Antiplatelet Therapy Use and the Risk of Venous Thromboembolic Events in the Raloxifene Use for the Heart (RUTH) Trial

Abstract Background: Raloxifene use in postmenopausal women with osteoporosis increases the risk of venous thromboembolic events (VTE) 2-fold compared with placebo. Platelet activation is involved in the pathophysiology of arterial thromboses more than venous thromboses, but aspirin may reduce VTE risk associated with estrogen use. This analysis examines the effects of concomitant antiplatelet therapy on VTE risk in raloxifene-treated women. Methods: In the Raloxifene Use for the Heart (RUTH) trial, 10,101 postmenopausal women from 177 sites in 26 countries at increased risk of coronary heart disease (CHD) (primary prevention cohort) or with CHD (secondary prevention cohort) were randomized to placebo or raloxifene 60?mg/day and followed for a median 5.6 years. Reports of clinical symptoms of VTE were assessed. Concomitant use of antiplatelet agents (aspirin, clopidogrel, ticlopidine, dipyridamole) was allowed. Cox proportional hazard models, with use of warfarin, presence of fracture, and hospitalization as covariates, were used to estimate hazard ratios (HR) with 95% confidence intervals (CI). Results: Overall, raloxifene use was associated with an increased VTE risk (HR 1.44, 95% CI 1.06-1.95) vs. placebo. Most women (72%) reported using aspirin, and 14.2% reported using nonaspirin antiplatelet agents during the study period. Users of antiplatelet agents were older, more likely to have CHD, and more likely to be hyperlipidemic. They had a higher VTE risk than nonusers. No difference in VTE risk was observed in women who used raloxifene alone vs. those who used raloxifene with antiplatelet agents during the study. The increase in VTE risk with raloxifene compared with placebo was not different between women who used antiplatelet agents at baseline (HR 1.44, 95% CI 0.98, 2.10) and those who did not use antiplatelet agents (HR 1.37, 95% CI 0.83, 2.27) (interaction p?=?0.88). Similar conclusions were noted for aspirin and nonaspirin antiplatelet use. Conclusions: In RUTH, postmenopausal women treated with raloxifene had an increased risk of VTE compared with placebo. Concomitant use of aspirin or nonaspirin antiplatelet agents along with raloxifene did not change VTE risk.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/85099/1/jwh_2009_1687.pd

Employment of a high throughput functional assay to define the critical factors that influence vaccine induced cross-variant neutralizing antibodies for SARS-CoV-2

10.1038/s41598-023-49231-wSCIENTIFIC REPORTS13

Employment of a high throughput functional assay to define the critical factors that influence vaccine induced cross-variant neutralizing antibodies for SARS-CoV-2

Acknowledgements: This work was supported by the Biomedical Research Council (BMRC), A*CRUSE (Vaccine monitoring project), the A*ccelerate GAP-funded project (ACCL/19-GAP064-R20H-H) from Agency of Science, Technology and Research (A*STAR), Singapore National Medical Research Council COVID-19 Research Fund (COVID19RF-001; COVID19RF-007; COVID19RF-0008; COVID19RF-060) and A*STAR COVID-19 Research funding (H/20/04/g1/006). This study is funded by the Singapore National Medical Research Council (R-571-000-081-213, R-711-000-058-598), Ministry of Health (R-571-000-093-114), National University of Singapore (R-571-000-081-213), and the Singapore-HUJ Alliance for Research and Enterprise (R-571-002-012-592). We thank Protein Production Platform of Nanyang Technological University for their help in making the nucleocapsid expression constructs and small-scale protein expression tests. We thank Assoc Prof. Tan Yee Joo, Department of Microbiology and Immunology, Yong Loo Lin, School of Medicine, National University of Singapore (NUS) for the ACE2 stably expressing CHO cells and plasmid encoding SARS-CoV-2 S protein for the pseudotyped lentiviral production. We thank Ms. Lang Si Min and Ms. Tan Siang Ling Isabelle for helping with the performance of experiments.AbstractThe scale and duration of neutralizing antibody responses targeting SARS-CoV-2 viral variants represents a critically important serological parameter that predicts protective immunity for COVID-19. In this study, we describe the development and employment of a new functional assay that measures neutralizing antibodies for SARS-CoV-2 and present longitudinal data illustrating the impact of age, sex and comorbidities on the kinetics and strength of vaccine-induced antibody responses for key variants in an Asian volunteer cohort. We also present an accurate quantitation of serological responses for SARS-CoV-2 that exploits a unique set of in-house, recombinant human monoclonal antibodies targeting the viral Spike and nucleocapsid proteins and demonstrate a reduction in neutralizing antibody titres across all groups 6 months post-vaccination. We also observe a marked reduction in the serological binding activity and neutralizing responses targeting recently newly emerged Omicron variants including XBB 1.5 and highlight a significant increase in cross-protective neutralizing antibody responses following a third dose (boost) of vaccine. These data illustrate how key virological factors such as immune escape mutations combined with host demographic factors such as age and sex of the vaccinated individual influence the strength and duration of cross-protective serological immunity for COVID-19.</jats:p

Lack of Clinical Manifestations in Asymptomatic Dengue Infection Is Attributed to Broad Down-Regulation and Selective Up-Regulation of Host Defence Response Genes

<div><p>Objectives</p><p>Dengue represents one of the most serious life-threatening vector-borne infectious diseases that afflicts approximately 50 million people across the globe annually. Whilst symptomatic infections are frequently reported, asymptomatic dengue remains largely unnoticed. Therefore, we sought to investigate the immune correlates conferring protection to individuals that remain clinically asymptomatic.</p><p>Methods</p><p>We determined the levels of neutralizing antibodies (nAbs) and gene expression profiles of host immune factors in individuals with asymptomatic infections, and whose cognate household members showed symptoms consistent to clinical dengue infection.</p><p>Results</p><p>We observed broad down-regulation of host defense response (innate, adaptive and matrix metalloprotease) genes in asymptomatic individuals as against symptomatic patients, with selective up-regulation of distinct genes that have been associated with protection. Selected down-regulated genes include: TNF α (<i>TNF</i>), <i>IL8</i>, <i>C1S</i>, factor B (<i>CFB</i>), <i>IL2</i>, <i>IL3</i>, <i>IL4</i>, <i>IL5</i>, <i>IL8</i>, <i>IL9</i>, <i>IL10</i> and <i>IL13</i>, <i>CD80</i>, <i>CD28</i>, and <i>IL18</i>, <i>MMP8</i>, <i>MMP10</i>, <i>MMP12</i>, <i>MMP15</i>, <i>MMP16</i>, and <i>MMP24</i>. Selected up-regulated genes include: RANTES (<i>CCL5</i>), MIP-1α (<i>CCL3L1/CCL3L3</i>), MIP-1β (<i>CCL4L1</i>), TGFβ (<i>TGFB</i>), and <i>TIMP1</i>.</p><p>Conclusion</p><p>Our findings highlight the potential association of certain host genes conferring protection against clinical dengue. These data are valuable to better explore the mysteries behind the hitherto poorly understood immunopathogenesis of subclinical dengue infection.</p></div

Lower vaccine-acquired immunity in the elderly population following two-dose BNT162b2 vaccination is alleviated by a third vaccine dose

Understanding the impact of age on vaccinations is essential for the design and delivery of vaccines against SARS-CoV-2. Here, we present findings from a comprehensive analysis of multiple compartments of the memory immune response in 312 individuals vaccinated with the BNT162b2 SARS-CoV-2 mRNA vaccine. Two vaccine doses induce high antibody and T cell responses in most individuals. However, antibody recognition of the Spike protein of the Delta and Omicron variants is less efficient than that of the ancestral Wuhan strain. Age-stratified analyses identify a group of low antibody responders where individuals ≥60 years are overrepresented. Waning of the antibody and cellular responses is observed in 30% of the vaccinees after 6 months. However, age does not influence the waning of these responses. Taken together, while individuals ≥60 years old take longer to acquire vaccine-induced immunity, they develop more sustained acquired immunity at 6 months post-vaccination. A third dose strongly boosts the low antibody responses in the older individuals against the ancestral Wuhan strain, Delta and Omicron variants

Association between night-time surgery and occurrence of intraoperative adverse events and postoperative pulmonary complications

Background: The aim of this post hoc analysis of a large cohort study was to evaluate the association between night-time surgery and the occurrence of intraoperative adverse events (AEs) and postoperative pulmonary complications (PPCs)