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Supplemental Digital Content is available in the text., Background and Purpose: Hypertensive disorders of pregnancy (HDP) comprise 4 subtypes. Previous studies have not investigated the relationship between stroke risk, different HDP subtypes, and follow-up time, which was the purpose of this study. Methods: Data of 17 588 women aged 18 to 45 years who had a history of HDP in Taiwan from 2000 to 2017 was retrospectively reviewed. After matching with confounders, 13 617 HDP women and 54 468 non-HDP women were recruited. Results: HDP women had an adjusted hazard ratio (aHR) of 1.71 (95% CI, 1.46−2.00) for stroke, and 1.60 (1.35−1.89) and 2.98 (2.13−4.18) for ischemic and hemorrhagic stroke, respectively (P0.05). Furthermore, multiple HDP combined with preeclampsia had aHR of 5.48 (1.14−26.42, P

Otosclerosis is an early adult-onset disease that is associated with 5–9% and 18–22% of all cases of hearing and conductive hearing loss, respectively, and it is suspected to have a viral etiology. However, the role of viral infection in otosclerosis is still inconclusive. This study aimed to investigate whether rubella infection was associated with otosclerosis risk. We conducted a nationwide case-control study in Taiwan. Data were retrospectively analyzed from the Taiwan National health Insurance Research Database. Cases consisted of all patients who were aged ≥6 years and had a first-time diagnosis of otosclerosis for the period between 2001 and 2012. The controls were exact matched to cases in a 4:1 ratio by birth year, sex, and must survive in the index year of their matched cases. Adjusted odds ratio (OR) and 95% confidence interval (CI) were estimated by using conditional logistic regression. We examined 647 otosclerosis cases and 2588 controls without otosclerosis. Among the 647 patients with otosclerosis, 241 (37.2%) were male and 406 (62.8%) were female, with most aged between 40 and 59 years, with a mean age of 44.9 years. After adjusting for age and sex, conditional logistic regression revealed that exposure to rubella was not associated with a significant increase in otosclerosis risk (adjusted OR, 2.0; 95% CI, 0.18–22.06, p = 0.57). In conclusion, this study did not show that rubella infection was associated with the risk of otosclerosis in Taiwan.

We thank Li and colleagues for their insightful comments [...]

Histamine-2-receptor antagonist (H2RA) has shown beneficial effects on the kidney, heart, and sepsis in animal models and on the heart and COVID-19 infection in clinical studies. However, H2RAshave been used as a reference in most epidemiological studies examining the association of proton pump inhibitors (PPI) with outcomes. Therefore, we aimed to evaluate the effect of H2RA on renal and survival outcomes in chronic kidney disease (CKD) patients. We used a Taiwanese nationalhealth insurance database from 2001 to 2016 to screen 45,767 CKD patients for eligibility. We identified new users of PPI (n = 7121), H2RA (n = 48,609), and users of neither PPI nor H2RA (as controls) (n = 47,072) during follow-up, and finally created 1:1:1 propensityscore-matchedcohorts; each cohort contained 4361 patients. Participants were followed up after receivingacid-suppression agents or on the corresponding date until the occurrence of end-stage renal disease (ESRD) in the presence of competing mortality, death, or through the end of 2016. Compared toneither users, H2RAand PPI users demonstrated adjusted hazard ratios of 0.40 (95% confidence interval, 0.30–0.53) for ESRDand 0.64 (0.57–0.72) for death and 1.15 (0.91–1.45) for ESRD and 1.83 (1.65–2.03) for death, respectively. A dose-response relationship betweenH2RA use with ESRD and overall, cardiovascular, and non-cardiovascular mortality was detected. H2RA consistently provided renal and survival benefits on multivariable stratified analyses and multiple sensitivity analyses. In conclusion, dose-dependent H2RA use was associated with a reduced risk of ESRD and overall mortality in CKD patients, whereas PPI use was associated with an increased risk of overall mortality, not in a dose-dependent manner.

The association between surgical treatment for obstructive sleep apnea (OSA) in chronic kidney disease (CKD) patients and end-stage renal disease (ESRD) and survival outcomes is not established, and this study aimed to evaluate this association. A retrospective cohort analysis was conducted from 2001 to 2015, including 32,220 eligible CKD patients with incident OSA. By 1:3 propensity score matching, 1078 CKD patients with incident OSA who received surgery (treated cohort) and 3234 untreated cohort who never received surgery were analyzed. The risk of ESRD in the competing mortality was significantly lower in the treated cohort than in the untreated cohort, with an adjusted hazard ratio (aHR) of 0.38 (95% confidence interval (CI0, 0.15–0.97; p = 0.043). In addition, the adjusted HRs of overall, cardiovascular, and non-cardiovascular mortality in the treated and untreated cohorts were 2.54 (95% CI, 1.79–3.59; p < 0.0001), 1.46 (95% CI, 0.29–7.22; p = 0.64), and 2.62 (95% CI, 1.83–3.75; p < 0.0001), respectively. Furthermore, the risks of overall and non-cardiovascular mortality for the treated cohort primarily occurred during a 3-month follow-up. In conclusion, surgical treatment for incident OSA in CKD patients was associated with decreased ESRD risk, but with increased non-cardiovascular mortality risk, especially within 3 months after surgical treatment.

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 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.

The commonly used vaccine for adults with a high risk of pneumonia is 23-valent pneumococcal polysaccharide vaccine (PPSV23). However, its effectiveness in patients with colorectal cancer has not been investigated. This study aimed to investigate the effectiveness of PPSV23 in reducing the risk of pneumonia among elderly patients with colorectal cancer. A total of 120,605 newly diagnosed patients with colorectal cancer were identified from the Taiwan National Health Insurance Research Database between 1996 and 2010. Of these patients, 18,468 were 75 years or older in 2007 to 2010, and 3515 received PPSV23. People aged 75 years or older have been considered eligible for receiving PPSV23 vaccination in Taiwan since 2007. The specific “vaccination period” of October 2008 to December 2008 was used to minimize the potential immortal time bias. Therefore, 893 patients who received PPSV23 outside this vaccination period or died before 2009 and 2960 unvaccinated patients who died before 2009 were excluded. After the propensity score was matched with a 1:3 ratio, 2622 vaccinated patients and 7866 unvaccinated patients were recruited. A multivariate log-linear Poisson regression model was performed and adjusted for potential confounders, including influenza vaccination, vaccination period, cancer treatment modalities, comorbidities, and sociodemographic variables. After 2 years of follow-up, the incidence rate of the pneumonia hospitalization of the vaccinated patients was significantly lower than that of the unvaccinated patients at 85.53 per 1000 person-years (PYs) of the former and 92.38 per 1000 PYs of the latter. The proportions of patients who had 2, 3, and >3 pneumonia hospitalizations per year were consistently lower in the vaccinated group than in the unvaccinated group (1.9% vs 2.0%, 0.5% vs 0.9%, and 0.7% vs 1.1%, respectively). After adjustment for covariates was made, PPSV23 vaccine was significantly associated with a reduced risk of pneumonia hospitalization, with an adjusted incidence rate ratio of 0.88 (P = .040). The overall pneumonia-free survival rate was also significantly higher in the vaccinated patients than in the unvaccinated patients (P = .001). PPSV23 vaccination was associated with a significantly reduced rate of pneumonia hospitalization in elderly patients with colorectal cancer.

summary The response of seedlings of black cherry (Prunus serotina Ehrh.) to ozone was evaluated in Great Smoky Mountains National Park using open-top chambers during the growing seasons of 1989 and 1992. Two separate sets of seedlings were each exposed to various concentrations of ozone (charcoal-filtered; 0.5 × (not used in 1989), 1.0 ×, 1.5 ×, and 2.0 × modified ambient) in two different seasons. Seasonal indices of exposure (SUM00, SUM06 and AOT40) for the 1.0 × treatments were 39.2, 1.9, and 1.62 ppm h respectively, in 1989, and 63.1, 0.9, and 0.78 ppm h, respectively, in 1992. No significant chamber effects were noted, except for reduced height growth in open plots compared with 1.0 × chambers in 1992. In both years, the 2.0 × treatment reduced total, leaf, root, and shoot-I-root biomass, although some of these changes were only marginally significant in 1992. Stem biomass was significantly reduced in 1989, but not 1992. Leaf area, count and weight were all highly correlated, and showed significant reductions in both years. The leaf area ratio (leaf area/total weight) was reduced in 1989, but not in 1992. Height was not affected by ozone, but diameter was reduced only in 1989. Chamber-to-chamber variation for biomass and leaf variates was greater in 1992, and as a result, significance levels were lower. Weibull functions were fitted to chamber means, and showed significant near-linear declines for most components when log-transformed data were plotted against the SUM06 and AOT40 indices. Individual Weibull models for the 1989 and 1992 data sets, and combined models over both years, were developed. Combined models were adequate for describing ozone responses for all biomass components, as determined by the likelihood ratio test. The data show-that the two years of exposure produced similar, but not identical effects, despite large differences in initial size of the seedlings and in seasonal ozone dynamics. Leaf and root biomass were most sensitive to ozone (as determined by the slope of decrease with increasing SUM06), whereas stem biomass was least sensitive. Black cherry seedlings are shown to be among the most sensitive to elevated ozone of the 21 tree species examined to date in Great Smoky Mountains National Park.

Survival rates and antiarrhythmic drug use were determined in 941 consecutive patients resuscitated from prehospital cardiac arrest due to ventricular fibrillation between March 7, 1970, and March 6, 1985. Of these patients, 18.7% were treated for at least a portion of the period with quinidine, 17.5% with procainamide, and 39.4% received no antiarrhythmic agent. Beta blockers were prescribed for 28.3% of the patients. Unadjusted comparisons of survival estimates showed dramatically lower survival rates for patients who received antiarrhythmic drugs independent of beta-blocker therapy and significantly improved survival for patients receiving beta-blocker therapy independent of antiarrhythmic use. Patients for whom antiarrhythmic therapy was prescribed also had more adverse baseline risk factors, whereas patients taking beta blockers had fewer such risk factors. After adjustment for these baseline risk factors, the use of antiarrhythmics was weakly (p less than 0.09) associated with worsened survival; 2-year survival for procainamide-treated patients was 30% and quinidine-treated patients 55% (p = 0.003). Beta-blocker therapy was associated with improved (p less than 0.001) survival. Thus, although neither procainamide nor quinidine appear to have had a benefit on mortality, the effect of procainamide appears to be significantly worse than that of quinidine. The use of antiarrhythmic drug therapy in patients resuscitated from prehospital ventricular fibrillation should be regarded as not only unproved, but potentially hazardous, and should probably be restricted to testing in randomized clinical trials.