pouce avec un score de KL ≥ 2. Les principaux critères d'exclusion étaient une arthrite inflammatoire et des arthropathies à cristaux. Le suivi a consisté en évaluations cliniques annuelles, avec des examens d'imagerie (radiographie des mains et des autres articulations atteintes d'arthrose symptomatique) et des prélèvements biologiques tous les trois ans. Les radiographies des mains ont été notées selon le score de KL et les phases anatomiques du score de Verbruggen-Veys. Les visites de suivi sont en cours. Nous présentons ici la méthodologie et les caractéristiques à l'inclusion de la cohorte. Entre avril 2013 et juin 2017, 436 patients atteints d'AD ont été inclus, parmi lesquels 426, dont 357 femmes (84 %), ont été analysés. L'âge moyen ± écart-type était de 66,7 ± 7,3 ans et la durée moyenne de la maladie de 12,6 ± 9,6 ans. Un syndrome métabolique était présent chez 151 patients (36,5 %). La douleur des mains moyenne sur l'échelle visuelle analogique (EVA) de 0 à 100 mm était de 44,4 ± 26,7 mm à l'activité. Le score fonctionnel FIHOA moyen (0–100) était de 19,9 ± 18,6. Un taux sérique élevé de CRP (≥ 5 mg/l) concernait 10 % des patients. Le score de KL moyen (0–128) était de 46,7 ± 18 et le nombre moyen d'articulations ayant un score de KL ≥ 2 était de 15,1 ± 6,3. L'AD érosive (définie par au moins une articulation en phase d'érosion [E] ou de remodelage [R] selon le score de Verbruggen-Veys) concernait 195 patients sur 426 (45,8 %) et le nombre médian (intervalle interquartile) d'articulations érosives était de 3,0 (1,0–5,0). DIGICOD est la première cohorte prospective d'AD bénéficiant d'une évaluation standardisée à long terme sur six ans et incluant des patients atteints d'AD radiologique sévère avec une forte prévalence de l'atteinte érosive. [ABSTRACT FROM AUTHOR]

Objective: To study the diagnostic yield, including variants in genes yet to be incriminated, of whole exome sequencing (WES) in familial cases of premature ovarian insufficiency (POI).Design: Cross-sectional study.Setting: Endocrinology and reproductive medicine teaching hospital departments.Patients: Familial POI cases were recruited as part of a nationwide multicentric cohort. A total of 36 index cases in 36 different families were studied. Fifty-two relatives were available, including 25 with POI and 27 affected who were nonaffected. Karyotype analysis, FMR1 screening, single nucleotide polymorphism array analysis, and WES were performed in all subjects.Interventions: None.Main Outcome Measures: The primary outcome was a molecular etiology, as diagnosed by karyotype, FMR1 screening, single nucleotide polymorphism array, and WES.Results: A likely molecular etiology (pathogenic or likely pathogenic variant) was identified in 18 of 36 index cases (50% diagnostic yield). In 12 families, we found a pathogenic or likely pathogenic variant in a gene previously incriminated in POI, and in 6 families, we found a pathogenic or likely pathogenic variant in new candidate genes. Most of the variants identified were located in genes involved in cell division and meiosis (n = 11) or DNA repair (n = 4).Conclusions: The genetic etiologic diagnosis in POI allows for genetic familial counseling, anticipated pregnancy planning, and ovarian tissue preservation or oocyte preservation. Identifying new genes may lead to future development of therapeutics in reproduction based on disrupted molecular pathways.Clinical Trial Registration Number: NCT 01177891. [ABSTRACT FROM AUTHOR]

Fetuin-A is a ubiquitous anti-inflammatory glycoprotein that counteracts proinflammatory cytokine production. Previous studies have shown that low fetuin-A concentration is associated with cardiovascular death and may play an important role in the prognosis of patients with acute coronary syndromes (ACS). The purpose of this study was to assess in large cohort of patients admitted for ACS the prognostic value of fetuin-A adjusted for C-reactive protein value (CRP) and Global Registry of Acute Coronary Events (GRACE) risk score. Plasma fetuin-A and CRP concentrations were measured on day 3 in 754 consecutive patients with ACS (mean age 66 ± 14 years, 404 with ST-segment elevation and 350 without ST-segment elevation) included in the French Registry of Acute ST-Elevation or Non-STElevation Myocardial Infarction (FAST-MI), and these data were correlated to 1-year mortality. Plasma fetuin-A and CRP concentrations at admission averaged 95 ± 27 and 12 ± 16 mg/L, respectively. Overall, 1-year cardiovascular mortality was 10% (28 in-hospital deaths and 51 deaths after discharge), 17% in patients with low fetuin-A (less than the first tertile), 18% with high CRP (higher than the third tertile), and 23% in patients with low fetuin associated with high CRP (p <0.01). In contrast, patients with neither low fetuin-A nor high CRP had a low mortality rate (5%). Multivariate analysis adjusted for GRACE risk score showed that low fetuin-A and high CRP concentration remained associated with outcomes (odds ratio 2.28, 95% confidence interval 1.20 to 4.33). In conclusion, fetuin-A combined with CRP level is associated with cardiovascular death in patients with ACS. [ABSTRACT FROM AUTHOR]

Triggering receptor expressing on myeloid cells (TREM)-1 is involved in the pathophysiology of ischemic heart disease. Plasma soluble TREM-1 levels (sTREM-1) has been associated with increased risk of major adverse cardiovascular events (MACE) in acute myocardial infarction (AMI) patients. However, the causative link between TREM-1 and MACE remains unknown and requires further investigation before developing potential therapeutic approaches. Using the serum and DNA data bank from the prospective, nationwide French registry of Acute ST-elevation and non-ST-elevation Myocardial Infarction (FAST-MI 2010, N = 1293), we studied the association of plasma levels of sTREM-1 with 9 common genetic variants at the TREM1 locus and their relationship with recurrent MACE over a 3-year follow up. Plasma levels of sTREM-1 were associated with an increased risk of MACEs (death, recurrent MI or stroke) (adjusted HR = 1.86, 95%CI = 1.06–3.26 and HR = 1.11, 95%CI = 0.61–2.02 respectively for tertiles 3 and 2 versus tertile 1, P < 0.001). The study of common variants identified two major genetic determinants of sTREM-1 (rs4714449: beta = −0.11, P add = 7.85 × 10−5 and rs3804276: beta = 0.18, P add = 2.65 × 10−11) with a potential role on maintenance and/or differentiation of hematopoietic stem cells. However, associated variants only explained 4% of sTREM-1 variance (P = 2.74 × 10−14). Moreover, the rs4714449 variant, individually and in haplotype, was not significantly associated with MACE (HR = 0.61, 95%CI: 0.35–1.05, P = 0.07). Despite its relationship with increased risk of death, recurrent MI and stroke, genetic determinants of plasma levels of sTREM-1 were not found to be causal prognostic factors in patients with acute myocardial infarction. • TREM-1 engagement activates myeloid cells and worsens cardiac remodeling in experimental acute myocardial infarction (AMI). • High plasma levels of soluble TREM-1 associate with higher risk of recurrent major adverse cardiac events in AMI patients. • Common TREM1 genetic variants are associated with sTREM-1 levels in AMI patients and explain ~4% of its total variance. • Further studies on MI patients are needed to assess the relationship between TREM1 genetic variants and outcome. [ABSTRACT FROM AUTHOR]

Background: The optimal management of patients with ST-segment elevation myocardial infarction (STEMI) presenting late->12 hours following symptom onset-is still under debate.Objectives: The purpose of this study was to describe characteristics, temporal trends, and impact of revascularization in a large population of latecomer STEMI patients.Methods: The authors analyzed the data of 3 nationwide observational studies from the FAST-MI (French Registry of Acute ST-elevation and non-ST-elevation Myocardial Infarction) program, conducted over a 1-month period in 2005, 2010, and 2015. Patients presenting between 12 and 48 hours after symptom onset were classified as latecomers.Results: A total of 6,273 STEMI patients were included in the 3 cohorts, 1,169 (18.6%) of whom were latecomers. After exclusion of patients treated with fibrinolysis and patients deceased within 2 days after admission, 1,077 patients were analyzed, of whom 729 (67.7%) were revascularized within 48 hours after hospital admission. At 30-day follow-up, all-cause death rate was significantly lower among revascularized latecomers (2.1% vs 7.2%; P < 0.001). After a median follow-up of 58 months, the rate of all-cause death was 30.4 (95% CI: 25.7-35.9) per 1,000 patient-years in the revascularized latecomers group vs 78.7 (95% CI: 67.2-92.3) per 1,000 patient-years in the nonrevascularized latecomers group (P < 0.001). In multivariate analysis, revascularization of latecomer STEMI patients was independently associated with a significant reduction of mortality occurrence during follow-up (HR: 0.65 [95% CI: 0.50-0.84]; P = 0.001).Conclusions: Coronary revascularization of latecomer STEMI patients is associated with better short and long-term clinical outcomes. [ABSTRACT FROM AUTHOR]

Background: Optimizing care continuum entry interventions is key to ending the HIV epidemic. Offering HIV screening to key populations in emergency departments (EDs) is a strategy that has been demonstrated to be effective. Analyzing patient and provider perceptions of such screening can help identify implementation facilitators and barriers. Objectives: The aim of this study was to investigate the acceptability of offering nurse-driven HIV screening to key populations based on data collected from patients, nurses, and other service providers. Methods: This convergentmixed-methods study was a substudy of a cluster-randomized two-period crossover trial conducted in eight EDs to evaluate the effectiveness of the screening strategy. During the DICI-VIH (Dépistage Infirmier CIblé du VIH) trial, questionnaires were distributed to patients aged 18-64 years. Based on their responses, nurses offered screening to members of key populations. Over 5 days during the intervention period in four EDs, 218 patients were secondarily questioned about the acceptability of screening. Nurses completed 271 questionnaires pre- and posttrial regarding acceptability in all eight EDs. Descriptive analyses were conducted on these quantitative data. Convenience and purposeful sampling was used to recruit 53 providers to be interviewed posttrial. Two coders conducted a directed qualitative content analysis of the interview transcripts independently. Results: The vastmajority of patients (95%) were comfortable with questions asked to determinemembership in key populations and agreed (89%) that screening should be offered to key populations in EDs. Nurses mostly agreed that offering screening to key populations was well accepted by patients (62.2% pretrial and 71.4% posttrial), was easy to implement, and fell within the nursing sphere of competence. Pretrial, 73%of the nurses felt that such screening could be implemented in EDs. Posttrial, the proportion was 41%. Three themes emerged from the interviews: preference for targeted screening and a written questionnaire to identify key populations, facilitators of long-term implementation, and implementation barriers. Nurses were favorable to such screening provided specific conditions were met regarding training, support, collective involvement, and flexibility of application to overcome organizational and individual barriers. Discussion: Screening for key populations was perceived as acceptable and beneficial by patients and providers. Addressing the identified facilitators and barriers would help increase screening implementation in EDs. [ABSTRACT FROM AUTHOR]

Women are under-represented as leaders of cardiovascular randomized controlled trials, representing 1 in 10 lead authors of cardiovascular trials published in high-impact journals. Although the proportion of cardiovascular specialists who are women has increased in recent years, the proportion of cardiovascular clinical trialists who are women has not. This gap, underpinned by systemic sexism, has not been adequately addressed. The benefits of diverse randomized controlled trial leadership extend to patients and professionals. In this position statement, we present strategies adopted by some organizations to end gender inequality in research leadership. We offer an actionable roadmap for early-career researchers, scientists, academic institutions, professional societies, trial sponsors, and journals to follow, with the goal of harnessing the strength of women and under-represented groups as research leaders and facilitating a just culture in the cardiovascular clinical trial enterprise. [ABSTRACT FROM AUTHOR]

Background: THEMIS (The Effect of Ticagrelor on Health Outcomes in Diabetes Mellitus Patients Intervention Study) (n = 19,220) and its pre-specified THEMIS-PCI (The Effect of Ticagrelor on Health Outcomes in Diabetes Mellitus Patients Intervention Study-Percutaneous Coronary Intervention) (n = 11,154) subanalysis showed, in individuals with type 2 diabetes mellitus (median duration 10.0 years; HbA1c 7.1%) and stable coronary artery disease without prior myocardial infarction (MI) or stroke, that ticagrelor plus aspirin (compared with placebo plus aspirin) produced a favorable net clinical benefit (composite of all-cause mortality, MI, stroke, fatal bleeding, and intracranial bleeding) if the patients had a previous percutaneous coronary intervention.Objectives: In these post hoc analyses, the authors examined whether the primary efficacy outcome (cardiovascular death, MI, stroke: 3-point major adverse cardiovascular events [MACE]), primary safety outcome (Thrombolysis In Myocardial Infarction-defined major bleeding) and net clinical benefit varied with diabetes-related factors.Methods: Outcomes were analyzed across baseline diabetes duration, HbA1c, and antihyperglycemic medications.Results: In THEMIS, the incidence of 3-point MACE increased with diabetes duration (6.7% for ≤5 years, 11.1% for >20 years) and HbA1c (6.4% for ≤6.0%, 11.8% for >10.0%). The relative benefits of ticagrelor plus aspirin on 3-point MACE reduction (hazard ratio [HR]: 0.90; p = 0.04) were generally consistent across subgroups. Major bleeding event rate (overall: 1.6%) did not vary by diabetes duration or HbA1c and was increased similarly by ticagrelor across all subgroups (HR: 2.32; p < 0.001). These findings were mirrored in THEMIS-PCI. The efficacy and safety of ticagrelor plus aspirin did not differ by baseline antihyperglycemic therapy. In THEMIS-PCI, but not THEMIS, ticagrelor generally produced favorable net clinical benefit across diabetes duration, HbA1c, and antihyperglycemic medications.Conclusion: Ticagrelor plus aspirin yielded generally consistent and favorable net clinical benefit across the diabetes-related factors in THEMIS-PCI but not in the overall THEMIS population. [ABSTRACT FROM AUTHOR]

Importance: The optimal transfusion strategy in patients with acute myocardial infarction and anemia is unclear.Objective: To determine whether a restrictive transfusion strategy would be clinically noninferior to a liberal strategy.Design, Setting, and Participants: Open-label, noninferiority, randomized trial conducted in 35 hospitals in France and Spain including 668 patients with myocardial infarction and hemoglobin level between 7 and 10 g/dL. Enrollment could be considered at any time during the index admission for myocardial infarction. The first participant was enrolled in March 2016 and the last was enrolled in September 2019. The final 30-day follow-up was accrued in November 2019.Interventions: Patients were randomly assigned to undergo a restrictive (transfusion triggered by hemoglobin ≤8; n = 342) or a liberal (transfusion triggered by hemoglobin ≤10 g/dL; n = 324) transfusion strategy.Main Outcomes and Measures: The primary clinical outcome was major adverse cardiovascular events (MACE; composite of all-cause death, stroke, recurrent myocardial infarction, or emergency revascularization prompted by ischemia) at 30 days. Noninferiority required that the upper bound of the 1-sided 97.5% CI for the relative risk of the primary outcome be less than 1.25. The secondary outcomes included the individual components of the primary outcome.Results: Among 668 patients who were randomized, 666 patients (median [interquartile range] age, 77 [69-84] years; 281 [42.2%] women) completed the 30-day follow-up, including 342 in the restrictive transfusion group (122 [35.7%] received transfusion; 342 total units of packed red blood cells transfused) and 324 in the liberal transfusion group (323 [99.7%] received transfusion; 758 total units transfused). At 30 days, MACE occurred in 36 patients (11.0% [95% CI, 7.5%-14.6%]) in the restrictive group and in 45 patients (14.0% [95% CI, 10.0%-17.9%]) in the liberal group (difference, -3.0% [95% CI, -8.4% to 2.4%]). The relative risk of the primary outcome was 0.79 (1-sided 97.5% CI, 0.00-1.19), meeting the prespecified noninferiority criterion. In the restrictive vs liberal group, all-cause death occurred in 5.6% vs 7.7% of patients, recurrent myocardial infarction occurred in 2.1% vs 3.1%, emergency revascularization prompted by ischemia occurred in 1.5% vs 1.9%, and nonfatal ischemic stroke occurred in 0.6% of patients in both groups.Conclusions and Relevance: Among patients with acute myocardial infarction and anemia, a restrictive compared with a liberal transfusion strategy resulted in a noninferior rate of MACE after 30 days. However, the CI included what may be a clinically important harm.Trial Registration: ClinicalTrials.gov Identifier: NCT02648113. [ABSTRACT FROM AUTHOR]

Importance: Clinical guidelines for the early management of acute heart failure in the emergency department (ED) setting are based on only moderate levels of evidence, with subsequent low adherence to these guidelines.Objective: To test the effect of an early guideline-recommended care bundle on short-term prognosis in older patients with acute heart failure in the ED.Design, Setting, and Participants: Stepped-wedge cluster randomized trial in 15 EDs in France of 503 patients 75 years and older with a diagnosis of acute heart failure in the ED from December 2018 to September 2019 and followed up for 30 days until October 2019.Interventions: A care bundle that included early intravenous nitrate boluses; management of precipitating factors, such as acute coronary syndrome, infection, or atrial fibrillation; and moderate dose of intravenous diuretics (n = 200). In the control group, patient care was left to the discretion of the treating emergency physician (n = 303). Each center was randomized to the order in which they switched to the "intervention period." After the initial 4-week control period for all centers, 1 center entered in the intervention period every 2 weeks.Main Outcomes and Measures: The primary end point was the number of days alive and out of hospital at 30 days. Secondary outcomes included 30-day all-cause mortality, 30-day cardiovascular mortality, unscheduled readmission, length of hospital stay, and kidney impairment.Results: Among 503 patients who were randomized (median age, 87 years; 298 [59%] women), 502 were analyzed. In the intervention group, patients received a median (interquartile range) of 27.0 (9-54) mg of intravenous nitrates in the first 4 hours vs 4.0 (2.0-6.0) mg in the control group (adjusted difference, 23.8 [95% CI, 13.5-34.1]). There was a significantly higher percentage of patients in the intervention group treated for their precipitating factors than in the control group (58.8% vs 31.9%; adjusted difference, 31.1% [95% CI, 14.3%-47.9%]). There was no statistically significant difference in the primary end point of the number of days alive and out of hospital at 30 days (median [interquartile range], 19 [0- 24] d in both groups; adjusted difference, -1.9 [95% CI, -6.6 to 2.8]; adjusted ratio, 0.88 [95% CI, 0.64-1.21]). At 30 days, there was no significant difference between the intervention and control groups in mortality (8.0% vs 9.7%; adjusted difference, 4.1% [95% CI, -17.2% to 25.3%]), cardiovascular mortality (5.0% vs 7.4%; adjusted difference, 2.1% [95% CI, -15.5% to 19.8%]), unscheduled readmission (14.3% vs 15.7%; adjusted difference, -1.3% [95% CI, -26.3% to 23.7%]), median length of hospital stay (8 d in both groups; adjusted difference, 2.5 [95% CI, -0.9 to 5.8]), and kidney impairment (1% in both groups).Conclusions and Relevance: Among older patients with acute heart failure, use of a guideline-based comprehensive care bundle in the ED compared with usual care did not result in a statistically significant difference in the number of days alive and out of the hospital at 30 days. Further research is needed to identify effective treatments for acute heart failure in older patients.Trial Registration: ClinicalTrials.gov Identifier: NCT03683212. [ABSTRACT FROM AUTHOR]

Evidence is lacking on long-term outcomes in unselected patients surviving the first year following myocardial infarction (MI). The TIGRIS (long-Term rIsk, clinical manaGement and healthcare Resource utilization of stable coronary artery dISease in post-myocardial infarction patients) prospective registry enrolled 9176 eligible patients aged ≥50 years, 1–3 years post-MI, from 25 countries. All had ≥1 risk factor: age ≥ 65 years, diabetes mellitus, second prior MI, multivessel coronary artery disease, chronic kidney disease (CKD). Primary outcome was a composite of MI, unstable angina with urgent revascularization, stroke, or all-cause death at 2-year follow-up. Bleeding requiring hospitalization was also recorded. 9027 patients (98.4%) provided follow-up data: the primary outcome occurred in 621 (7.0%), all-cause mortality in 295 (3.3%), and bleeding in 109 (1.2%) patients. Events accrued linearly over time. In multivariable analyses, qualifying risk factors were associated with increased risk of primary outcome (incidence rate ratio [RR] per 100 patient-years [95% confidence interval]): CKD 2.06 (1.66, 2.55), second prior MI 1.71 (1.38, 2.10), diabetes mellitus 1.63 (1.39, 1.92), age ≥ 65 years 1.53 (1.28, 1.83), and multivessel disease 1.24 (1.05, 1.48). Risk of bleeding events was greater in older patients (vs <65 years) 65–74 years 2.68 (1.53, 4.70), ≥75 years 4.62 (2.57, 8.28), and those with CKD 1.99 (1.18, 3.35). In stable patients recruited 1–3 years post-MI, recurrent cardiovascular and bleeding events accrued linearly over 2 years. Factors independently predictive of ischemic and bleeding events were identified, providing a context for deciding on treatment options. • TIGRIS enrolled stable patients 1–3 years post-MI, all with ≥1 risk factor. • Among 9027 patients, the primary outcome occurred in 7.0%. • All qualifying risk factors were associated with increased risk of primary outcome. • Older age and chronic kidney disease were associated with increased bleeding risk. • These findings provide a context for treatment decisions. [ABSTRACT FROM AUTHOR]

Introduction: In the work-up strategy for pulmonary embolism (PE) in the ED, the recently introduced YEARS rule allows the raising of the D-dimer threshold to 1000 ng/ml in patients with no signs of deep venous thrombosis and no hemoptysis and in whom PE is not the most likely diagnosis. However, this decision rule has never been prospectively compared to the usual strategy. Furthermore, it is unclear if the YEARS rule can be used on top of the Pulmonary Embolism Rule-out Criteria (PERC). We aim to assess the non-inferiority of YEARS compared to current guidelines to rule out PE among PERC-positive ED patients with suspicion of PE.Methods/design: The MODIGLIANI study is a multicenter, European, non-inferiority, cluster-randomized, two periods cross-over, controlled trial. Each center will be randomized for the sequence of two 4-month periods: intervention (MOdified Diagnostic Strategy: MODS) followed by control (usual care), or control followed by intervention with 1 month of "wash-out" between the two periods. In the control period, the threshold will be as usual (500 ng/ml for patients aged 50 years or younger and age × 10 for older patients). In the MODS period, the threshold of D-dimers to rule out PE will be raised to 1000 ng/ml if no item of the YEARS score is present or will remain unchanged otherwise. Patients will be included if they have a suspicion of PE, defined as chest pain, dyspnea, or syncope. Non-inclusion criteria comprise a high clinical probability of PE or PERC-negative patients with low clinical probability.Ethics and Dissemination: The study has received the following approvals: Comité de protection des personnes Ile de France XI (France) and Comité de Ética de la Investigación con medicamentos del Hospital Clínic de Barcelona (Spain). Results will be made available to all included participants and other researchers.Trial Registration: ClinicalTrials.gov, NCT04032769. Registered on 24 July 2019. [ABSTRACT FROM AUTHOR]

Aims: Few studies describe recent changes in the prevalence, management, and outcomes of cardiogenic shock (CS) patients complicating acute myocardial infarction (AMI) in the era of widespread use of invasive strategies. The aim of the present study was to analyse trends observed in CS complicating AMI over the past 10 years, focusing on the timing of CS occurrence (i.e. primary CS, CS on admission vs. secondary CS, CS developed subsequently during hospitalization).Methods and Results: Three nationwide French registries conducted and designed to evaluate AMI management and outcomes in 'real-life' practice included consecutive AMI patients (n = 9951) admitted to intensive cardiovascular care units (ICCUs) over a 1-month period, 5 years apart. The prevalence of CS complicating AMI decreased from 2005 to 2015: 5.9%, mean age 74.1 ± 12.7 in 2005; 4.0%, mean age 73.9 ± 12.7 in 2010, 2.8%, mean age 71.1 ± 15.0 in 2015 (P < 0.001). It decreased for both primary (1.8% to 1.0%) and secondary CS (4.1% to 1.8%). The profile of CS patients also changed over time with more patients presenting out-of-hospital cardiac arrest. In both primary and secondary CS, the use of percutaneous coronary intervention increased markedly over time, as did the use of mechanical ventilation and cardiac assist devices. Over the 10-year period, in-hospital mortality remained unchanged for both primary CS (41.8% to 37.8%) or secondary CS (57.3% to 58.8%). However, 1-year mortality decreased in patients with primary CS (from 60% to 37.8%, P = 0.038), and remained unchanged in patients developing secondary CS (from 64.5% to 69.1%, P = 0.731).Conclusion: Cardiogenic shock complicating AMI has become less frequent but, if present, CS, and particularly secondary CS, carries a very high mortality, which has not substantially improved over the past 10 years, in spite of the more frequent use of invasive strategies. [ABSTRACT FROM AUTHOR]

We aimed to explore triggering receptor expressed on myeloid cells-1 (TREM-1) activation in familial Mediterranean fever (FMF), the most frequent monogenic auto-inflammatory disease, through the measurement of its serum soluble form, named sTREM-1. Blood samples from patients with FMF according to Livneh criteria followed in the French FMF national center and carrying two pathogenic MEFV mutations were collected. Serum level of sTREM-1 was assessed using ELISA. Demographic data, presence of FMF attack, association with histologically proven AA amyloidosis, and blood levels of C-reactive protein (CRP), serum amyloid A (SAA) protein, and creatinine were collected. TREM-1 was available in 56 patients (33.9% male, mean age 43 yr); AA amyloidosis was associated in six patients (19.6% in FMF). Mean sTREM-1 level did not differ significantly between patients having an attack or not and there was also no significant correlation between the level of sTREM-1 and CRP and SAA protein. However, the mean rate of sTREM-1 was significantly higher among FMF patients with AA amyloidosis versus without, though the concomitant SAA protein level was normal. Serum level of sTREM-1 was higher in patients with amyloidosis even though the concomitant SAA protein level was normal. sTREM-1 plasma levels could be an accurate tool to specifically identify FMF patients with amyloidosis. [ABSTRACT FROM AUTHOR]

Introduction: Atrial fibrillation (AF) is associated with increased risk in patients with acute myocardial infarction. Hypothesis: We sought to establish the impact of pre-existing and new onset AF on anti-thrombotic management and survival. Methods: Data were extracted from the 2 French nationwide registries FAST-MI 2010 (n=4160) and FAST-MI 2015 (n=5291). Patients were categorized according to pre-existing FA: no history of AF (AF0, n=8224, 87%), history of AF (AF1, n=610, 6.4%) or new-onset AF (AF2, n=626, 6.6%). The impact of existing or new onset AF on 12 month mortality was assessed by an adjusted Cox model. Results: Compared to AF0 patients, those with AF1 had worse baseline characteristics and received fewer guidelines-recommended treatments. AF2 patients had intermediate baseline characteristics. Prescription at discharge of dual antiplatelet therapy was 85% (AF0) vs 66% (AF1) and 69% (AF2). Despite a CHADS score of 2.4±1.4 (AF1) and 2.25±1.3 (AF2), anticoagulants were prescribed in only 56% (AF1) and 28% (AF2). Crude 1 year mortality was low in AF0 (6.1%) as compared to AF1 (20.2%) and AF2 (19.3%); this was confirmed by multivariate Cox analysis (adjusted Hazard Ratio AF1 vs AF0= 2.42 (95% CI=1.70; 3.22) AF2 vs AF0= 1.40 (95%CI=1.02; 1.96) (Figure). Conclusions: Patients with pre-existing and new onset AF have more comorbidities, receive fewer effective treatments, and have respectively a 2.4 and 1.4 higher risk of 1-year mortality compared to patients without AF. Whatever the type of AF, the use of guidelines-recommended treatments is sub-optimal, suggesting room for improvement. [ABSTRACT FROM AUTHOR]

Introduction: Recent studies have demonstrated the clinical benefit on coronary events and mortality of lowering C-Reactive Protein (CRP) in patients with coronary heart disease and elevated CRP at baseline. In routine practice, the use of CRP for risk stratification in patient admitted for acute myocardial infarction (AMI) is poorly documented. Hypothesis: We aimed to investigate the prognostic value of high CRP in 3 nationwide registries. Methods: The FAST-MI 2005, 2010 and 2015 registries collected information on patients admitted for AMI to 76% of French hospitals over a 1-month period. Patients were classified according to the quartiles of CRP (0-2.5, 2.5-5, 5-15 and >15 mg/dL), high CRP was defined as CRP at inclusion >15 mg/L. Quartiles were compared using appropriate tests and trends. Predictors of high CRP were determined by logistic regression. A propensity score (for having high CRP) was used to build a matched population (n=2648 pts) and 12 month all cause mortality was compared between patients with vs without high CRP. Results: Among 13,130 patients included, CRP at admission was available in 9,615(73%); median value was 5 mg/dL (interquartiles 2.5; 15). With higher CRP quartiles, there was higher 12 month mortality (4.0%, 5.2%; 8.1% and 20.3%, p<0.001), but also higher baseline risk features and fewer guidelines-recommended treatments, including less prescription of statins at discharge (92%, 91%, 90% and 85%). Adjustment for these variables did not overcome the higher risk (HR high CRP vs non high CRP =1.49, 95%CI 1.09; 2.04). Matched comparison showed a remaining 53% higher residual of death associated with high CRP (HR=1.53; 95% CI 1.25; 1.89) (figure: Kaplan Meier curves for mortality in the matched population, according to CRP±15 mg/dL). Conclusions: In the FAST-MI registries, the increased mortality at 12 months after acute MI associated with high CRP levels was partially explained by high risk features at baseline and fewer guidelines-recommended treatments. Nevertheless, high CRP(>15mg/dL) remained associated with a 53% higher mortality, compatible with a direct impact of CRP. [ABSTRACT FROM AUTHOR]

Background: Patients with stable coronary artery disease and diabetes with previous percutaneous coronary intervention (PCI), particularly those with previous stenting, are at high risk of ischaemic events. These patients are generally treated with aspirin. In this trial, we aimed to investigate if these patients would benefit from treatment with aspirin plus ticagrelor.Methods: The Effect of Ticagrelor on Health Outcomes in diabEtes Mellitus patients Intervention Study (THEMIS) was a phase 3 randomised, double-blinded, placebo-controlled trial, done in 1315 sites in 42 countries. Patients were eligible if 50 years or older, with type 2 diabetes, receiving anti-hyperglycaemic drugs for at least 6 months, with stable coronary artery disease, and one of three other mutually non-exclusive criteria: a history of previous PCI or of coronary artery bypass grafting, or documentation of angiographic stenosis of 50% or more in at least one coronary artery. Eligible patients were randomly assigned (1:1) to either ticagrelor or placebo, by use of an interactive voice-response or web-response system. The THEMIS-PCI trial comprised a prespecified subgroup of patients with previous PCI. The primary efficacy outcome was a composite of cardiovascular death, myocardial infarction, or stroke (measured in the intention-to-treat population).Findings: Between Feb 17, 2014, and May 24, 2016, 11 154 patients (58% of the overall THEMIS trial) with a history of previous PCI were enrolled in the THEMIS-PCI trial. Median follow-up was 3·3 years (IQR 2·8-3·8). In the previous PCI group, fewer patients receiving ticagrelor had a primary efficacy outcome event than in the placebo group (404 [7·3%] of 5558 vs 480 [8·6%] of 5596; HR 0·85 [95% CI 0·74-0·97], p=0·013). The same effect was not observed in patients without PCI (p=0·76, pinteraction=0·16). The proportion of patients with cardiovascular death was similar in both treatment groups (174 [3·1%] with ticagrelor vs 183 (3·3%) with placebo; HR 0·96 [95% CI 0·78-1·18], p=0·68), as well as all-cause death (282 [5·1%] vs 323 [5·8%]; 0·88 [0·75-1·03], p=0·11). TIMI major bleeding occurred in 111 (2·0%) of 5536 patients receiving ticagrelor and 62 (1·1%) of 5564 patients receiving placebo (HR 2·03 [95% CI 1·48-2·76], p<0·0001), and fatal bleeding in 6 (0·1%) of 5536 patients with ticagrelor and 6 (0·1%) of 5564 with placebo (1·13 [0·36-3·50], p=0·83). Intracranial haemorrhage occurred in 33 (0·6%) and 31 (0·6%) patients (1·21 [0·74-1·97], p=0·45). Ticagrelor improved net clinical benefit: 519/5558 (9·3%) versus 617/5596 (11·0%), HR=0·85, 95% CI 0·75-0·95, p=0·005, in contrast to patients without PCI where it did not, pinteraction=0·012. Benefit was present irrespective of time from most recent PCI.Interpretation: In patients with diabetes, stable coronary artery disease, and previous PCI, ticagrelor added to aspirin reduced cardiovascular death, myocardial infarction, and stroke, although with increased major bleeding. In that large, easily identified population, ticagrelor provided a favourable net clinical benefit (more than in patients without history of PCI). This effect shows that long-term therapy with ticagrelor in addition to aspirin should be considered in patients with diabetes and a history of PCI who have tolerated antiplatelet therapy, have high ischaemic risk, and low bleeding risk.Funding: AstraZeneca. [ABSTRACT FROM AUTHOR]

Clinical pharmacology as a scientific discipline and medical specialty was unarguably born in the twentieth century. Whilst pharmacology—the science behind the treatment of disease—had been in evolution since at least medieval times, the clinical discipline of pharmacology has had a more recent genesis and rather insidious evolution. During the 1900s, there were some clear father (parent) figures of clinical pharmacology in Europe that emerged and were responsible for the development of the specialty in this continent. This was a time when there were parallel developments in geographically dispersed academic departments (around the globe), during an age of excitement in drug discovery and clinical application of new therapeutic agents. It was the meeting of minds of some of these progenitors of the specialty that led to the development of the European Association for Clinical Pharmacology and Therapeutics (EACPT) 25 years ago arising from a working party supported by the World Health Organization in Europe. The EACPT now includes all major national organizations for clinical pharmacology in Europe, representing over 4000 individual professionals interested in clinical pharmacology and therapeutics. The EACPT has a major interest in promoting the safe use of medicines across Europe and internationally and has supported these aims since 1995, through biennial international scientific congresses and summer schools with delegates and presenters from around the world as well as various working group activities. In this article, the current executive committee members of EACPT recall this history, describe the evolution of the association over the last quarter of a century, and provide an update on the activities and ambitions of the association today. [ABSTRACT FROM AUTHOR]

Background: Systems vaccinology allows cutting-edge analysis of innate biomarkers of vaccine efficacy. We have been exploring novel strategies to shape the adaptive immune response, by targeting innate immune cells through novel immunization routes.Methods: This randomized phase I/II clinical study (n=60 healthy subjects aged 18-45 years old) used transcriptomic analysis to discover early biomarkers of immune response quality after transcutaneous (t.c.), intradermal (i.d.), and intramuscular (i.m.) administration of a trivalent influenza vaccine (TIV season 2012-2013) (1:1:1 ratio). Safety and immunogenicity (hemagglutinin inhibition (HI), microneutralization (MN) antibodies and CD4, CD8 effector T cells) were measured at baseline Day (D)0 and at D21. Blood transcriptome was analyzed at D0 and D1.Results: TIV-specific CD8+GranzymeB+(GRZ) T cells appeared in more individuals immunized by the t.c. and i.d. routes, while immunization by the i.d. and i.m. routes prompted high levels of HI antibody titers and MN against A/H1N1 and A/H3N2 influenza viral strains. The early innate gene signature anticipated immunological outcome by discriminating two clusters of individuals with either distinct humoral or CD8 cytotoxic responses. Several pathways explained this dichotomy confirmed by nine genes and serum level of CXCL10 were correlated with either TIV-specific cytotoxic CD8+GRZ+ T-cell or antibody responses. A logistic regression analysis demonstrated that these nine genes and serum levels of CXCL10 (D1/D0) best foreseen TIV-specific CD8+GRZ+ T-cell and antibody responses at D21.Conclusion: This study provides new insight into the impact of immunization routes and innate signature in the quality of adaptive immune responses. [ABSTRACT FROM AUTHOR]

Abstract Background The COMPASS trial assessed the impact of adding low dose rivaroxaban to aspirin in selected patients (pts). After an acute myocardial infarction (MI), when dual antiplatelet treatment is no longer needed, patients might be eligible for aspirin/rivaroxaban co-therapy. The characteristics and risks of such a population are unclear. Methods Data were extracted from the FAST-MI 2005, 2010 and 2015 nationwide French registries. Characteristics and long-term mortality were compared according to COMPASS eligibility and between registry and trial populations. Results Among 9954 patients alive and free of events at one year, 4402 (44%) were classified as COMPASS-Like (i.e. meeting COMPASS inclusion and without exclusion criteria), 1720 (17%) COMPASS-Excluded (i.e. meeting any exclusion criterion) and 3832 (39%) Non-COMPASS (i.e. meeting neither COMPASS inclusion nor exclusion criteria). COMPASS-Like patients were at higher risk and had higher 5-year mortality compared with Non-COMPASS patients. COMPASS-Excluded patients had the highest mortality. COMPASS enrichment criteria defined a population at increased risk of death: eligible pts. had 40% higher 5-year adjusted mortality (Hazard Ratio = 1.40 [1.15; 1.70]), while excluded pts. had 57% higher risk (Hazard Ratio = 1.57 [1.25; 1.97]). Patients meeting the COMPASS criteria one year after MI differed from those included in the randomized trial. Conclusions Based on the population included in the French FAST-MI registries, enrichment criteria used in COMPASS defined a population representing 44% of the overall population of MI patients surviving to one year, and these patients are at high risk of 5-year mortality. They were at higher risk compared to chronic stable vascular patients enrolled in the trial. Registered with Clinicaltrials.gov under the number: NCT00673036. Highlights • The applicability of the COMPASS trial criteria in routine practice is unclear. • We compared characteristics and mortality according to COMPASS eligibility. • We compared characteristics and mortality between registry and trial populations. • Patients with COMPASS criteria 1 year after MI differ from patients in the trial. • Applying COMPASS in practice may yield more benefits than the trial suggests. [ABSTRACT FROM AUTHOR]