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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 mixed linear regression 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 1414 included patients, 1217 (86%) were analyzed in the per-protocol analysis (648 in the intervention group and 623 in the control group). At three month, there were no statistically significant differences in total costs (€-47; 95% CI: €-103 to €4), 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) calculated that each patient without diagnostic failure was associated with cost savings of €7,343 in the intervention strategy compared with the controls. There was a 90% probability that the intervention was dominant. Similar results were found in the as randomized population. Conclusions: This trial suggests that there is an economic advantage to using the YEARS rule combined with the PERC rule and the age-adjusted D-dimer threshold in PERC-positive patients, as this strategy is non-inferior and less costly than the standard diagnostic strategy. Trial registration number ClinicalTrials.gov Identifier: NCT04032769; July 25, 2019

We previously reported the safety and immunogenicity data from a randomized trial comparing the monovalent (MV) recombinant protein Beta-variant (MVB.1.351) and MV ancestral protein (MVD614) booster vaccines with AS03 adjuvant (Sanofi/GSK) to mRNA BNT162b2 vaccine (Pfizer-BioNTech). First booster of the vaccines was administered in adult participants previously primed with 2 doses of BNT162b2. A subset of these participants with available blood samples collected at Day 0 (D0), at 28 days (D28), and 3 months (M3) post-booster were contacted for additional testing (195/208 participants). The persistence of cross-neutralizing antibodies, including against Omicron BA.1 and BA.4/5, up to 3 months after boosting was evaluated using a validated pseudovirus neutralization assay. The data showed that the MVB.1.351 vaccine induced higher and durable cross-neutralizing antibodies against Omicron subvariants up to 3 months after boosting compared to a MV ancestral and the mRNA BNT162b2 booster vaccine.

Acute myocardial infarction (MI) is a common condition responsible for heart failure and sudden death. Here, we show that following acute MI in mice, CD8+ T lymphocytes are recruited and activated in the ischemic heart tissue, and release Granzyme B leading to cardiomyocyte apoptosis, adverse ventricular remodeling and deterioration of myocardial function. Depletion of CD8+ T lymphocytes decreases apoptosis within the ischemic myocardium, hampers inflammatory response, limits myocardial injury and improves heart function. These effects are recapitulated in mice with Granzyme B-deficient CD8+ T cells. The protective effect of CD8 depletion on heart function was confirmed by using a model of ischemia/reperfusion in pigs. Finally, we reveal that elevated circulating levels of Granzyme B in patients with acute MI predict increased risk of death at 1-year follow-up. Our work unravels an unsuspected deleterious role of CD8+ T lymphocytes following acute ischemia, and identifies novel therapeutic strategy targeting pathogenic CD8+ T lymphocytes in the setting of acute MI.

Background: Acute heart failure (AHF) is one of the most common diagnoses for elderly patients in the emergency department (ED), with an admission rate higher than 80% and 1-month mortality around 10%. The European guidelines for the management of AHF are based on moderate levels of evidence, due to the lack of randomized controlled trials and the scarce evidence of any clinical added value of a specific treatment to improve outcomes. Recent reports suggest that the very early administration of full recommended therapy may decrease mortality. However, several studies highlighted that elderly patients often received suboptimal treatment. Our hypothesis is that an early care bundle that comprises early and comprehensive management of symptoms, along with prompt detection and treatment of precipitating factors should improve AHF outcome in elderly patients. Method/design: ELISABETH is a stepped-wedge, controlled cluster randomized, clinical trial in 15 emergency departments in France recruiting all patients aged 75 years and older with a diagnosis of AHF. The tested intervention is a care bundle with a checklist that mandates detection and early treatment of AHF precipitating factors, early and intensive treatment of congestion with intravenous nitrates boluses, and application of other recommended treatment (low dose diuretics, non-invasive ventilation when indicated, and preventive low molecular weight heparin). Each centre are randomized to the order in which they will switch from “control period” to “intervention period”. All centers begin the trials with the control period for two weeks, then after each two-weeks step a new centre will be in the intervention period. At the end of the trial, all clusters will receive the intervention regimen. The primary outcome is the number of days alive and out of the hospital at 30 days. Discussion: If our hypothesis is confirmed, this trial will strengthen the level of evidence of AHF guidelines and stress the importance of the associated early and comprehensive treatment of precipitating factors. This trial could be the first to report a reduction in short term morbidity and mortality in elderly AHF patients. Registration: NCT03683212, prospectively registered on September 25th 2018 Keywords: Elderly, acute heart failure, emergency department