Immunogenicity and Safety Following 1 Dose of AS01E-Adjuvanted Respiratory Syncytial Virus Prefusion F Protein Vaccine in Older Adults: A Phase 3 Trial.

BACKGROUND: The recently approved AS01E-adjuvanted respiratory syncytial virus (RSV) prefusion F protein-based vaccine for older adults (RSVPreF3 OA) demonstrated high efficacy against RSV-related disease in ≥60-year-olds. METHODS: This ongoing phase 3 study in ≥60-year-olds evaluates immune persistence until 3 years after RSVPreF3 OA vaccination. Here, we describe interim results on humoral and cell-mediated immunogenicity, reactogenicity, and safety until 1 year post-dose 1. RESULTS: In total, 1653 participants were vaccinated. One month post-dose 1, neutralization titers increased 10.5-fold (RSV-A) and 7.8-fold (RSV-B) vs pre-dose 1. Titers then declined to levels 4.4-fold (RSV-A) and 3.5-fold (RSV-B) above pre-dose 1 at month 6 and remained 3.1-fold (RSV-A) and 2.3-fold (RSV-B) above pre-dose 1 levels after 1 year. RSVPreF3-binding immunoglobulin G levels and CD4+ T-cell frequencies showed similar kinetics. Solicited administration-site and systemic adverse events (mostly mild to moderate and transient) were reported by 62.2% and 49.5% of participants. Serious adverse events were reported by 3.9% of participants within 6 months post-dose 1; 1 case was considered vaccine related. CONCLUSIONS: One RSVPreF3 OA dose elicited cell-mediated and RSV-A- and RSV-B-specific humoral immune responses that declined over time but remained above pre-dose 1 levels for at least 1 year. The vaccine was well tolerated with an acceptable safety profile. Clinical Trials Registration. NCT04732871 (ClinicalTrials.gov).

Respiratory syncytial virus (RSV) is a major cause of illness and hospitalization in older adults. An RSV vaccine for older adults developed by GSK was recently approved. The vaccine was well tolerated and provided protection against RSV disease in adults aged ≥60 years during at least 1 RSV season. In this ongoing study, we are evaluating the magnitude and durability of the immune response, as well as vaccine safety, until 3 years after vaccination of adults aged ≥60 years from 5 countries. Here, we report the results of an interim analysis until 1 year after vaccination with 1 dose. In total, 1653 participants were vaccinated. We found that the vaccine induced a strong immune response that was evident 1 month after vaccination, after which it declined but persisted for at least 1 year. Study participants most often reported pain at the injection site, muscle pain, tiredness, and headache as adverse reactions, which were mostly mild to moderate and of short duration. One serious adverse reaction was considered related to the vaccine. The long-term immune response that was observed in this study is consistent with the vaccine providing protection during at least 1 RSV season.

Addressing causal relationship between drinking behavior and metabolic syndrome: one-sample Mendelian randomization analysis.

AIMS: Alcohol drinking is associated with central obesity, hypertension, and hyperlipidemia, which further causes metabolic syndrome (MetS). However, prior epidemiological studies on such associations lack experimental evidence for a causal relationship. This study aims to explore the causal relationship between drinking behavior and MetS in Taiwan population by using Mendelian randomization (MR) analysis. METHODS: A cross-sectional study was conducted using the Taiwan Biobank database, which comprised 50 640 Han Chinese who were 30-70 years old without cancer from 2008 to 2020. In MR analysis, we constructed weighted and unweighted genetic risk scores by calculating SNP alleles significantly associated with alcohol drinking. We calculated odds ratios and 95% confidence interval (CI) by using a two-stage regression model. RESULTS: A total of 50 640 participants were included with a mean age of 49.5 years (SD: 1.67 years), 36.6% were men. The adjusted odds ratio (aOR) of MetS per 5% increase in the likelihood of genetic predisposition to drink based on weighted genetic risk score with adjustment was 1.11 (95% CI: 1.10, 1.12, P < .001). Analysis was also conducted by grouping the likelihood of genetic predisposition to drink based on quartiles with multivariate adjustment. Using Q1 as the reference group, the aORs of MetS for Q2, Q3, and Q4 were 1.19 (1.12, 1.27, p < .001), 1.31 (1.23, 1.40, p < .001), and 1.87 (1.75, 2.00, p < .001), respectively, for the weighted genetic risk score. CONCLUSIONS: This study shows a modest relationship between drinking behavior and MetS by using MR analysis.

Impact of occupational noise exposure on the hearing level in hospital staffs: a longitudinal study.

The study aimed to evaluate the impact of occupational noise on hearing loss among healthcare workers using audiometry. A longitudinal study was conducted with a six-month follow-up period in a hospital with 21 participants, divided into high-noise-exposure (HNE) and low-noise-exposure (LNE) groups. Mean noise levels were higher in the HNE group (70.4 ± 4.5 dBA), and hearing loss was measured using pure-tone audiometry at baseline and follow-up. The HNE group had significantly higher mean threshold levels at frequencies of 0.25 kHz, 0.5 kHz, 4.0 kHz, and an average of 0.5, 1, 2, and 4 kHz (all p-values < 0.05) after the follow-up period. After adjusting for confounding factors, the HNE group had significantly higher hearing loss levels at 0.25 kHz, 0.5 kHz, and average frequencies of 0.5, 1, 2, and 4 kHz compared to the LNE group at the second measurement. Occupational noise levels above 65 dBA over six months were found to cause significant threshold changes at frequencies of 0.25 kHz, 0.5 kHz, and an average of 0.5-4.0 kHz. This study highlights the risk of noise-induced hearing loss among healthcare workers and emphasizes the importance of implementing effective hearing conservation programs in the workplace. Regular monitoring and assessment of noise levels and hearing ability, along with proper use of personal protective equipment, are crucial steps in mitigating the impact of occupational noise exposure on the hearing health of healthcare workers.

Comparison of benzbromarone and allopurinol on the risk of chronic kidney disease in people with asymptomatic hyperuricemia.

OBJECTIVE: The objective of the study was to compare the relative effects of benzbromarone and allopurinol on the risk of developing chronic kidney disease in persons with asymptomatic hyperuricemia. METHODS: A retrospective cohort study was conducted to analyze a 2003-2015 national database including all claims data of 2 million beneficiaries in Taiwan. Asymptomatic hyperuricemia was defined as follows: persons using urate-lowering drugs who never developed gout flares. The benzbromarone group included persons ages 20-84 that had asymptomatic hyperuricemia and received benzbromarone alone. The allopurinol group included persons ages 20-84 that had asymptomatic hyperuricemia and received allopurinol alone. The maximum follow-up time was set as 5 years in this study. The main outcome was defined as follows: persons were newly diagnosed with chronic kidney disease. A Cox proportional hazards regression analysis was performed to test the association between variables and the risk of chronic kidney disease. RESULTS: After propensity score matching, 9107 persons in the benzbromarone group and 4554 persons in the allopurinol group were eligible for the study. Approximately 71% of the study subjects were males. The mean age was 56 years old. The incidence rate of chronic kidney disease was lower in the benzbromarone group than in the allopurinol group (1.18 versus 1.99/per 100 person-years, incidence ratio = 0.60, and 95% confidence interval = 0.52-0.68).The Cox proportional hazards regression analysis disclosed that after adjusting for co-variables, there was a decreased risk of developing chronic kidney disease in the benzbromarone group as compared with the allopurinol group (hazard ratio = 0.59, 95% confidence interval = 0.52-0.67 and P<0.001). CONCLUSIONS: The use of benzbromarone is associated with a lower hazard of developing chronic kidney disease as compared to allopurinol use among persons ages 20-84 with asymptomatic hyperuricemia. More studies are needed to confirm our findings.

Determination of potential sources of heavy metals in patients with urothelial carcinoma in central Taiwan: a biomonitoring case-control study.

The clarification of possible exposure sources of multiple metals to identify associations between metal doses and urothelial carcinoma (UC) risk is currently limited in the literature. We sought to identify the exposure sources of 10 metals (Vanadium, chromium, manganese, cobalt, nickel, copper, zinc, arsenic, cadmium, and lead) using principal component analysis (PCA) and then linked various principal component (PC) scores with environmental characteristics, including smoking-related indices, PM2.5, and distance to the nearest bus station. In addition, urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) and DNA hypomethylation markers (5-methyl-2'-deoxycytidine levels; %5-MedC) were investigated in combination with UC risks. We conducted this hospital-based case control study in 359 UC patients with histologically confirmed disease and 718 controls. All data were collected from face-to-face interviews and medical records. Approximately 6 mL blood was collected from participants for analysis of multiple heavy metal and DNA methylation in leukocyte DNA. Further, a 20 mL urine sample was collected to measure urinary cotinine and 8-OHdG levels. In addition, average values for PM2.5 for individual resident were calculated using the hybrid kriging/land-use regression model. In UC patients, significantly higher cobalt, nickel, copper, arsenic, and cadmium (µg/L) levels were observed in blood when compared with controls. Three PCs with eigenvalues > 1 accounted for 24.3, 15.8, and 10.7% of UC patients, and 26.9, 16.7, and 11.1% of controls, respectively. Environmental metal sources in major clusters were potentially associated with industrial activities and traffic emissions (PC1), smoking (PC2), and food consumption, including vitamin supplements (PC3). Multiple metal doses were linked with incremental urinary 8-OHdG and DNA hypomethylation biomarkers. For individuals with high PC1 and PC2 scores, both displayed an approximate 1.2-fold risk for UC with DNA hypomethylation.In conclusion, we provide a foundation for health education and risk communication strategies to limit metal exposure in environment, so that UC risks can be improved potentially.

Allopurinol use and the risk of dementia: A meta-analysis of case-control studies.

BACKGROUND: This study aimed to compare the risk of dementia between exposed to allopurinol and not exposed to allopurinol in persons who had gout and/or hyperuricemia. METHODS: The meta-analysis was conducted to select case-control research written in English through the help of PubMed and Web of Science. The pooled odds ratio (OR) with 95% confidence interval based on the fixed-effect model was applied to compare the allopurinol exposure among cases (subjects with dementia) and controls (subjects without dementia). RESULTS: A total of 4 case-control studies relating the allopurinol exposure to the risk of dementia were identified. The study duration was from 9 to 14 years. The number of study persons was from 3148 to 137,640. The male percentage of study subjects was from 36.9 to 62.5. The mean age of study persons was from 72.3 to 78.7 years. Overall, the odds of the allopurinol exposure among cases were lower than the odds of the allopurinol exposure among control subjects (OR = 0.91, 95% confidence interval = 0.87-0.95, P < .001). The heterogeneity between these eligible studies was low (I² = 0%). The sensitivity analysis revealed that after excluding the studies with concern, the pooled OR did not achieve statistical significance. CONCLUSIONS: This is the first meta-analysis to report that there is a negative relationship between the allopurinol exposure and the risk of dementia. Although the results favor the hypothesis, currently it is unable to draw strong conclusions about the protective effect of allopurinol against dementia due to inclusion of only a few eligible studies. Randomized controlled trials are needed to explore the relationship between allopurinol exposure and the probability of dementia.

Relationships of multiple metals exposure, global DNA methylation, and urothelial carcinoma in central Taiwan.

The relationship between heavy metal exposure and human health has been investigated mostly for individual metals, failing to consider their potential interactions. In this study, we assessed the joint effects of multiple metals using generalized weighted quantile sum (WQS) regression on the risk of urothelial carcinoma (UC). Also, we performed mediation analysis to evaluate the mediator %5-MedC in DNA involved in the mechanism of urothelial carcinogenesis. We conducted a hospital-based case-control study of 355 UC patients and 710 controls, where diagnosis of UC was histologically confirmed. All data were collected from face-to-face interviews and medical records. Also, we measured six metals and 8-OHdG in urine samples along with %5-MedC in peripheral blood. Ni and Pb levels increased with UC risk in single-pollutant analysis using traditional logistic regression, and similar results were obtained in multi-pollutant analysis, where all metals analyzed were considered. In WQS analysis, the weights of Ni (27%), Pb (20%), Cr (18%), and Co (16%) predominated in the metal mixture index. WQS score and UC risk showed odds ratios of 1.65 (95%CI: 1.26, 2.15) and 1.43 (95%CI: 1.00, 2.05) for a linear and non-linear relationship, respectively. Finally, we did not observe a natural indirect effect of %5-MedC in DNA; however, a marginal effect of WQS score and natural direct effect were still found after considering a natural indirect effect. In conclusion, positive associations between WQS scores and increased risk of UC were observed. Interactions of multiple metals should be considered in assessing human health risk.

Derivation and validation of a clinical prediction model for risks of venous thromboembolism in diabetic and general populations.

ABSTRACT: Most studies on the prediction of venous thromboembolism (VTE) focused on hospitalized, surgery, and cancer patients or women receiving hormonal contraceptives or menopausal hormone therapy. No study considered diabetic and general populations to establish a VTE prediction model, especially in Asia. We developed a predictive model for VTE among type 2 diabetic patients and the general population.This study considered 2 nationwide retrospective cohort studies consisting of 52,427 diabetic participants and 508,664 participants from the general population aged 30 to 85 years during 2001 to 2004 in Taiwan. All participants were followed up until VTE event, death, or December 2011. The outcome event was VTE, including deep venous thrombosis and pulmonary embolism. Candidate predictors consisted of socio-demographic factors, diabetes-related factors and biomarkers, comorbidities, and medicine use. Our study followed the procedures proposed by the Framingham Heart Study to develop prediction models by using a Cox regression model. The predictive accuracy and performance characteristics were assessed using the area under curve of receiver operating characteristics curve and calibration of a risk score were performed by Hosmer-Lemeshow goodness-of-fit test.The common factors for persons with type 2 diabetes and general population included age, hospitalization status 1 year before the baseline, hypertension, chronic kidney disease, chronic obstructive pulmonary disease, and anti-diabetes medications; the specific factors for persons with type 2 diabetes consisted of body mass index, glycosylated hemoglobin A1C, and creatinine; and the factors for general population included gender, peripheral vascular disease, cancer, hypertension medication, cardiovascular medication, and non-steroidal anti-inflammatory drug. The area under curve of 3-, 5-, and 8-year VTE prediction models were 0.74, 0.71, and 0.69 in the diabetic population and 0.77, 0.76, and 0.75 in the general population, respectively.The new clinical prediction models can help identify a high risk of VTE and provide medical intervention in diabetic and general populations.

A Head-To-Head Comparison of Benzbromarone and Allopurinol on the Risk of Type 2 Diabetes Mellitus in People With Asymptomatic Hyperuricemia.

Objective: The study aimed to thoroughly address the influence of benzbromarone and allopurinol on the risk of the development of type 2 diabetes mellitus (T2DM) in people with asymptomatic hyperuricemia. Methods: We conducted a retrospective cohort study to examine the 2000-2015 national dataset containing all claims data of 23 million beneficiaries in Taiwan. Subjects who already had diabetes mellitus, gout-related diseases, and any cancer prior to the index date were excluded. Asymptomatic hyperuricemia was defined as subjects taking urate-lowering drugs who never had a gout flare. Subjects aged 20-84 with asymptomatic hyperuricemia who had benzbromarone prescriptions were selected as the benzbromarone group. Sex-matched and age-matched subjects with asymptomatic hyperuricemia who had allopurinol prescriptions were identified as the allopurinol group. The maximum follow-up duration was set as 5 years in our study. The outcome was set as subjects who had a new diagnosis of T2DM. The incidence density of T2DM was calculated in the benzbromarone and allopurinol groups. The hazard ratio (HR) and 95% confidence interval (CI) for T2DM was utilized to estimate the association between medications and the risk of T2DM. Results: The incidence of T2DM among benzbromarone users was significantly lower than that of allopurinol users (7.91 versus 8.48 per 100 person-years, incidence rate ratio = 0.93, and 95% CI = 0.87-0.99). After adjustment for co-variables, the adjusted HR of T2DM would be 0.91 (95% CI = 0.85-0.98 and p = 0.008) in benzbromarone users as compared to allopurinol users. Conclusion: There is a small but statistically significant risk reduction of developing T2DM in people with asymptomatic hyperuricemia taking benzbromarone as compared to those taking allopurinol during 5 years of follow-up. It indicates a future research direction for the use of individual urate-lowering drugs on the prevention of T2DM in the general population.

Renal markers and risks of all cause and cardiovascular mortality from the Taichung community based cohort study.

This study aimed to explore the associations between renal-related and arterial stiffness biomarkers with all-cause and expanded cardiovascular disease (CVD) mortality in a general Taiwanese population. This prospective community-based cohort study included 4883 subjects aged ≥ 20 years who were followed up until December 31, 2016. Renal-related biomarkers consisted of blood urea nitrogen (BUN), estimated glomerular filtration rate (eGFR), and urine albumin-to-creatinine ratio (UACR). Arterial stiffness biomarker consisted of brachial-ankle pulse wave velocity (baPWV). The death status of the subjects was ascertained by matching information from death records with the identification number and date of birth of the subjects. Cox proportional hazard models with restricted cubic splines estimated the hazard ratios and 95% confidence intervals for all-cause mortality and expanded CVD mortality. During a mean 8.3 years of follow up, 456 deaths were recorded, 146 of which were due to expanded CVD mortality. The multivariable-adjusted hazard ratios of all-cause mortality was 1.53 (95% CI 1.21-1.94) for BUN (≥ 20 mg/dL vs. < 20 mg/dL), 1.57 (1.15-2.14) for eGFR (< 90 mL/min/1.73 m2 vs. ≥ 90 mL/min/1.73 m2), 1.55 (1.25-1.92) for UACR (≥ 30 mg/g vs. < 30 mg/g), and 1.75 (1.14-2.67) for baPWV (≥ 1400 cm/s vs. < 1400 cm/s). The expanded CVD mortality was 1.89 (95% CI 1.30-2.73) for BUN (≥ 20 mg/dL vs. < 20 mg/dL), 2.28 (1.13-4.57) for eGFR (< 90 mL/min/1.73 m2 vs. ≥ 90 mL/min/1.73 m2), 2.13 (1.52-2.99) for UACR (≥ 25 mg/g vs. < 25 mg/g), and 15.73 (2.14-115.61) for baPWV (≥ 1400 cm/s vs. < 1400 cm/s). High levels of BUN, UACR, and baPWV and low levels of eGFR showed high risks with all-cause and expanded CVD mortality. Our study provides insights into screening tests to target populations at high risk of premature death due to CVD.