ContextThe role of estrogens in ischemic heart disease (IHD) is uncertain. Evidence suggests that genetic variations in the estrogen receptor ␣ (ESR1) gene may influence IHD risk, but the role of common sequence variations in the ESR1 gene is unclear.Objective To determine whether the ESR1 haplotype created by the c.454-397TϾC (PvuII) and c.454-351AϾG (XbaI) polymorphisms is associated with myocardial infarction (MI) and IHD risk. Design, Setting, and ParticipantsIn 2617 men and 3791 postmenopausal women from The Rotterdam Study (enrollment between 1989(enrollment between -1993(enrollment between and follow-up to January 2000, a population-based, prospective cohort study of participants aged 55 years and older, ESR1 c.454-397TϾC and c.454-351AϾG haplotypes were determined. Detailed interviews and physical examinations were performed, blood samples were obtained, and cardiovascular risk factors were assessed.Main Outcome Measure The primary outcome was MI and IHD defined as MIs, revascularization procedures, and IHD mortality.Results Approximately 29% of women and 28.2% of men were homozygous carriers of the ESR1 haplotype 1 (−397 T and −351 A) allele, 49% of women and 50% of men were heterozygous carriers, and 22% of women and 21.4% of men were noncarriers. During a mean follow-up of 7.0 years, 285 participants (115 women; 170 men) had MI, and 440 (168 women; 272 men) had an IHD event, of which 97 were fatal. After adjustment for known cardiovascular risk factors, female heterozygous carriers of haplotype 1 had an increased risk of MI (event rate, 2.8%; relative risk [RR], 2.23; 95% confidence interval [CI], 1.13-4.43) compared with noncarriers (event rate, 1.3%), whereas homozygous carriers had an increased risk (event rate, 3.2%; RR, 2.48; 95% CI, 1.22-5.03). For IHD events, we observed a similar association. In women, the effect of haplotype 1 on fatal IHD was larger than on nonfatal IHD. In men, the ESR1 haplotypes were not associated with an increased risk of MI (event rate, 5.7%; RR, 0.93; 95% CI, 0.59-1.46 for heterozygous carriers; and event rate, 5.1%; RR, 0.82; 95% CI, 0.49-1.38 for homozygous carriers) compared with noncarriers (event rate, 5.8%) and were not associated with an increased risk of IHD. ConclusionsIn this population-based, prospective cohort study, postmenopausal women who carry ESR1 haplotype 1 (c.454-397 T allele and c.454-351 A allele) have an increased risk of MI and IHD, independent of known cardiovascular risk factors. In men, no association was observed.

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Background The immune response to COVID-19 vaccination is inferior in kidney transplant recipients (KTR), and to a lesser extent in patients on dialysis or with chronic kidney disease (CKD). We assessed the immune response 6 months after mRNA-1273 vaccination in kidney patients and compared this to controls. Methods 152 participants with CKD stages G4/5 (eGFR <30  mL/min/1.73m2), 145 participants on dialysis, 267 KTR, and 181 controls were included. SARS-CoV-2 Spike S1-specific IgG antibodies were measured by fluorescent bead-based multiplex-immunoassay, neutralizing antibodies to ancestral, Delta and Omicron (BA.1) variants by plaque reduction, and T-cell responses by IFN-γ release assay. Results At 6 months after vaccination S1-specific antibodies were detected in 100% of controls, 98.7% of CKD G4/5 patients, 95.1% of dialysis patients, and 56.6% of KTR. These figures were comparable to the response rates at 28 days, but antibody levels waned significantly. Neutralization of the ancestral and Delta variant was detected in most participants, whereas neutralization of Omicron was mostly absent. S-specific T-cell responses were detected 6 months in 75.0% of controls, 69.4% of CKD G4/5 patients, 52.6% of dialysis patients, and 12.9% of KTR. T-cell responses at 6 months were significantly lower than responses at 28 days. Conclusions Although seropositivity rates at 6 months were comparable to that at 28 days after vaccination, significantly decreased antibody levels and T-cell responses were observed. The combination of low antibody levels, reduced T-cell responses, and absent neutralization of the newly-emerging variants indicates the need for additional boosts or alternative vaccination strategies in KTR.

publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. thermore, apoptosis may contribute to ethanol-induced liver injury via complement activation.Interferon (IFN) administration is the main therapy for HCV-infected individuals, but still a fraction of them are not completely responsive to the treatment. Several HCV proteins such as core, E2, and NS5A proteins have been demonstrated to attenuate IFN responses through different mechanisms. In the present study, we examined whether HCV NS4B, a membrane-bound protein whose functions are mostly unknown, exerted any effects on IFN-induced antiviral responses. From the reporter assay, we showed that NS4B significantly suppressed IFN-induced activation of IFNstimulated responsive element (ISRE) promoter activity. We further examined the ability of HCV NS4B to confer IFN resistance on VSV, an originally IFN-sensitive virus, by a trans-rescue assay. The viral titer was low when cells were treated with IFN-a, which, however, was significantly increased by HCV NS4B. We also examined the effects of HCV NS4B on the transcription of interferon-stimulated genes (ISGs) by qRT-PCR and found that the IFN-induced expression of ISG15, ISG54, ISG56, and OAS2-p69 was significantly downregulated by NS4B. The results were confirmed by chromatin immunoprecipitation (ChIP) assay . The levels and the activation status of the interferon-stimulated gene factor 3 (ISGF3), known to regulate the IFN pathway, were also noticeably reduced by NS4B. Taken together, these results strongly suggest that, in addition to the above mentioned HCV proteins, HCV NS4B may also play a role in IFN antagonism.