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Vitamin D deficiency has been epidemiologically linked to Alzheimer's disease (AD) and other dementias, but no interventional studies have proved causality. Our previous work revealed that the genomic vitamin D receptor (VDR) is already converted into a non-genomic signaling pathway by forming a complex with p53 in the AD brain. Here, we extend our previous work to assess whether it is beneficial to supplement AD mice and humans with vitamin D. Intriguingly, we first observed that APP/PS1 mice fed a vitamin D-sufficient diet showed significantly lower levels of serum vitamin D, suggesting its deficiency may be a consequence not a cause of AD. Moreover, supplementation of vitamin D led to increased Aβ deposition and exacerbated AD. Mechanistically, vitamin D supplementation did not rescue the genomic VDR/RXR complex but instead enhanced the non-genomic VDR/p53 complex in AD brains. Consistently, our population-based longitudinal study also showed that dementia-free older adults (n = 14,648) taking vitamin D

Background Clarithromycin-based therapy is important for Helicobacter pylori eradication treatment. However, clarithromycin may increase cardiovascular risk. Hence, we investigated the association between clarithromycin use and outcomes in adults with stable coronary heart disease (CHD) and subsequent peptic ulcer disease (PUD). Methods This nationwide cohort study used a national health insurance database to screen 298,417 Taiwanese residents who were diagnosed with coronary heart disease from 2001 to 2015 for eligibility in the study and to evaluate select eligible patients with CHD–PUD from 2004 to 2015. Data were obtained from new users of clarithromycin (n = 4183) and nonusers of clarithromycin (n = 24,752) during follow-up. A total of 4070 eligible clarithromycin users and 4070 nonusers were subject to final analysis by 1:1 propensity score matching. Participants were followed up after receiving clarithromycin or at the corresponding date until the occurrence of cardiovascular morbidity in the presence of competing mortality, overall mortality and cardiovascular mortality, or through the end of 2015. The incidence rates and risks of overall mortality and cardiovascular outcomes were evaluated. The associations between clarithromycin and arrhythmia risk, as well as its dose and duration and overall mortality and cardiovascular outcomes were also addressed. Results Clarithromycin users were associated with adjusted hazard ratios of 1.08 (95% confidence interval, 0.93–1.24; 21.5 compared with 21.2 per 1000 patient-years) for overall mortality, 0.95 (0.57–1.59; 1.5 compared with 1.8 per 1000 patient-years) for cardiovascular mortality, and 0.94 (0.89–1.09; 19.6 compared with 20.2 per 1000 patient-years) for cardiovascular morbidity in the presence of competing mortality, as compared with nonusers. We found no relationship between dose and duration of clarithromycin and overall mortality and cardiovascular outcomes and no increased risk of arrhythmia during follow-up period. After inclusion of arrhythmia events to re-estimate the risks of all study outcomes, the results remained insignificant. Conclusion Concerning overall mortality, cardiovascular mortality, and cardiovascular morbidity, our results suggest clarithromycin-based therapy for Helicobacter pylori eradication may be safe in patients with stable CHD and subsequent PUD.

BACKGROUND The 23-valent pneumococcal polysaccharide vaccine (PPSV23) is indicated for adults who have a high risk of pneumonia; however, its effectiveness in patients with prostate cancer who are at a risk of pneumonia because of age and cancer treatments, including androgen-deprivation therapy, is unknown. METHODS Between 2000 and 2010, 38,735 patients with prostate cancer were diagnosed in Taiwan. After exclusions and exact matching for age, previous pneumonia, and influenza vaccination, 2188 vaccinated patients and 2188 unvaccinated patients were recruited. The incidence density of all-cause bacterial pneumonia hospitalizations was analyzed. RESULTS Over 7 years of follow-up, patients who received the PPSV23 had a significantly lower incidence density, with 142.8 per 1000 person-years versus 162.0 per 1000 person-years for unvaccinated patients. More patients in the vaccinated cohort were never hospitalized for pneumonia compared with those in the unvaccinated cohort (64.2% vs 62.2%, respectively). After adjusting for the Charlson comorbidity index, cancer treatment modalities, and socioeconomic levels, the risk of pneumonia-related hospitalization in the PPSV23 vaccination cohort was 0.48 times lower than that in the unvaccinated cohort (adjusted incidence rate ratio, 0.48; P = .046). For patients who received the influenza vaccination, subgroup analysis demonstrated that PPSV23 vaccination significantly decreased the risk (adjusted incidence rate ratio, 0.45; P < .001). Compared with unvaccinated controls, PPSV23-vaccinated patients had a lower cumulative incidence for the first occurrence of pneumonia-related hospitalization (34.49% vs 36.36%; P = .178) and higher overall survival (47.5% and 42.3%, respectively; P < .001). CONCLUSIONS Vaccination of elderly patients who have prostate cancer with the relatively common and inexpensive PPSV23 can decrease the risk of pneumonia and prolong survival.

Objective No study ever investigated the long-term risk of stroke in women with pre-eclampsia/eclampsia. The purpose of this study is to explore long-term stroke risks, differentiating subtypes and their time trends. Design Nationwide population-based cohort study Methods Between 2000 and 2017, 1,384,427 pregnant women were registered in the National Health Insurance Research Database in Taiwan. After excluding women with previous stroke history and exact matching with all confounders, 6,053 women with pre-eclampsia/eclampsia and 24,212 controls were recruited. Main Outcome Measures Hemorrhagic and ischemic strokes after child-birth Results Over the 17-year follow-up, the adjusted hazard ratio (aHR) for stroke in women with a history of pre-eclampsia/eclampsia was 2.05 (95% confidence interval, CI = 1.67-2.52, p

Chinese herbal medicine (CHM) has been used as adjuvant treatment of chronic kidney disease (CKD) for years. Astragalus membranaceus (A. membranaceus, Huangqi [A]), Angelica sinensis (Oliv.) Diels (Danggui [S]), Rheum palmatum L. (Dahuang [R]), and Salvia miltiorrhiza Bunge (Danshen [D]) are considered as potentially renoprotective CHMs. However, there is limited evidence on whether ASRD use affects outcomes and causes hyperkalemia in patients with stage 4 and stage 5 advanced CKD.To investigate between ASRD use (vs. nonuse) and risks of end-stage renal disease (ESRD), death, and hyperkalemia in patients with advanced CKD.Retrospective nationwide cohort study using claims data from the Taiwan's 2005 Longitudinal Generation Tracking Database in 2000-2016.A total of 24,572 patients with advanced CKD were identified and 15,729 eligible patients were enrolled in the propensity score matching, with 1,401 incident ASRD users (8.9%) and 14,328 nonusers (91.1%). Finally, 1,076 ASRD users and 4,304 matched nonusers were subjected to analysis. We used Cox proportional hazards regression model to estimate the hazard ratios for ESRD and death and Poisson regression to estimate incidence rate ratio of hyperkalemia. The additive effect of one to four ASRD and the pooling effect of individual ASRD on risks of ESRD and death were also addressed.In a total follow-up of 15,740 person-years, 2,703 patients (50.2%) developed ESRD and 499 (9.3%) died before progression to ESRD. As compared with nonusers, ASRD users were associated with adjusted hazard ratios of 0.83 (95% confidence interval, 0.76-0.91) for ESRD and 0.78 (0.30-0.93) for death, as well as adjusted incidence rate ratios of 0.54 (0.48-0.60) for inpatient hyperkalemia and 0.44 (0.42-0.46) for total hyperkalemia. The renal and survival benefits of ASRD use were consistent across almost patient subgroups on multivariate stratified analyses. Using all four ASRD provided the lowest risks of ESRD (0.30; 0.71-0.52) and death (0.32; 0.17-0.63). Individual use of ASRD also demonstrated comparable renal and survival benefits.ASRD use was associated with lower risks of ESRD and death among advanced CKD patients. This benefit did not increase hyperkalemia risk.

Context Although α-glucosidase inhibitors (AGIs) have been shown to reduce the risk of myocardial infarction in patients with impaired glucose tolerance, the cardiovascular benefits of AGIs in those with type 2 diabetes (T2D) remains unclear. Objective We compared the clinical outcomes of adding acarbose vs sulfonylureas to metformin therapy in patients with T2D. Design, setting, and participants The study population was drawn from the database of the Diabetes Pay-for-Performance program in Taiwan. Sulfonylureas and acarbose were prescribed to 196,143 and 14,306 patients with T2D, respectively, from 2004 to 2015, who had been treated with metformin. A propensity score-matched cohort study was conducted. The patients were followed up for clinical adverse events of all-cause mortality and hospitalizations of major atherosclerotic events (i.e., myocardial infarction and ischemic stroke), heart failure, or hypoglycemia. Results A total of 14,306 propensity score-matched pairs (age, 55.8 ± 13.1 years; 47.8% men) were enrolled in the present analysis. Compared with sulfonylureas as the add-on therapy to metformin, the use of acarbose was associated with significantly lower risks of hospitalizations for major atherosclerotic events [hazard ratio (HR), 0.69; 95% CI, 0.52 to 0.91], ischemic stroke (HR, 0.68; 95% CI, 0.49 to 0.94), and hypoglycemia (HR, 0.23; 95% CI, 0.08 to 0.71), after accounting for major confounding factors. Conclusions In T2D treatment, the use of acarbose as an add-on remedy to metformin was associated with lower risks of major atherosclerotic events, ischemic stroke, and hypoglycemia compared with the use of sulfonylurea as an add-on remedy.

Background The prevalence of diabetes is growing, and diabetes is an independent risk factor for both atrial fibrillation (AF) and stroke. However, the relative effectiveness and safety of different oral anticoagulants for diabetic patients with non-valvular AF remain unclear. We aimed to compare thromboembolic events, bleeding and mortality in diabetic AF patients treated with rivaroxaban, dabigatran and warfarin. Methods and Results Diabetic AF patients taking dabigatran (n = 322), rivaroxaban (n = 320) or warfarin (n = 1,899) were identified from the nationwide diabetes pay-for-performance program (n = 814,465) in Taiwan. Outcomes and comorbidities were evaluated by linking with Taiwan National Health Insurance Research Database. Propensity score weighting method was used to balance covariates across study groups. Patients were followed up until the first occurrence of any study outcome or the study end date. Compared with warfarin, dabigatran significantly decreased the risk of all-cause mortality (hazard ratio [HR] = 0.348, 95% confidence interval [CI] = 0.157–0.771) and gastrointestinal bleeding (HR = 0.558, 95% CI = 0.327–0.955). Relative effectiveness and safety outcomes between rivaroxaban and warfarin were comparable. Compared with rivaroxaban, dabigatran significantly decreased the risk of all-cause mortality (HR = 0.310, 95% CI = 0.121–0.798) and was associated with a borderline reduced risk for composite safety end points (HR = 0.670, 95% CI = 0.421–1.067). Conclusion In diabetic AF patients, dabigatran and rivaroxaban showed a superior or non-inferior effectiveness and safety profile compared with warfarin. Dabigatran was associated with a significantly lower risk of mortality than rivaroxaban.