056: Biological efficacy of a 600mg loading dose of clopidogrel in ST-elevation myocardial infarction

BackgroundOptimal platelet reactivity (PR) inhibition is critical to prevent thrombotic events in primary percutaneous coronary intervention (PCI). We aimed to determine the relationship between high on-treatment platelet reactivity (HTPR) and ST-elevation myocardial infarction (STEMI) following a 600mg loading dose (LD) of clopidogrel.Methods and resultsWe performed a prospective monocentre study enrolling patients on clopidogrel undergoing PCI. The VASP index was used to assess PR inhibition after clopidogrel LD. HTPR was defined according to the consensus as a VASP index ≥50%. The present study included 833 patients undergoing PCI. Most patients had PCI for an acute coronary syndrome (58.7%). The mean VASP index was 50±23% with a large inter-individual variability (range: 1–94%). Patients with a VASP index ≥50% were significantly older (p=0.03), with a higher BMI (p<0.001), more often diabetic (p=0.03), taking omeprazole (p=0.03), admitted for an ACS and with a high fibrinogen level compared to good responders (VASP<50%). In multivariate analysis BMI, omeprazole use, acute coronary syndrome and high fibrinogen level (p<0.001) remained significantly associated with HTPR. Of importance, in this analysis STEMI was independently associated with HTPR when compared with the other forms of ACS (NSTEMI and unstable angina) with an odd ratio of 2.14 (95% CI: 1.3 –3.5; p=0.003).ConclusionSTEMI is associated with high on-treatment platelet reactivity following 600mg of clopidogrel. The present results suggest that 600mg of clopidogrel may not be able to achieve an optimal PR inhibition in STEMI patients undergoing PCI and more potent drugs may be preferred

039: Platelet reactivity predicts both ischemic and bleeding events at one year follow-up in acute coronary syndome patients receiving prasugrel

There are evidences of a link between platelet reactivity inhibition and thrombotic and bleeding events. We have previously demonstrated that PR after prasugrel loading dose (LD) predicts short-term thrombotic events. We aimed to further investigate the relationship between PR under prasugrel and one-year thrombotic and bleeding events.MethodPatients were prospectively included in this multicentre study if they had a successful PCI for an acute coronary syndrome (ACS) and received prasugrel. Vasodilator-Stimulated Phosphoprotein (VASP index) was measured after prasugrel LD. Endpoint included the rate of thrombotic events (cardiovascular death, myocardial infarction and stent thrombosis) and bleeding events (TIMI) at one year.ResultsThree hundreds and one patients were enrolled. Nine patients (3%) were lost to follow-up at one year. The rates of thrombotic and bleeding events at one year were 7.5 and 6.8% respectively. The mean VASP index after a 60mg LD of prasugrel was 34}23% and 76 patients (25%) were considered as having high on-treatment platelet reactivity (HTPR). Patients with HTPR had a higher rate of thrombotic events compared to good responders (19.7 vs 3.1%;p<0.001). Patients with a minor or major non-CABG related TIMI bleeding had lower PR compared to patients with no bleeding events (21}18 vs 35}23%;p=0.008). In multivariate analysis, the VASP index predicted both thrombotic and bleeding events (OR: 1.44 (95% CI: 1.2–1.72; p<0.001 and 0.75 (95% CI: 0.59–0.96;p=0.024 (respectively, per 10% increase)).ConclusionPlatelet reactivity measurement after prasugrel LD predicts both ischemic and bleedings events at one year follow-up for ACS patients undergoing PCI

Pahs, Ionized Gas, and Molecular Hydrogen in Brightest Cluster Galaxies of Cool Core Clusters of Galaxies

We present measurements of 5-25 {\mu}m emission features of brightest cluster galaxies (BCGs) with strong optical emission lines in a sample of 9 cool-core clusters of galaxies observed with the Infrared Spectrograph on board the Spitzer Space Telescope. These systems provide a view of dusty molecular gas and star formation, surrounded by dense, X-ray emitting intracluster gas. Past work has shown that BCGs in cool-core clusters may host powerful radio sources, luminous optical emission line systems, and excess UV, while BCGs in other clusters never show this activity. In this sample, we detect polycyclic aromatic hydrocarbons (PAHs), extremely luminous, rotationally-excited molecular hydrogen line emission, forbidden line emission from ionized gas ([Ne II] and [Ne III]), and infrared continuum emission from warm dust and cool stars. We show here that these BCGs exhibit more luminous forbidden neon and H2 rotational line emission than star-forming galaxies with similar total infrared luminosities, as well as somewhat higher ratios of 70 {\mu}m / 24 {\mu}m luminosities. Our analysis suggests that while star formation processes dominate the heating of the dust and PAHs, a heating process consistent with suprathermal electron heating from the hot gas, distinct from star formation, is heating the molecular gas and contributing to the heating of the ionized gas in the galaxies. The survival of PAHs and dust suggests that dusty gas is somehow shielded from significant interaction with the X-ray gas.Comment: 27 preprint pages, 18 figures, accepted by Astrophysical Journa

New Respiratory Enterovirus and Recombinant Rhinoviruses among Circulating Picornaviruses

Increased genomic diversity of these viruses is demonstrated

Ezrin Ubiquitylation by the E3 Ubiquitin Ligase, WWP1, and Consequent Regulation of Hepatocyte Growth Factor Receptor Activity

The membrane cytoskeleton linker ezrin participates in several functions downstream of the receptor Met in response to Hepatocyte Growth Factor (HGF) stimulation. Here we report a novel interaction of ezrin with a HECT E3 ubiquitin ligase, WWP1/Aip5/Tiul1, a potential oncogene that undergoes genomic amplification and overexpression in human breast and prostate cancers. We show that ezrin binds to the WW domains of WWP1 via the consensus motif PPVY477 present in ezrin’s C-terminus. This association results in the ubiquitylation of ezrin, a process that requires an intact PPVY477 motif. Interestingly ezrin ubiquitylation does not target the protein for degradation by the proteasome. We find that ezrin ubiquitylation by WWP1 in epithelial cells leads to the upregulation of Met level in absence of HGF stimulation and increases the response of Met to HGF stimulation as measured by the ability of the cells to heal a wound. Interestingly this effect requires ubiquitylated ezrin since it can be rescued, after depletion of endogenous ezrin, by wild type ezrin but not by a mutant of ezrin that cannot be ubiquitylated. Taken together our data reveal a new role for ezrin in Met receptor stability and activity through its association with the E3 ubiquitin ligase WWP1. Given the role of Met in cell proliferation and tumorigenesis, our results may provide a mechanistic basis for understanding the role of ezrin in tumor progression

Vaccine breakthrough hypoxemic COVID-19 pneumonia in patients with auto-Abs neutralizing type I IFNs

Life-threatening `breakthrough' cases of critical COVID-19 are attributed to poor or waning antibody response to the SARS- CoV-2 vaccine in individuals already at risk. Pre-existing autoantibodies (auto-Abs) neutralizing type I IFNs underlie at least 15% of critical COVID-19 pneumonia cases in unvaccinated individuals; however, their contribution to hypoxemic breakthrough cases in vaccinated people remains unknown. Here, we studied a cohort of 48 individuals ( age 20-86 years) who received 2 doses of an mRNA vaccine and developed a breakthrough infection with hypoxemic COVID-19 pneumonia 2 weeks to 4 months later. Antibody levels to the vaccine, neutralization of the virus, and auto- Abs to type I IFNs were measured in the plasma. Forty-two individuals had no known deficiency of B cell immunity and a normal antibody response to the vaccine. Among them, ten (24%) had auto-Abs neutralizing type I IFNs (aged 43-86 years). Eight of these ten patients had auto-Abs neutralizing both IFN-a2 and IFN-., while two neutralized IFN-omega only. No patient neutralized IFN-ss. Seven neutralized 10 ng/mL of type I IFNs, and three 100 pg/mL only. Seven patients neutralized SARS-CoV-2 D614G and the Delta variant (B.1.617.2) efficiently, while one patient neutralized Delta slightly less efficiently. Two of the three patients neutralizing only 100 pg/mL of type I IFNs neutralized both D61G and Delta less efficiently. Despite two mRNA vaccine inoculations and the presence of circulating antibodies capable of neutralizing SARS-CoV-2, auto-Abs neutralizing type I IFNs may underlie a significant proportion of hypoxemic COVID-19 pneumonia cases, highlighting the importance of this particularly vulnerable population

Socioeconomic position, lifestyle habits and biomarkers of epigenetic aging: A multi-cohort analysis

Differences in health status by socioeconomic position (SEP) tend to be more evident at older ages, suggesting the involvement of a biological mechanism responsive to the accumulation of deleterious exposures across the lifespan. DNA methylation (DNAm) has been proposed as a biomarker of biological aging that conserves memory of endogenous and exogenous stress during life. We examined the association of education level, as an indicator of SEP, and lifestyle-related variables with four biomarkers of age-dependent DNAm dysregulation: the total number of stochastic epigenetic mutations (SEMs) and three epigenetic clocks (Horvath, Hannum and Levine), in 18 cohorts spanning 12 countries. The four biological aging biomarkers were associated with education and different sets of risk factors independently, and the magnitude of the effects differed depending on the biomarker and the predictor. On average, the effect of low education on epigenetic aging was comparable with those of other lifestyle-related risk factors (obesity, alcohol intake), with the exception of smoking, which had a significantly stronger effect. Our study shows that low education is an independent predictor of accelerated biological (epigenetic) aging and that epigenetic clocks appear to be good candidates for disentangling the biological pathways underlying social inequalities in healthy aging and longevity

Socioeconomic position, lifestyle habits and biomarkers of epigenetic aging: A multi-cohort analysis

Differences in health status by socioeconomic position (SEP) tend to be more evident at older ages, suggesting the involvement of a biological mechanism responsive to the accumulation of deleterious exposures across the lifespan. DNA methylation (DNAm) has been proposed as a biomarker of biological aging that conserves memory of endogenous and exogenous stress during life.We examined the association of education level, as an indicator of SEP, and lifestyle-related variables with four biomarkers of age-dependent DNAm dysregulation: the total number of stochastic epigenetic mutations (SEMs) and three epigenetic clocks (Horvath, Hannum and Levine), in 18 cohorts spanning 12 countries.The four biological aging biomarkers were associated with education and different sets of risk factors independently, and the magnitude of the effects differed depending on the biomarker and the predictor. On average, the effect of low education on epigenetic aging was comparable with those of other lifestyle-related risk factors (obesity, alcohol intake), with the exception of smoking, which had a significantly stronger effect.Our study shows that low education is an independent predictor of accelerated biological (epigenetic) aging and that epigenetic clocks appear to be good candidates for disentangling the biological pathways underlying social inequalities in healthy aging and longevity

Inherited Human ITK Deficiency Impairs IFN-γ Immunity and Underlies Tuberculosis

Inborn errors of IFN-γ immunity can underlie tuberculosis (TB). We report three patients from two kindreds without EBV viremia or disease but with severe TB and inherited complete ITK deficiency, a condition associated with severe EBV disease that renders immunological studies challenging. They have CD4+ αβ T lymphocytopenia with a concomitant expansion of CD4-CD8- double-negative (DN) αβ and Vδ2- γδ T lymphocytes, both displaying a unique CD38+CD45RA+T-bet+EOMES- phenotype. Itk-deficient mice recapitulated an expansion of the γδ T and DN αβ T lymphocyte populations in the thymus and spleen, respectively. Moreover, the patients\u27 T lymphocytes secrete small amounts of IFN-γ in response to TCR crosslinking, mitogens, or forced synapse formation with autologous B lymphocytes. Finally, the patients\u27 total lymphocytes secrete small amounts of IFN-γ, and CD4+, CD8+, DN αβ T, Vδ2+ γδ T, and MAIT cells display impaired IFN-γ production in response to BCG. Inherited ITK deficiency undermines the development and function of various IFN-γ-producing T cell subsets, thereby underlying TB

EuReCa ONE—27 Nations, ONE Europe, ONE Registry A prospective one month analysis of out-of-hospital cardiac arrest outcomes in 27 countries in Europe

AbstractIntroductionThe aim of the EuReCa ONE study was to determine the incidence, process, and outcome for out of hospital cardiac arrest (OHCA) throughout Europe.MethodsThis was an international, prospective, multi-centre one-month study. Patients who suffered an OHCA during October 2014 who were attended and/or treated by an Emergency Medical Service (EMS) were eligible for inclusion in the study. Data were extracted from national, regional or local registries.ResultsData on 10,682 confirmed OHCAs from 248 regions in 27 countries, covering an estimated population of 174 million. In 7146 (66%) cases, CPR was started by a bystander or by the EMS. The incidence of CPR attempts ranged from 19.0 to 104.0 per 100,000 population per year. 1735 had ROSC on arrival at hospital (25.2%), Overall, 662/6414 (10.3%) in all cases with CPR attempted survived for at least 30 days or to hospital discharge.ConclusionThe results of EuReCa ONE highlight that OHCA is still a major public health problem accounting for a substantial number of deaths in Europe.EuReCa ONE very clearly demonstrates marked differences in the processes for data collection and reported outcomes following OHCA all over Europe. Using these data and analyses, different countries, regions, systems, and concepts can benchmark themselves and may learn from each other to further improve survival following one of our major health care events