Triglyceride Lowering with Pemafibrate to Reduce Cardiovascular Risk.

BACKGROUND: High triglyceride levels are associated with increased cardiovascular risk, but whether reductions in these levels would lower the incidence of cardiovascular events is uncertain. Pemafibrate, a selective peroxisome proliferator-activated receptor α modulator, reduces triglyceride levels and improves other lipid levels. METHODS: In a multinational, double-blind, randomized, controlled trial, we assigned patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia (triglyceride level, 200 to 499 mg per deciliter), and high-density lipoprotein (HDL) cholesterol levels of 40 mg per deciliter or lower to receive pemafibrate (0.2-mg tablets twice daily) or matching placebo. Eligible patients were receiving guideline-directed lipid-lowering therapy or could not receive statin therapy without adverse effects and had low-density lipoprotein (LDL) cholesterol levels of 100 mg per deciliter or lower. The primary efficacy end point was a composite of nonfatal myocardial infarction, ischemic stroke, coronary revascularization, or death from cardiovascular causes. RESULTS: Among 10,497 patients (66.9% with previous cardiovascular disease), the median baseline fasting triglyceride level was 271 mg per deciliter, HDL cholesterol level 33 mg per deciliter, and LDL cholesterol level 78 mg per deciliter. The median follow-up was 3.4 years. As compared with placebo, the effects of pemafibrate on lipid levels at 4 months were -26.2% for triglycerides, -25.8% for very-low-density lipoprotein (VLDL) cholesterol, -25.6% for remnant cholesterol (cholesterol transported in triglyceride-rich lipoproteins after lipolysis and lipoprotein remodeling), -27.6% for apolipoprotein C-III, and 4.8% for apolipoprotein B. A primary end-point event occurred in 572 patients in the pemafibrate group and in 560 of those in the placebo group (hazard ratio, 1.03; 95% confidence interval, 0.91 to 1.15), with no apparent effect modification in any prespecified subgroup. The overall incidence of serious adverse events did not differ significantly between the groups, but pemafibrate was associated with a higher incidence of adverse renal events and venous thromboembolism and a lower incidence of nonalcoholic fatty liver disease. CONCLUSIONS: Among patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia, and low HDL and LDL cholesterol levels, the incidence of cardiovascular events was not lower among those who received pemafibrate than among those who received placebo, although pemafibrate lowered triglyceride, VLDL cholesterol, remnant cholesterol, and apolipoprotein C-III levels. (Funded by the Kowa Research Institute; PROMINENT ClinicalTrials.gov number, NCT03071692.).

Detecting time-evolving phenotypic components of adverse reactions against BNT162b2 SARS-CoV-2 vaccine via non-negative tensor factorization.

Symptoms of adverse reactions to vaccines evolve over time, but traditional studies have focused only on the frequency and intensity of symptoms. Here, we attempt to extract the dynamic changes in vaccine adverse reaction symptoms as a small number of interpretable components by using non-negative tensor factorization. We recruited healthcare workers who received two doses of the BNT162b2 mRNA COVID-19 vaccine at Chiba University Hospital and collected information on adverse reactions using a smartphone/web-based platform. We analyzed the adverse-reaction data after each dose obtained for 1,516 participants who received two doses of vaccine. The non-negative tensor factorization revealed four time-evolving components that represent typical temporal patterns of adverse reactions for both doses. These components were differently associated with background factors and post-vaccine antibody titers. These results demonstrate that complex adverse reactions against vaccines can be explained by a limited number of time-evolving components identified by tensor factorization.

Elevated Myl9 reflects the Myl9-containing microthrombi in SARS-CoV-2-induced lung exudative vasculitis and predicts COVID-19 severity.

The mortality of coronavirus disease 2019 (COVID-19) is strongly correlated with pulmonary vascular pathology accompanied by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection-triggered immune dysregulation and aberrant activation of platelets. We combined histological analyses using field emission scanning electron microscopy with energy-dispersive X-ray spectroscopy analyses of the lungs from autopsy samples and single-cell RNA sequencing of peripheral blood mononuclear cells to investigate the pathogenesis of vasculitis and immunothrombosis in COVID-19. We found that SARS-CoV-2 accumulated in the pulmonary vessels, causing exudative vasculitis accompanied by the emergence of thrombospondin-1-expressing noncanonical monocytes and the formation of myosin light chain 9 (Myl9)-containing microthrombi in the lung of COVID-19 patients with fatal disease. The amount of plasma Myl9 in COVID-19 was correlated with the clinical severity, and measuring plasma Myl9 together with other markers allowed us to predict the severity of the disease more accurately. This study provides detailed insight into the pathogenesis of vasculitis and immunothrombosis, which may lead to optimal medical treatment for COVID-19.

Antibody responses and SARS-CoV-2 infection after BNT162b2 mRNA booster vaccination among healthcare workers in Japan.

INTRODUCTION: Vaccine effectiveness against SARS-CoV-2 infections decreases due to waning immunity, and booster vaccination was therefore introduced. We estimated the anti-spike antibody (AS-ab) recovery by booster vaccination and analyzed the risk factors for SARS-CoV-2 infections. METHODS: The subjects were health care workers (HCWs) in a Chiba University Hospital vaccination cohort. They had received two doses of vaccine (BNT162b2) and a booster vaccine (BNT162b2). We retrospectively analyzed AS-ab titers and watched out for SARS-CoV-2 infection for 90 days following booster vaccination. RESULTS: AS-ab titer eight months after two-dose vaccinations had decreased to as low as 587 U/mL (median, IQR (interquartile range) 360-896). AS-ab titer had then increased to 22471 U/mL (15761-32622) three weeks after booster vaccination. There were no significant differences among age groups. A total of 1708 HCWs were analyzed for SARS-CoV-2 infection, and 48 of them proved positive. SARS-CoV-2 infections in the booster-vaccinated and non-booster groups were 1.8% and 4.0%, respectively, and were not significant. However, when restricted to those 20-29 years old, SARS-CoV-2 infections in the booster-vaccinated and non-booster groups were 2.9% and 13.6%, respectively (p = 0.04). After multivariate logistic regression, COVID-19 wards (adjusted odds ratio (aOR):2.9, 95% confidence interval (CI) 1.5-5.6) and those aged 20-49 years (aOR:9.7, 95%CI 1.3-71.2) were risk factors for SARS-CoV-2 infection. CONCLUSIONS: Booster vaccination induced the recovery of AS-ab titers. Risk factors for SARS-CoV-2 infection were HCWs of COVID-19 wards and those aged 20-49 years. Increased vaccination coverage, together with implementing infection control, remains the primary means of preventing HCWs from SARS-CoV-2 infection.

Immunological features that associate with the strength of antibody responses to BNT162b2 mRNA vaccine against SARS-CoV-2.

Predictive clinical factors associated with favorable responses to BNT162b2 mRNA vaccine against SARS-CoV-2 have been reported in some studies; however, there is a subgroup with low antibodytiters without well-known clinical factors reducing antibody responses. To clarify the immunological backgrounds that underlie the difference in antibody responses, we analyzed peripheral blood mononuclear cells (PBMCs) of each 20 individuals with a high anti-SARS-CoV-2 antibody titer and a low antibody titer out of 1774 healthcare workers who received BNT162b2 mRNA vaccine. A higher percentage of B cells before vaccination was associated with a higher antibody titer. Among B cells, naïve and transitional B cell frequencies were positively correlated with a higher antibody titer, whereas the frequencies of late memory B cells and plasmablasts were associated with a lower antibody titer. Fold change in the frequency of activated CD8+ T cells upon vaccination was also correlated with high antibody titers.

Antibody responses to BNT162b2 mRNA COVID-19 vaccine and their predictors among healthcare workers in a tertiary referral hospital in Japan.

OBJECTIVES: This study aimed to determine antibody responses in healthcare workers who receive the BNT162b2 mRNA COVID-19 vaccine and identify factors that predict the response. METHODS: We recruited healthcare workers receiving the BNT162b2 mRNA COVID-19 vaccine at the Chiba University Hospital COVID-19 Vaccine Center. Blood samples were obtained before the 1st dose and after the 2nd dose vaccination, and serum antibody titers were determined using Elecsys® Anti-SARS-CoV-2S, an electrochemiluminescence immunoassay. We established a model to identify the baseline factors predicting post-vaccine antibody titers using univariate and multivariate linear regression analyses. RESULTS: Two thousand fifteen individuals (median age 37-year-old, 64.3% female) were enrolled in this study, of which 10 had a history of COVID-19. Before vaccination, 21 participants (1.1%) had a detectable antibody titer (≥0.4 U/mL) with a median titer of 35.9 U/mL (interquartile range [IQR] 7.8 - 65.7). After vaccination, serum anti-SARS-CoV-2S antibodies (≥0.4 U/mL) were detected in all 1774 participants who received the 2nd dose with a median titer of 2060.0 U/mL (IQR 1250.0 - 2650.0). Immunosuppressive medication (p < 0.001), age (p < 0.001), time from 2nd dose to sample collection (p < 0.001), glucocorticoids (p = 0.020), and drinking alcohol (p = 0.037) were identified as factors predicting lower antibody titers after vaccination, whereas previous COVID-19 (p < 0.001), female (p < 0.001), time between 2 doses (p < 0.001), and medication for allergy (p = 0.024) were identified as factors predicting higher serum antibody titers. CONCLUSIONS: Our data demonstrate that healthcare workers universally have good antibody responses to the BNT162b2 mRNA COVID-19 vaccine. The predictive factors identified in our study may help optimize the vaccination strategy.

Once-Weekly Semaglutide in Adults with Overweight or Obesity.

BACKGROUND: Obesity is a global health challenge with few pharmacologic options. Whether adults with obesity can achieve weight loss with once-weekly semaglutide at a dose of 2.4 mg as an adjunct to lifestyle intervention has not been confirmed. METHODS: In this double-blind trial, we enrolled 1961 adults with a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or greater (≥27 in persons with ≥1 weight-related coexisting condition), who did not have diabetes, and randomly assigned them, in a 2:1 ratio, to 68 weeks of treatment with once-weekly subcutaneous semaglutide (at a dose of 2.4 mg) or placebo, plus lifestyle intervention. The coprimary end points were the percentage change in body weight and weight reduction of at least 5%. The primary estimand (a precise description of the treatment effect reflecting the objective of the clinical trial) assessed effects regardless of treatment discontinuation or rescue interventions. RESULTS: The mean change in body weight from baseline to week 68 was -14.9% in the semaglutide group as compared with -2.4% with placebo, for an estimated treatment difference of -12.4 percentage points (95% confidence interval [CI], -13.4 to -11.5; P<0.001). More participants in the semaglutide group than in the placebo group achieved weight reductions of 5% or more (1047 participants [86.4%] vs. 182 [31.5%]), 10% or more (838 [69.1%] vs. 69 [12.0%]), and 15% or more (612 [50.5%] vs. 28 [4.9%]) at week 68 (P<0.001 for all three comparisons of odds). The change in body weight from baseline to week 68 was -15.3 kg in the semaglutide group as compared with -2.6 kg in the placebo group (estimated treatment difference, -12.7 kg; 95% CI, -13.7 to -11.7). Participants who received semaglutide had a greater improvement with respect to cardiometabolic risk factors and a greater increase in participant-reported physical functioning from baseline than those who received placebo. Nausea and diarrhea were the most common adverse events with semaglutide; they were typically transient and mild-to-moderate in severity and subsided with time. More participants in the semaglutide group than in the placebo group discontinued treatment owing to gastrointestinal events (59 [4.5%] vs. 5 [0.8%]). CONCLUSIONS: In participants with overweight or obesity, 2.4 mg of semaglutide once weekly plus lifestyle intervention was associated with sustained, clinically relevant reduction in body weight. (Funded by Novo Nordisk; STEP 1 ClinicalTrials.gov number, NCT03548935).