Inborn errors of type I IFN immunity in patients with life-threatening COVID-19.

Clinical outcome upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ranges from silent infection to lethal coronavirus disease 2019 (COVID-19). We have found an enrichment in rare variants predicted to be loss-of-function (LOF) at the 13 human loci known to govern Toll-like receptor 3 (TLR3)- and interferon regulatory factor 7 (IRF7)-dependent type I interferon (IFN) immunity to influenza virus in 659 patients with life-threatening COVID-19 pneumonia relative to 534 subjects with asymptomatic or benign infection. By testing these and other rare variants at these 13 loci, we experimentally defined LOF variants underlying autosomal-recessive or autosomal-dominant deficiencies in 23 patients (3.5%) 17 to 77 years of age. We show that human fibroblasts with mutations affecting this circuit are vulnerable to SARS-CoV-2. Inborn errors of TLR3- and IRF7-dependent type I IFN immunity can underlie life-threatening COVID-19 pneumonia in patients with no prior severe infection

Optimal dose of bivalirudin in dialysis patients at high risk of heparin-induced thrombocytopenia undergoing percutaneous coronary intervention: case report

Bivalirudin is a direct thrombin inhibitor that has been approved for use in patients with or at risk for heparin-induced thrombocytopenia undergoing percutaneous coronary intervention. The efficacy of bivalirudin has been well documented in the setting of percutaneous coronary intervention, but there are only few data on its use in chronic dialysis-dependent patients. Bivalirudin is mainly eliminated enzymatically (80%) and to a lesser extent renally (20%). Nevertheless, in patients with chronic kidney disease a substantial increase in coagulation time and bleeding complications has been reported. Therefore, dosage adjustments may be necessary in patients with renal impairment. Dosing and monitoring recommendations in dialysis patients have not yet been established. We describe the case of a 77-year-old man with non-ST-elevation acute coronary syndrome complicated by heparin-induced thrombocytopenia and acute renal failure requiring dialysis treatment. During percutaneous coronary intervention, anticoagulant therapy with bivalirudin was administered at non-standard doses, though already documented in the literature

A rare ventricular septal defect: a case repor

Left ventricular-right atrial communications, known collectively as the Gerbode defect, are rare types of ventricular septal defects. Acquired forms of this defect have been described as a complication of cardiac surgery, bacterial endocarditis, chest trauma, or myocardial infarction. Diagnosis of this rare defect is challenging, but can be confirmed with echocardiography or cardiac magnetic resonance imaging. Until 6 years ago, these communications were corrected only surgically, often with relatively high mortality. However, few case reports of transcatheter closures of the defects have recently been reported with excellent results. We describe a 69-year-old patient with left ventricular-right atrial communication secondary to mitral valve surgery. The diagnosis was made by transesophageal and real-time three-dimensional echocardiography. The defect was closed percutaneously using an Amplatzer device. At follow-up, there was no residual flow and the patient improved clinically.© 2013 Il Pensiero Scientifico Editore

Association of bleeding, mortality and sex in acute coronary syndromes: the missing triangle

AimsPercutaneous coronary intervention (PCI) and antithrombotic drugs are the standard therapy for patients with acute coronary syndromes (ACS), but their impact on bleeding and mortality in women has not been adequately investigated.MethodsThis was a prospective observational cohort study of ACS patients, who were referred to 6 of the 13 centres belonging to the REgistro regionale AngiopLastiche dell'Emilia-Romagna programme in Emilia-Romagna for coronary angiography and PCI between June 2010 and November 2011. The aim of the study was to verify whether the incidence of Global Registry of Acute Coronary Events-defined in-hospital bleeding after an ACS is significantly higher in women than in men, and to evaluate its impact on short and long-term mortality.ResultsThe analysis involved a total of 1686 patients (511 women and 1175 men). The women were older and more frequently affected by hypertension, congestive heart failure and single-vessel disease; however, none of the clinical or procedural variables was significantly different between the sexes after statistical adjustment. There was a significantly higher rate of in-hospital bleeding among the women [8.6 vs. 5.8%; adjusted odds ratio 1.73, 95% confidence interval (CI) 1.19-2.52, P=0.004], but the adjusted hazard ratio for short and long-term all-cause mortality was not significantly different. After optimal adjustment, bleeding, but not female sex, was identified as a predictor of short-term all-cause mortality (hazard ratio 2.68, 95% CI 1.21-5.93, P=0.01), but this was not confirmed in the case of long-term mortality (hazard ratio 1.57, 95% CI 0.91-2.71, P=0.10).ConclusionAfter optimal adjustment for baseline differences, the findings of this contemporary Italian PCI registry study showed that women experience bleeding more frequently, but do not have worse mortality outcomes than men. Bleeding was confirmed as an independent predictor of short-term mortality

61. Rapid and portable, lab-on-chip, point-of-care genotyping for evaluating clopidogrel metabolism

Background: Dual antiplatelet therapy with aspirin and a platelet P2Y12 receptor inhibitors (clopidogrel, prasugrel, ticagrelor) is a cornerstone of antithrombotic treatment in patients with acute coronary syndromes (ACS). Clopidogrel has been the standard of care for nearly a decade; however, its clinical efficacy is influenced by a considerable inter-patient variability in response, clearly associated to cytochrome P (CYP) enzyme genetic variations. We used a novel point-of-care lab-on-chip instrument to genotype ACS patients in order to identify carriers of the ATB-binding cassette ABCB1 3435, CYP2C19*2 and CYPC2C19*17 alleles and adjust the pharmacological approach accordingly. Methods and results: Between October 2012 and January 2013, 160 ACS patients were enrolled at the Cardiology Unit of the Ospedale Niguarda Ca Granda and genotyped at the patients' point-of-care using the newly developed Q3 portable real-time PCR instrument which remarkably scored the CYP2C19*2, CYP2C19*17, and ABCB13435 alleles in a time of 70 min from DNA extraction to final genotype calls; concordance with the other gold-standard genotyping techniques was 100%. Conclusions: The Q3 instrument proved to be as reliable as the current conventional techniques. As genotyping in the ACS setting cannot be delegated to centralised clinical laboratories for reasons of time, genotyping at the patients' bedside provides an opportunity to conduct large-scale randomised trials in order to assess whether adding genotype data to clinical variables improves clinical outcomes. (C) 2015 Elsevier B.V. All rights reserved

Influence of 9p21.3 genetic variants on clinical and angiographic outcomes in early-onset myocardial infarction.

OBJECTIVES: The purpose of this study was to test whether the 9p21.3 variant rs1333040 influences the occurrence of new cardiovascular events and coronary atherosclerosis progression after early-onset myocardial infarction. BACKGROUND: 9p21.3 genetic variants are associated with ischemic heart disease, but it is not known whether they influence prognosis after an acute coronary event. METHODS: Within the Italian Genetic Study of Early-onset Myocardial Infarction, we genotyped rs1333040 in 1,508 patients hospitalized for a first myocardial infarction before the age of 45 years who underwent coronary angiography without index event coronary revascularization. They were followed up for major cardiovascular events and angiographic coronary atherosclerosis progression. RESULTS: Over 16,599 person-years, there were 683 cardiovascular events and 492 primary endpoints: 77 cardiovascular deaths, 223 reoccurrences of myocardial infarction, and 383 coronary artery revascularizations. The rs1333040 genotype had a significant influence (p = 0.01) on the primary endpoint, with an adjusted hazard ratio of 1.19 (95% confidence interval [CI]: 1.08 to 1.37) for heterozygous carriers and 1.41 (95% CI: 1.06 to 1.87) for homozygous carriers. Analysis of the individual components of the primary endpoints provided no significant evidence that the rs1333040 genotype influenced the hazard of cardiovascular death (p = 0.24) or the reoccurrence of myocardial infarction (p = 0.57), but did provide significant evidence that it influenced on the hazard of coronary revascularization, with adjusted heterozygous and homozygous ratios of 1.38 (95% CI: 1.17 to 1.63) and 1.90 (95% CI: 1.36 to 2.65) (p = 0.00015), respectively. It also significantly influenced the angiographic endpoint of coronary atherosclerosis progression (p = 0.002). CONCLUSIONS: In early-onset myocardial infarction, the 9p21.3 variant rs1333040 affects the progression of coronary atherosclerosis and the probability of coronary artery revascularization during long-term follow-up