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Background: Although chronic kidney disease (CKD) is associated with worse stroke outcomes, data regarding the influence of CKD on intravenous thrombolysis outcomes are scarce. We sought to assess the efficacy and safety of intravenous thrombolysis for acute ischemic stroke with unknown onset time in patients with CKD. Methods: Patients with an acute stroke of unknown onset time from the EOS trials (Evaluation of Unknown Onset Stroke Thrombolysis) collaboration were evaluated using an individual patient-level database of randomized controlled trials comparing intravenous thrombolysis with placebo/standard treatment. CKD was defined as baseline estimated glomerular filtration rate of 2 Mixed-effect logistic-regression analysis was performed to evaluate treatment effects. A favorable outcome was defined as a modified Rankin Scale score of 0 to 1 at 90 days. Safety outcomes were symptomatic intracranial hemorrhage at 22 to 36 hours and 90-day mortality. Results: Baseline data on renal function were available for 688 of 843 patients. Of these, CKD was present in 146 (21%), including 69 of 351 patients receiving alteplase and 77 of 337 patients receiving placebo/standard treatment. Overall, treatment with alteplase was associated with higher odds of favorable outcome, and CKD did not modify the treatment effect ( P interaction =0.834). A favorable outcome was observed in 31 of 69 (46%) patients with CKD in the alteplase group and in 28 of 77 (36%) patients with CKD in the control group (adjusted odds ratio, 1.19 [95% CI, 0.55–2.58]). Among patients with CKD, symptomatic intracranial hemorrhage occurred in 2 patients (3%) in the alteplase group but in none of the controls ( P =0.133). At 90 days, death was reported in 3 patients (4%) in the alteplase group compared with 2 patients (3%) in the controls ( P =0.539). Conclusions: The present analysis indicates that the benefit of alteplase does not differ between stroke patients with unknown onset time with and without CKD, although the statistical power was lacking to confirm the efficacy in subgroups. This study only applies to mild-to-moderate or predialysis CKD.

Background: We evaluated the effect of persistent hyperglycemia on outcomes in 1000 patients with intracerebral hemorrhage enrolled within 4.5 hours of symptom onset. Methods: We defined moderate and severe hyperglycemia based on serum glucose levels ≥140 mg/dL— Results: In the multivariate analysis, both moderate (odds ratio, 1.8 [95% CI, 1.1–2.8]) and severe (odds ratio, 1.8 [95% CI, 1.2–2.7]) hyperglycemia were associated with higher 90-day death or disability after adjusting for Glasgow Coma Scale score, hematoma volume, presence or absence of intraventricular hemorrhage, hyperlipidemia, cigarette smoking, and hypertension (no interaction between hyperglycemia and preexisting diabetes, P =0.996). Among the patients without preexisting diabetes, both moderate (odds ratio, 1.8 [95% CI, 1.0–3.2]) and severe (odds ratio, 2.0 [95% CI, 1.1–3.7]) hyperglycemia were associated with 90-day death or disability after adjusting for above mentioned potential confounders. Among the patients with preexisting diabetes, moderate and severe hyperglycemia were not associated with 90-day death or disability. Conclusions: Persistent hyperglycemia, either moderate or severe, increased the risk of death or disability in nondiabetic patients with intracerebral hemorrhage. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01176565.

OBJECTIVE We assessed the effect of glucagon-like peptide 1 receptor agonists (GLP-1RAs) on ischemic stroke prevention in the Asian population with type 2 diabetes (T2D) without established cardiovascular disease. RESEARCH DESIGN AND METHODS This retrospective cohort study examined data obtained from the Taiwan National Health Insurance Research Database for the period from 1998 to 2018. The follow-up ended upon the occurrence of hospitalization for ischemic stroke. The median follow-up period was 3 years. The effect of GLP-1RA exposure time on the development of hospitalization for ischemic stroke was assessed. RESULTS The GLP-1RA and non–GLP-1RA user groups both included 6,534 patients. Approximately 53% of the patients were women, and the mean age was 49 ± 12 years. The overall risk of ischemic stroke hospitalization for GLP-1RA users was not significantly lower than that for GLP-1RA nonusers (adjusted hazard ratio [HR] 0.69 [95% CI 0.47–1.00]; P = 0.0506), but GLP-1RA users with a >251-day supply during the study period had a significantly lower risk of ischemic stroke hospitalization than GLP-1RA nonusers (adjusted HR 0.28 [95% CI 0.11–0.71]). Higher cumulative dose of GLP-1 RAs (>1,784 mg) was associated with significantly lower risk of ischemic stroke hospitalization. The subgroup analyses defined by various baseline features did not reveal significant differences in the observed effect of GLP-1RAs. CONCLUSIONS Longer use and higher dose of GLP-1 RAs were associated with a decreased risk of hospitalization for ischemic stroke among Asian patients with T2D who did not have established atherosclerotic cardiovascular diseases, but who did have dyslipidemia or hypertension.

Background and aims Nicardipine has strong, rapidly acting antihypertensive activity. The effects of acute systolic blood pressure levels achieved with intravenous nicardipine after onset of intracerebral hemorrhage on clinical outcomes were determined. Methods A systematic review and individual participant data analysis of articles before 1 October 2020 identified on PubMed were performed (PROSPERO: CRD42020213857). Prospective studies involving hyperacute intracerebral hemorrhage adults treated with intravenous nicardipine whose outcome was assessed using the modified Rankin Scale were eligible. Outcomes included death or disability at 90 days, defined as the modified Rankin Scale score of 4–6, and hematoma expansion, defined as an increase ≥6 mL from baseline to 24-h computed tomography. Summary of review Three studies met the eligibility criteria. For 1265 patients enrolled (age 62.6 ± 13.0 years, 484 women), death or disability occurred in 38.2% and hematoma expansion occurred in 17.4%. Mean hourly systolic blood pressure during the initial 24 h was positively associated with death or disability (adjusted odds ratio (aOR) 1.12, 95% confidence interval (CI) 1.00–1.26 per 10 mmHg) and hematoma expansion (1.16, 1.02–1.32). Mean hourly systolic blood pressure from 1 h to any timepoint during the initial 24 h was positively associated with death or disability. Later achievement of systolic blood pressure to ≤140 mmHg increased the risk of death or disability (aOR 1.02, 95% CI 1.00–1.05 per hour). Conclusions Rapid lowering of systolic blood pressure by continuous administration of intravenous nicardipine during the initial 24 h in hyperacute intracerebral hemorrhage was associated with lower risks of hematoma expansion and 90-day death or disability without increasing serious adverse events.

We conducted this study to investigate the long-term outcomes of sulfonylurea (SU) use in patients with chronic obstructive pulmonary disease (COPD) and type 2 diabetes (T2D). We used propensity-score matching to identify 6008 pairs of SU users and nonusers from Taiwan’s National Health Insurance Research Database from 1 January 2000 to 31 December 2017. Cox proportional hazard models were used to compare the risks of mortality, cardiovascular events, non-invasive positive pressure ventilation, invasive mechanical ventilation, bacterial pneumonia, lung cancer, and hypoglycemia between SU users and nonusers. In the matched cohorts, the mean follow-up time for SU users and nonusers was 6.57 and 5.48 years, respectively. Compared with nonusers, SU users showed significantly lower risks of mortality [aHR 0.53(0.48–0.58)], cardiovascular events [aHR 0.88(0.81–0.96)], non-invasive positive pressure ventilation [aHR 0.74(0.6–0.92)], invasive mechanical ventilation [aHR 0.57(0.5–0.66)], and bacterial pneumonia [aHR 0.78(0.7–0.87)]. A longer cumulative duration of SU use was associated with a lower risk of these outcomes. This nationwide cohort study demonstrated that SU use was associated with significantly lower risks of cardiovascular events, ventilation use, bacterial pneumonia, and mortality in patients with COPD and T2D. SU may be a suitable option for diabetes management in these patients.

Statin therapy can effectively reduce recurrent transient ischemic attack (TIA) risk. However, studies have reported that statin use is associated with incidence of diabetes mellitus (DM). Whether statin therapy remains associated with higher DM risk in patients with TIA remains unknown. This study investigated whether statin treatment influences incident DM risk in patients with TIA. We conducted a retrospective cohort study using the Longitudinal Health Insurance Database 2000. Participants who were newly diagnosed with TIA (ICD-9-CM code 435) from 1 January 1997 to 31 December 2011 were recruited. The Kaplan–Meier method and Cox proportional risk model of time-dependent covariance were used. We enrolled 8342 patients with newly diagnosed TIA from 1 January 1997 to 31 December 2011. Of these, 1255 patients were classified as statin users and 7087 as nonusers. During the 14-year follow-up, the incidence of newly diagnosed DM was 0.545-fold lower in the statins group compared with nonusers (95% confidence interval [CI] = 0.457–0.650). According to cumulative defined daily doses (cDDDs), the adjusted hazard ratios for DM were 0.689, 0.594, and 0.463 when patients were treated with statins at cDDDs = 28–89, 90–180, and >180, respectively. In patients with TIA, statin use is associated with a lower incident DM risk compared with the nonuse of statins.

This study aimed to investigate the relationship between nontyphoidal salmonellosis (NTS) and new-onset hematological malignancy. We conducted a 17-year nationwide, population-based, retrospective cohort study to examine the association between NTS and the risk of hematological malignancies by using the Longitudinal Health Insurance Database (LHID) of Taiwan. Participants were enrolled from 2000 to 2015 and were monitored until 2017. We traced the years 1998-2000 to ensure that the cases included were newly diagnosed with NTS. The NTS cohort included 13,790 patients with newly diagnosed NTS between 2000 and 2015. Each patient was propensity score matched at a 1:4 ratio with people without NTS. Cumulative incidence, hazard ratios (HRs), and 95% confidence intervals (CIs) were calculated after adjusting for age, sex, income, urbanization, and medical comorbidities. The adjusted hazard ratio (aHR) of hematological malignancies for NTS patients relative to those without NTS was 1.42 (95% CI 0.91-2.20). In the age subgroup analysis, NTS had a significantly greater risk of hematological malignancies for patients older than 60 (aHR 3.04, 95% CI 1.46-6.34), with an incidence rate of 11.7 per 10,000 person-years. In patients over 60 years of age, a prominent risk of hematological malignancies was observed at a follow-up of more than 3 years after the index date (aHR 3.93, 95% CI 1.60-9.65). A history of NTS is associated with the risk of subsequent hematological malignancies in Taiwanese subjects older than 60.

Women with abnormal uterine bleeding (AUB) have been reported to develop chronic spontaneous urticaria (CSU). Nevertheless, whether or not AUB women have an increased risk of CSU has not been examined in large-scale epidemiologic studies. This study aimed to investigate the risk of CSU among reproductive-aged women with AUB. A total of 79 595 patients and 79 107 propensity-score matched controls were recruited from Taiwan's National Health Insurance Research Database to conduct a nationwide cohort study. The Cox proportional-hazard regression model was applied to examine the adjusted hazard ratios (aHR) and 95% confidence intervals (CI) for CSU in relation to AUB. We found that women with AUB had a higher risk for CSU (aHR = 1.83; 95% CI, 1.76-1.90) than women without AUB. Subgroup analyses revealed that AUB with an abnormal bleeding frequency (aHR = 1.70; 95% CI, 1.60-1.79), irregular bleeding (aHR = 1.80; 95% CI, 1.71-1.89), and intermenstrual bleeding (aHR = 1.65; 95% CI, 1.49-1.83) were associated with an increased risk of CSU compared with those without abnormalities. The Kaplan-Meier analysis revealed that the cumulative incidence of developing CSU was consistently higher in the AUB cohort than in the non-AUB cohort during the entire follow-up period (log-rank test, p

This study aimed to determine the effect of colchicine use on the risk of stroke among patients with diabetes mellitus (DM). We retrospectively enrolled patients with DM between 2000 and 2013 from the Longitudinal Health Insurance Database and divided them into a colchicine cohort (n = 8761) and noncolchicine cohort (n = 8761) by using propensity score matching (PSM). The event of interest was a stroke, including ischemic stroke and hemorrhagic stroke. The incidence of stroke was analyzed using multivariate Cox proportional hazards models between the colchicine cohort and the comparison cohort after adjustment for several confounding factors. The subdistribution hazard model was also performed for examination of the competing risk. The colchicine cohort had a significantly lower incidence of stroke [adjusted hazard ratios (aHR), 95% confidence intervals (95%CI)] (aHR = 0.61, 95%CI = 0.55–0.67), ischemic stroke (aHR = 0.59, 95%CI = 0.53–0.66), and hemorrhagic stroke (aHR = 0.66, 95%CI = 0.53–0.82) compared with the noncolchicine cohort. Drug analysis indicated that patients in the colchicine cohort who received colchicine of cumulative daily defined dose (cDDD) > 14 and duration > 28 days had a lower risk of stroke and ischemic stroke compared with nonusers. The colchicine cohort (cDDD > 150, duration > 360 days) also had a lower risk of stroke, ischemic stroke, and hemorrhagic stroke. The cumulative incidence of stroke, ischemic stroke, and hemorrhagic stroke in the colchicine cohort was significantly lower than that in the noncolchicine cohort (log-rank P 14 and duration > 28 days was associated with lower risk of stroke and ischemic stroke, and colchicine use with cDDD > 150 and duration > 360 days played an auxiliary role in the prevention of stroke, ischemic stroke, and hemorrhagic stroke in patients with DM. The colchicine for the hemorrhagic stroke in DM patients without gout seem to be null effect.

Aim Chronic kidney disease (CKD) is associated with unfavorable outcomes in patients with ischemic stroke. One major metabolic derangement of CKD is dyslipidemia, which can be managed by statins. This study aimed to investigate whether the association of statins with post-stroke outcomes would be affected by renal function. Methods We evaluated the association of statin therapy at discharge with 3-month outcomes according to the estimated glomerular filtration rate (eGFR) of 50,092 patients with acute ischemic stroke from the Taiwan Stroke Registry from August 2006 to May 2016. The outcomes were mortality, functional outcome as modified Rankin Scale (mRS), and recurrent ischemic stroke at 3 months after index stroke. Results Statin therapy at discharge was associated with lower risks of mortality (adjusted hazard ratio [aHR], 0.41; 95% confidence interval [CI], 0.34 to 0.50) and unfavorable functional outcomes (mRS 3-5; aHR, 0.80; 95% CI, 0.76 to 0.84) in ischemic stroke patients. After stratification by eGFR, the lower risk of mortality associated with statins was limited to patients with an eGFR above 15 mL/min/1.73 m2. Using statins at discharge was correlated with a lower risk of unfavorable functional outcomes in patients with an eGFR of 60-89 mL/min/1.73 m2. Statin therapy in patients with an eGFR of 60-89 mL/min/1.73 m2 may be associated with a higher risk of recurrent ischemic stroke compared with nonusers (aHR, 1.29; 95% CI, 1.07 to 1.57). Conclusions In patients with acute ischemic stroke, the associations of statins with mortality and functional outcomes was dependent on eGFR.

Background/purpose Metabolites in blood have been found associated with the occurrence of vascular diseases, but its role in the functional recovery of stroke is unclear. The aim of this study is to investigate whether the untargeted metabolomics at the acute stage of ischemic stroke is able to predict functional recovery. Methods One hundred and fifty patients with acute ischemic stroke were recruited and followed up for 3 months. Fasting blood samples within 7 days of stroke were obtained, liquid chromatography and mass spectrometry were applied to identify outcome-associated metabolites. The patients’ clinical characteristics and identified metabolites were included for constructing the outcome prediction model using machine learning approaches. Results By using multivariate analysis, 220 differentially expressed metabolites (DEMs) were discovered between patients with favorable outcomes (modified Rankin Scale, mRS ≤ 2 at 3 months, n = 77) and unfavorable outcomes (mRS ≥ 3 at 3 months, n = 73). After feature selection, 63 DEMs were chosen for constructing the outcome prediction model. The predictive accuracy was below 0.65 when including patients' clinical characteristics, and could reach 0.80 when including patients' clinical characteristics and 63 selected DEMs. The functional enrichment analysis identified platelet activating factor (PAF) as the strongest outcome-associated metabolite, which involved in proinflammatory mediators release, arachidonic acid metabolism, eosinophil degranulation, and production of reactive oxygen species. Conclusion Metabolomics is a potential method to explore the blood biomarkers of acute ischemic stroke. The patients with unfavorable outcomes had a lower PAF level compared to those with favorable outcomes.

Objective:To compare the impact of intensive blood pressure (BP) lowering right after intracerebral hemorrhage (ICH) on clinical and hematoma outcomes among patients from different geographic locations, we performed a prespecified sub-analysis of the randomized, multi-national, two-group, open-label trial to determine the efficacy of rapidly lowering BP in hyperacute ICH (ATACH-2), involving 537 patients from East Asia and 463 recruited outside of Asia.Methods:Eligible patients were randomly assigned to a systolic BP (SBP) target of 110-139 mmHg (intensive treatment) or 140-179 mmHg (standard treatment). Pre-defined outcomes were: poor functional outcome (modified Rankin Scale score of 4-6 at 90 days), death within 90 days, hematoma expansion at 24 hours; and cardio-renal adverse events within 7 days.Results:Poor functional outcomes (32.0% versus 45.9%), death (1.9% versus 13.3%), and cardio-renal adverse events (3.9% versus 11.2%) occurred significantly less in patients from Asia than those outside of Asia. The treatment-by-cohort interaction was not significant for any outcomes. Only patients from Asia showed a lower incidence of hematoma expansion with intensive treatment (adjusted RR 0.56, 95% CI 0.38-0.83). Both Asian (3.53, 1.28-9.64) and non-Asian cohorts (1.71, 1.00-2.93) showed a higher incidence of cardio-renal adverse events with intensive treatment.Conclusions:Poor functional outcomes and death 90 days after ICH were less common in patients from East Asia than those outside of Asia. Hematoma expansion, a potential predictor for poor clinical outcome, was attenuated by intensive BP lowering only in the Asian cohort.Clinicaltrials.gov identifierNCT01176565.Classification of evidence:This study provides Class II evidence that, for patients from East Asia with intracerebral hemorrhage, intensive blood pressure lowering significantly reduces the risk of hematoma expansion.

Despite intracerebral haemorrhage causing 5% of deaths worldwide, few evidence-based therapeutic strategies other than stroke unit care exist. Tranexamic acid decreases haemorrhage in conditions such as acute trauma and menorrhoea. We aimed to assess whether tranexamic acid reduces intracerebral haemorrhage growth in patients with acute intracerebral haemorrhage.We did a prospective, double-blind, randomised, placebo-controlled, investigator-led, phase 2 trial at 13 stroke centres in Australia, Finland, and Taiwan. Patients were eligible if they were aged 18 years or older, had an acute intracerebral haemorrhage fulfilling clinical criteria (eg, Glasgow Coma Scale score of7, intracerebral haemorrhage volume70 mL, no identified or suspected secondary cause of intracerebral haemorrhage, no thrombotic events within the previous 12 months, no planned surgery in the next 24 h, and no use of anticoagulation), had contrast extravasation on CT angiography (the so-called spot sign), and were treatable within 4·5 h of symptom onset and within 1 h of CT angiography. Patients were randomly assigned (1:1) to receive either 1 g of intravenous tranexamic acid over 10 min followed by 1 g over 8 h or matching placebo, started within 4·5 h of symptom onset. Randomisation was done using a centralised web-based procedure with randomly permuted blocks of varying size. All patients, investigators, and staff involved in patient management were masked to treatment. The primary outcome was intracerebral haemorrhage growth (33% relative or6 mL absolute) at 24 h. The primary and safety analyses were done in the intention-to-treat population. The trial is registered at ClinicalTrials.gov (NCT01702636).Between March 1, 2013, and Aug 13, 2019, we enrolled and randomly assigned 100 participants to the tranexamic acid group (n=50) or the placebo group (n=50). Median age was 71 years (IQR 57-79) and median intracerebral haemorrhage volume was 14·6 mL (7·9-32·7) at baseline. The primary outcome was not different between the two groups: 26 (52%) patients in the placebo group and 22 (44%) in the tranexamic acid group had intracerebral haemorrhage growth (odds ratio [OR] 0·72 [95% CI 0·32-1·59], p=0·41). There was no evidence of a difference in the proportions of patients who died or had thromboembolic complications between the groups: eight (16%) in the placebo group vs 13 (26%) in the tranexamic acid group died and two (4%) vs one (2%) had thromboembolic complications. None of the deaths was considered related to study medication.Our study does not provide evidence that tranexamic acid prevents intracerebral haemorrhage growth, although the treatment was safe with no increase in thromboembolic complications. Larger trials of tranexamic acid, with simpler recruitment methods and an earlier treatment window, are justified.National Health and Medical Research Council, Royal Melbourne Hospital Foundation.

Background Angiotensin receptor blockers (ARBs) have been reported to ameliorate anxiety and mood disorders in animal models. Cohort links between ARB use and suicide risk in humans require clarification. Methods Data were obtained from the National Health Insurance Research Database. Patients diagnosed as having hypertension according to the criteria of the International Classification of Diseases, Ninth Revision, Clinical Modification (401-405) from January 1, 2000 to December 31, 2012 were enrolled as the target population. We defined enrollees who had received ARB prescriptions for at least 28 days as ARB users. Those who had never taken ARB prior or during the study period were defined as ARB nonusers and were propensity score–matched with ARB users. The end outcome was confirmation of a suicide attempt. Results After propensity score matching was conducted, 40,976 ARB users and 40,976 nonusers were selected as the matched cohorts. The overall incidence rate of suicide attempt was significantly lower in ARB users than in nonusers (0.51 vs. 1.07 per 10,000 person-years; adjusted hazard ratio = 0.48, 95% confidence interval = 0.26–0.87). A Kaplan–Meier survival analysis with a log-rank test revealed a lower cumulative incidence of suicide attempt in ARB users than in nonusers (p Conclusions ARB use was not associated with an increased risk for suicide compared with non-ARB use.

Summary Objective This study used the Taiwan Stroke Registry data to evaluate the efficacy and safety of intravenous tissue plasminogen activator (tPA) in treating acute ischemic stroke in patients with renal dysfunction. Design We identified 3525 ischemic stroke patients and classified them into two groups according to the estimated glomerular filtration rate (eGFR) at the emergency department: ≥60, and Results Among patients with eGFR levels of Conclusions tPA for acute ischemic stroke could improve functional outcomes without increasing the risks of upper gastrointestinal bleeding for patients with or without renal dysfunction. The low eGFR was not a significant risk factor for intracerebral hemorrhage among patients receiving tPA treatment.

Background Knee osteoarthritis (OA) is known to be a progressive degenerative disorder; however, recent evidence suggests that inflammatory mediators contribute to cartilage degradation. Studies have reported that N-acetylcysteine (NAC) had a promising effect on the reduction of the synthesis of proinflammatory and structural mediators by synovial cells. Given the lack of relevant clinical trials, we conducted this study to determine the relationship between NAC use and risk of knee OA. Methods We designed a retrospective cohort study from 2000 to 2013. Patients who received oral NAC over 28 days within 1 year after the first prescription were defined as the case group, whereas those without NAC use were considered as candidates of the control group. We adopted 1:4 propensity-score matching by age, sex, index year, and comorbidities to obtain the control group. The primary outcome was a new diagnosis of knee OA during the follow-up period. Results Our study sample comprised 12,928 people who used NAC and 51,715 NAC nonusers. NAC users had a significantly higher incidence of osteoarthritis (adjusted hazard ratio: 1.42, P P Conclusions Long-term use of oral NAC is associated with a higher risk of knee OA.

Background We hypothesized that renin–angiotensin system (RAS) blockers have systemic protective effects beyond the respiratory tract and could reduce the risk of viral infections. Methods We used the National Health Insurance Research Database and identified 2 study cohorts: the angiotensin receptor blocker (ARB) cohort and angiotensin-converting enzyme inhibitor (ACEI) cohort. Propensity score matching was applied at a 1:1 ratio by all associated variables to select 2 independent control cohorts for the ARB and ACEI cohorts. A Cox proportional hazards model was applied to assess the end outcome of viral infection. Results The number of ARB and ACEI users was 20 207 and 18 029, respectively. The median age of ARB users and nonusers was 53.7 and 53.8 years, respectively. The median follow-up duration of ARB users and nonusers was 7.96 and 7.08 years; the median follow-up duration of ACEI users and nonusers was 8.70 and 8.98 years, respectively. The incidence rates of viral infections in ARB users and nonusers were 4.95 and 8.59 per 1000 person-years, respectively, and ARB users had a lower risk of viral infection than nonusers (adjusted hazard ratio [aHR], 0.53 [95% confidence interval {CI}, .48–.58]). The incidence rates of viral infections in ACEI users and nonusers were 6.10 per 1000 person-years and 7.72 per 1000 person-years, respectively, and ACEI users had a lower risk of viral infection than nonusers (aHR, 0.81 [95% CI, .74–.88]). Conclusions Hypertensive patients using either ARBs or ACEIs exhibit a lower risk of viral infection than nonusers.

Background Women with endometriosis (EM) have increased vulnerability to certain psychiatric disorders, including depression and anxiety, as well as bipolar disorder (BD). This study investigates the risk of BD development in EM patients. Also, the impact of EM treatment on the risk of developing BD is examined. Methods A total of 17,832 EM patients and 17,832 non-EM controls matched by age, index year, and Charlson Comorbidity Index (CCI) score were included between 2000–2012 and followed to the end of 2013. Participants newly diagnosed as BD by board-certified psychiatrist were defined as incidents. Cox regression analysis was used to calculate the hazard ratio (HR) with 95% confidence interval (CI) of the BD incidence rate between two studied groups. Results EM patients were associated with an increased risk of BD development compared with non-EM controls after adjusting for age, CCI score, and different treatment options (1.04 versus 0.56 per 1,000 person-years, HR: 2.34, 95% CI: 1.75–3.12). Also, there was no significant difference in the risk estimate between different hormonal or surgical treatment groups, suggesting a limited impact of EM treatment on the risk of BD development. Limitations This study deals with the duration of hormonal treatment, whether operated or not, which reduces the chances of showing the effect of individual EM treatment on the risk of BD development. Conclusion This study shows that EM patients are associated with an increased risk of BD development. Further studies would be needed to elucidate the mechanism linking the EM and BD.

Objectives Narcolepsy symptoms, such as excessive daytime sleepiness or cataplexy, can pose a risk to safety. Stimulants or antidepressants have been used to treat these symptoms. The study investigated the risk of bone fractures in narcolepsy patients. Also, the exposure pattern of stimulants and antidepressants to the risk of bone fractures was examined. Methods In all, 493 narcolepsy patients and 490 controls matched by gender, age, index year, and comorbidity severity were enrolled between 1998 and 2012, then followed until the end of 2013 using Taiwan's National Health Insurance Research Database. During the follow-up period, participants who developed bone fractures were identified. Cox regression analysis was used to calculate the hazard ratio (HR) with 95% confidence interval (CI) for the incidence rates of bone fractures between narcolepsy patients and unaffected controls. Results Narcolepsy patients had a significantly increased risk of bone fractures compared with unaffected controls (19.6 versus 12.3 per 1000 person-years, HR: 1.74, 95% CI: 1.29–2.35). In addition, the use of stimulants in narcolepsy patients showed lower incidence rates of bone fractures compared to non-users (incidence rates were 14.2, 11.9, and 20.0 per 1000 person-years, respectively, among frequent users, infrequent users, and non-users), but the risk estimate was not statistically significant. The evidence for associations between antidepressant use in narcolepsy patients and bone fractures was contradictory. Conclusion This study highlights the need to pay attention to the risk of bone fractures in narcolepsy patients, and the importance of adequate stimulants use might reduce the risk of bone fractures.

Patients with schizophrenia (SCZ) have a higher prevalence of known risk factors for obstructive sleep apnea (OSA). This study aims to determine if SCZ patients are at increased risk of incident OSA. A total of 5092 newly diagnosed SCZ patients and 5092 non-SCZ controls matched by gender, age, and index year were included between 2000 and 2012 and followed to 2013. Participants newly diagnosed with OSA were defined as incidents. Cox regression analysis was used to calculate the hazard ratio (HR) with 95% confidence intervals (CI) of the OSA incidence rate between the two groups studied. SCZ patients were at increased risk of OSA compared to non-SCZ controls after adjusting for gender, age, comorbidities, and duration of antipsychotic use (2.12 versus 1.01 per 1000 person-years, HR: 1.97, 95% CI: 1.36–2.85). Also, this study confirmed the existence of some known risk factors for OSA, including male gender (HR 1.65, 95% CI 1.14–2.37), obesity (HR 2.62, 95% CI 1.19–5.80), hypertension (HR 1.61, 95% CI 1.06–2.47), hyperlipidemia (HR 1.55, 95% CI 1.04–2.38), diabetes (HR 1.53, 95% CI 1.01–2.38), and antipsychotic use (duration

To investigate whether patients with polycystic ovary syndrome (PCOS) are at increased risk for incident schizophrenia and whether PCOS treatment (clomiphene, cyproterone, or metformin) affects the incidence of schizophrenia.An overall of 7146 PCOS patients and 28,580 non-PCOS controls matched by age, index year, and Charlson Comorbidity Index (CCI) score were included between 2000 and 2012 and followed up until 2013 using a validated nationally representative sample from Taiwan. Participants newly diagnosed as schizophrenia were defined as incidents. Cox regression analysis was used to calculate the hazard ratio (HR) with a 95% confidence interval (CI) of the schizophrenia incidence rate between the two studied groups.PCOS patients were at increased risk of incident schizophrenia compared to non-PCOS controls after adjusting for age, CCI score, comorbidities, and different treatment options (0.49 versus 0.09 per 1000 person-years, HR: 6.93, 95% CI: 3.25-14.7). After adjusting for above-mentioned covariates, metformin treatment had a protective effect against the incident schizophrenia compared to non-users (HR: 0.16, 95% CI: 0.06-0.41). Also, treatment with clomiphene and cyproterone had only a limited impact on the incident schizophrenia.This study shows PCOS patients are at increased risk of incident schizophrenia, and the metformin treatment has a protective effect against incident schizophrenia.

Background The study investigated the risk of newly developed bipolar disorder (BD) in patients with polycystic ovary syndrome (PCOS) and examined the relationship between PCOS treatment (hormone therapy (clomiphene or cyproterone) or metformin) and risk of BD development. Methods In all, 7175 PCOS patients and 28,697 non-PCOS controls matched by age, index year, and Charlson Comorbidity Index (CCI) score were included between 2000 and 2012, then followed until the end of 2013. Participants newly diagnosed as BD by board-certified psychiatrists were defined as incidents. Cox regression analysis was used to calculate the hazard ratio (HR) with 95% confidence interval (CI) of the BD incidence rate between two studied groups. Results PCOS patients had a significantly increased risk of developing BD compared to unaffected controls after adjusting for age, CCI score, and different treatment options (1.05 vs. 0.12 per 1,000 person-years, HR: 8.29, 95% CI: 4.65–14.7). Also, the use of metformin in PCOS patients showed a significantly reduced risk of developing BD compared to non-users after adjusting for the above-mentioned variables (HR: 0.36, 95% CI: 0.16–0.81). Although hormone therapy in PCOS patients showed a lower incidence rate of BD development compared to non-users, the risk estimate was not statistically significant (HR: 0.68, 95% CI: 0.35–1.32). Limitations This study didn't assess the PCOS severity, which reduced the chances of showing the effects of PCOS severity on BD development. Conclusion This study shows PCOS patients have an increased risk of developing BD, and the use of metformin may reduce its risk.

Purpose Atrial fibrillation (AF) is a significant independent risk factor for 1-year mortality in patients with first acute ischemic stroke (AIS). The CHA2DS2-VASc score was initially developed to assess the risk of stroke in patients with AF. Recently, this scoring system has been demonstrated to have clinical value for predicting long-term clinical outcomes in AIS but the evidence is insufficient. This large-scale prospective cohort study investigated the independent predictive value of the score in such patients. Methods We included patients with AIS from the Taiwan Stroke Registry (TSR) during 2006–2016 as the present study population. Patients were divided into those with high (≥2) and low ( Results A total of 62,227 patients with AIS were enrolled. The median age was 70.3 years, and 59% of the patients were women. After confounding factors were controlled, patients with high CHA2DS2-VASc scores had significantly higher incidence of 1-year MACCEs (adjusted hazard ratio [HR] = 1.63; 95% confidence interval [CI] = 1.52, 1.76), re-stroke (adjusted HR = 1.28; 95% CI = 1.16, 1.42), and all-cause mortality (adjusted HR = 2.03; 95% CI = 1.83, 2.24) than those with low CHA2DS2-VASc scores did. In the comparison between AF and non-AF groups, the AF group had increased MACCEs (adjusted HR = 1.74; 95% CI = 1.60, 1.89), myocardial infarction (adjusted HR = 4.86; 95% CI = 2.07, 11.4), re-stroke (adjusted HR = 1.47; 95% CI = 1.26, 1.71), and all-cause mortality (adjusted HR = 1.90; 95% CI = 1.72, 2.10). The Kaplan–Meier curve revealed that both CHA2DS2-VASc scores and AF were independent risk predictors for 1-year MACCEs and mortality. Conclusions The CHA2DS2-VASc score and AF appeared to consistently predict 1-year MACCEs of AIS patients and provide more accurate risk stratification. Therefore, increased use of the CHA2DS2-VASc score may help improve the holistic clinical assessment of AIS patients with or without AF.

Background: The association between polycystic ovary syndrome (PCOS) and the risk of herpes zoster (HZ) remains unclear. This study investigated the risk of HZ in women with PCOS. Methods: This study used data from the Longitudinal Generation Tracking Database (LGTD 2005) which contains the information of 2 million randomly selected from National Health Insurance beneficiaries. Patients who received a diagnosis of PCOS between 2000 and 2017 were included in the PCOS cohort. Patients who were not diagnosed as having PCOS were randomly selected from the LGTD 2005 and included in the control cohort. Patients who were aged

RationaleHaematoma growth is common early after intracerebral haemorrhage (ICH), and is a key determinant of outcome. Tranexamic acid, a widely available antifibrinolytic agent with an excellent safety profile, may reduce haematoma growth.Methods and designStopping intracerebral haemorrhage with tranexamic acid for hyperacute onset presentation including mobile stroke units (STOP-MSU) is a phase II double-blind, randomised, placebo-controlled, multicentre, international investigator-led clinical trial, conducted within the estimand statistical framework.HypothesisIn patients with spontaneous ICH, treatment with tranexamic acid within 2 hours of onset will reduce haematoma expansion compared with placebo.Sample size estimatesA sample size of 180 patients (90 in each arm) would be required to detect an absolute difference in the primary outcome of 20% (placebo 39% vs treatment 19%) under a two-tailed significance level of 0.05. An adaptive sample size re-estimation based on the outcomes of 144 patients will allow a possible increase to a prespecified maximum of 326 patients.InterventionParticipants will receive 1 g intravenous tranexamic acid over 10 min, followed by 1 g intravenous tranexamic acid over 8 hours; or matching placebo.Primary efficacy measureThe primary efficacy measure is the proportion of patients with haematoma growth by 24±6 hours, defined as either ≥33% relative increase or ≥6 mL absolute increase in haematoma volume between baseline and follow-up CT scan.DiscussionWe describe the rationale and protocol of STOP-MSU, a phase II trial of tranexamic acid in patients with ICH within 2 hours from onset, based in participating mobile stroke units and emergency departments.

BackgroundFew investigations have evaluated the influences on peripheral arterial disease (PAD) risk of statin treatment in hemodialysis (HD) subjects with hyperlipidemia (HL).MethodsFrom the National Health Insurance Research Dataset, we identified 3658 HD patients with statin therapy for HL as the statin cohort, and then selected, by 1:1 propensity score matching, 3658 HD patients with HL but without statin use as the nonstatin cohort in 2000–07. The cohorts were followed through until the end of 2011. We used Cox proportional hazards regression analysis to assess the hazard ratio (HR) of PAD development.ResultsThe average follow-up period was 4.18 years; the incident PAD risk was 1.35-fold greater in statin users than in nonusers (16.87 versus 12.46/1000 person-years), with an adjusted HR (aHR) of 1.34 for PAD [95% confidence interval (CI) 1.12–1.62]. The PAD risk increases were significant for patients receiving fluvastatin (aHR 1.88; 95% CI 1.12–3.14) and atorvastatin (aHR 1.60; 95% CI 1.24–2.08). The risk increased with higher annual average statin dosage (P for trend ConclusionsHD patients with HL on statin medication were at increased PAD risk, which increased with cumulative statin dosage. Thorough considerations are needed before prescribing statins to HD patients.

On the basis of increased mortality associated with hyperchloremia among critically ill patients, we investigated the effect of occurrence of early hyperchloremia on death or disability at 90 days in patients with intracerebral hemorrhage (ICH).We analyzed the data from Antihypertensive Treatment of Cerebral Hemorrhage 2 trial, which recruited patients with spontaneous ICH within 4.5 h of symptom onset. Patients with increased serum chloride levels (110 mmol/L or greater) at either baseline or 24, 48, or 72 h after randomization were identified. We further graded hyperchloremia into one occurrence or two or more occurrences within the first 72 h. Two logistic regression analyses were performed to determine the effects of hyperchloremia on (1) death within 90 days and (2) death or disability at 90 days after adjustment for potential confounders.Among the total of 1,000 patients analyzed, hyperchloremia within 72 h was seen in 114 patients with one occurrence and in 154 patients with two or more occurrences. Patients with one occurrence of hyperchloremia (odds ratio [OR] 2.5, 95% confidence interval [CI] 1.1-5.5) and those with two or more occurrences (OR 2.6, 95% CI 1.3-5.0) had significantly higher odds of death within 90 days after adjustment for age, race and ethnicity, National Institutes of Health Stroke Scale score strata, hematoma volume, presence or absence of intraventricular hemorrhage, cigarette smoking, previous stroke, and maximum hourly dose of nicardipine. Patients with two or more occurrences of hyperchloremia (OR 3.4, 95% CI 2.1-5.6) had significantly higher odds of death or disability at 90 days compared with patients without hyperchloremia after adjustment for the abovementioned potential confounders.The independent association between hyperchloremia and death or disability at 90 days suggests that avoidance of hyperchloremia may reduce the observed death or disability in patients with ICH.ClinicalTrials.gov: NCT01176565.

Background Evidences have shown that the stroke risk associated with long-term exposure to particulate matter with an aerodynamic diameter of ≤2.5 μm (PM2.5) varies among people in North America, Europe and Asia, but studies in Asia rarely evaluated the association by stroke type. We examined whether long-term exposure to PM2.5 is associated with developing all strokes, ischemic stroke and hemorrhagic stroke. Methods The retrospective cohort study consisted of 1,362,284 adults identified from beneficiaries of a universal health insurance program in 2011. We obtained data on air pollutants and meteorological measurements from air quality monitoring stations across Taiwan in 2010–2015. Annual mean levels of all environmental measurements in residing areas were calculated and assigned to cohort members. We used Cox proportional hazards models to estimate hazard ratio (HR) and 95% confidence interval (CI) of developing stroke associated with 1-year mean levels of PM2.5 at baseline in 2010, and yearly mean levels from 2010 to 2015 as the time-varying exposure, adjusting for age, sex, income and urbanization level. Results During a median follow-up time of 6.0 years, 12,942 persons developed strokes, 9919 (76.6%) were ischemic. The adjusted HRs (95% CIs) per interquartile range increase in baseline 1-year mean PM2.5 were 1.03 (1.00–1.06) for all stroke, 1.06 (1.02–1.09) for ischemic stroke, and 0.95 (0.89–1.10) for hemorrhagic stroke. The concentration-response curves estimated in the models with and without additional adjustments for other environmental measurements showed a positively linear association between baseline 1-year mean PM2.5 and ischemic stroke at concentrations greater than 30 μg/m3, under which no evidence of association was observed. There was an indication of an inverse association between PM2.5 and hemorrhagic stroke, but the association no longer existed after controlling for nitrogen dioxide or ozone. We found similar shape of the concentration-response association in the Cox regression models with time-varying PM2.5 exposures. Conclusion Long-term exposure to PM2.5 might be associated with increased risk of developing ischemic stroke. The association with high PM2.5 concentrations remained significant after adjustment for other environmental factors.

ObjectiveTo determine the effect of statins on risk of cancer in patients with interstitial lung disease (ILD) and pulmonary fibrosis.SettingWe retrospectively enrolled patients with ILD and pulmonary fibrosis and divided them into two cohorts by statin use (statin users (n=10 036) and statin non-users (n=10 036)).ParticipantsWe selected patients with ILD and pulmonary fibrosis (N=53 862) from Taiwan’s National Health Insurance Research Database. Time-dependent Cox models were used to compare risk of cancer of propensity-matched statin users and non-users. Cumulative cancer incidence was analysed through Cox proportional regression. We calculated adjusted HRs (aHRs) and their 95% CIs for cancer after adjusting for sex, age, comorbidities, and use of inhaled corticosteroids, oral steroids and statins.ResultsCompared with statin non-users, the aHRs (95% CIs) for statin users were 0.60 (0.55 to 0.65) for cancer, 0.52 (0.35 to 0.78) for haematological malignancy, 0.52 (0.38 to 0.72) for cancer of the head and neck, 0.73 (0.59 to 0.89) for colorectal cancer, 0.34 (0.26 to 0.43) for liver cancer, 0.39 (0.23 to 0.67) for pancreatic cancer, 0.40 (0.17 to 0.96) for skin cancer, 0.67 (0.52 to 0.87) for breast cancer, 0.27 (0.14 to 0.54) for cervical cancer, 0.37 (0.30 to 0.46) for other immunological cancers, 0.73 (0.54 to 0.98) for bladder/kidney cancer and 0.88 (0.71 to 1.09) for lung cancer.ConclusionStatin use is associated with lower risk of cancer in the ILD and pulmonary fibrosis cohort.

We conducted this study to determine the effect of metformin use on the risk of new-onset chronic urticaria in patients with type 2 diabetes (T2D). In total, 24,987 pairs of metformin users and nonusers were identified with propensity score-matching from Taiwan’s National Health Insurance Research Database from 1 January 2000, to 31 December 2017. Multivariable Cox proportional hazards models were used to compare the risks of chronic urticaria development, severe chronic urticaria, and hospitalization for chronic urticaria between metformin users and nonusers. Compared with metformin nonuse, the aHRs (95% CI) for metformin use in chronic urticaria development, severe chronic urticaria, and hospitalization for chronic urticaria were 1.56 (1.39–1.74), 0.40 (0.12–1.30), and 1.45 (0.82–2.56), respectively. The cumulative incidence of chronic urticaria development was significantly higher in metformin users than in nonusers (p < 0.0001). A longer average cumulative duration of metformin use was associated with higher risks of new-onset and hospitalization for chronic urticaria than metformin nonuse. This nationwide cohort study showed that metformin use was associated with a significantly higher risk of chronic urticaria development. A longer average cumulative duration of metformin use was associated with a higher risk of outcomes. More prospective studies are needed to verify our results.

OBJECTIVES Studies on the association of estimated glomerular filtration rate (eGFR) levels with hospital discharge disposition after stroke are limited with inconsistent results. This study investigated the odds of home discharge with eGFR levels at admission for patients with stroke using the Taiwan Stroke Registry (TSR) data. METHODS From the TSR database, a total of 51,338 stroke patients from 2006 to 2015 were categorized into five groups based on eGFR levels at admission. The proportion of home discharge by the eGFR levels was calculated and logistic regression analysis was used to estimate the related odds ratio (OR) and 95% confidence interval. RESULTS Near 85% of stroke patients were discharged to home. The proportion of home discharges decreased as the eGFR level declined. Compared to patients with eGFR ≥90 mL/min/1.73 m2, the adjusted ORs of home discharge were 0.91, 0.85, 0.63, 0.56 for patients with eGFR 60-89, eGFR 30-59, eGFR 15-29, and eGFR < 15 mL/min/1.73 m2 or on dialysis, respectively, in a graded relationship. The trends were consistent in the ischemic stroke and hemorrhagic stroke patients. The areas under the receiver operating characteristic curve for all stroke patients, ischemic stroke patients, and hemorrhagic stroke patients were 0.801, 0799, 0.815, respectively. CONCLUSION The odds of home discharge for stroke patients decreased with a significant independent graded association with declining eGFR levels. Renal function could predict home discharge after stroke.

Background We aimed to identify associations between the risk of acute respiratory failure (ARF) and types of antihypertensive agents in patients with viral pneumonia. Methods In this case-control study, data extracted from the Taiwan National Health Insurance Research Database were analysed. The base population comprised patients with viral pneumonia treated from 2000 to 2013. The case group comprised patients with ARF and the control group comprised participants without ARF. Adjusted odds ratios (ORs) were calculated using a multivariable logistic regression model. Results In total, 4427 viral pneumonia patients with ARF and 4427 matched control participants without ARF were recruited. Patients with diabetes, alcohol-related disease, asthma, chronic kidney disease or end-stage renal disease, chronic obstructive pulmonary disease, cancer, congestive heart failure, stroke, acute pulmonary oedema and shock had increased odds of developing ARF, especially shock (adjusted OR = 49.3; 95% CI = 27.4, 88.7), cancer (12.6; 8.67, 18.2) and stroke (7.51; 5.32, 10.6). Increasing odds of developing ARF were noted in patients using potassium-sparing diuretics (2.95; 1.54, 5.64), loop diuretics (68.2; 48.1, 96.6), calcium channel blockers (1.64; 1.26, 2.13) and angiotensin-converting enzyme inhibitors (1.70; 1.15, 2.53). Patients with prescriptions of α-blockers (0.44; 0.26, 0.74), β-blockers (0.37; 0.26, 0.52), thiazides (0.38; 0.25, 0.59) and angiotensin receptor blockers (0.65; 0.51, 0.83) had lower odds of having ARF. Conclusion Patients with viral pneumonia who received α-blockers, β-blockers, thiazides or angiotensin receptor blockers during hospitalisation had a lower risk of developing ARF.

Background/aim Oral cavity cancer is a major health problem worldwide. The herpes zoster vaccine is an effective method to protect against herpes zoster infection. In this study we aimed to determine the relationship between herpes zoster and oral cavity cancer. Patients and methods The Longitudinal Generation Tracking Database in Taiwan was used to select oral and non-oral cavity cancer patients. The primary endpoint was herpes zoster. Results We included 3131 oral cavity cancer patients and 3131 non-oral cavity cancer patients. Patients with oral cavity cancer [adjusted hazard ratio (HR)=1.66, 95% confidence interval (CI)=1.27-2.16] had a significantly higher risk of herpes zoster compared to the control group. The oral cavity patients who received radiotherapy (adjusted HR=1.79, 95%CI=1.12-2.86) had a significantly higher risk of herpes zoster compared to the oral cavity patients who did not receive radiotherapy. Conclusion Radiotherapy increases the incidence of herpes zoster infection in oral cavity cancer patients.

BACKGROUND Emerging evidence supports a strong association between the skin and the gut. The association between seborrheic dermatitis (SD) and peptic ulcer disease (PUD) was largely unknown. This study aimed to investigate the association of SD and PUD. METHODS This nationwide population-based cohort study was conducted using the Taiwan's National Health Insurance Research Database. A total of 19 445 participants was recruited. Each patient with a diagnosis of incident SD was matched to four patients without SD using propensity scores based on age, gender, index year, insurance amount, urbanisation level, Charlson comorbidity index (CCI), the presence of comorbidities and medication use. The primary endpoint was the development of incident PUD. Hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) for PUD occurrence in relation to the presence of SD were calculated. RESULTS Overall, patients with SD had a significantly higher risk for incident PUD than those without SD in both univariable (crude HR = 1.60, 95% CI 1.38-1.86, P

Forkhead box protein C1 (FOXC1) is known to regulate developmental processes in the skull and brain. Methods: The unique multipotent arachnoid-pia stem cells (APSCs) isolated from human and mouse arachnoid-pia membranes of meninges were grown as 3D spheres and displayed a capacity for self-renewal. Additionally, APSCs also expressed the surface antigens as mesenchymal stem cells. By applying the FOXC1 knockout mice and mouse brain explants, signaling cascade of FOXC1-STI-1-PrPC was investigated to demonstrate the molecular regulatory pathway for APSCs self-renewal. Moreover, APSCs implantation in stroke model was also verified whether neurogenic property of APSCs could repair the ischemic insult of the stroke brain. Results: Activated FOXC1 regulated the proliferation of APSCs in a cell cycle-dependent manner, whereas FOXC1-mediated APSCs self-renewal was abolished in FOXC1 knockout mice (FOXC1-/- mice). Moreover, upregulation of STI-1 regulated by FOXC1 enhanced cell survival and self-renewal of APSCs through autocrine signaling of cellular prion protein (PrPC). Mouse brain explants STI-1 rescues the cortical phenotype in vitro and induces neurogenesis in the FOXC1 -/- mouse brain. Furthermore, administration of APSCs in ischemic brain restored the neuroglial microenvironment and improved neurological dysfunction. Conclusion: We identified a novel role for FOXC1 in the direct regulation of the STI-1-PrPC signaling pathway to promote cell proliferation and self-renewal of APSCs.

Our study aimed to establish the role of hemojuvelin (HJV) in acute ischemic stroke (AIS). We performed immunohistochemistry for HJV expression in human brain tissues from 10 AIS and 2 non-stroke autopsy subjects. Plasma HJV was measured in 112 AIS patients within 48 h after stroke. The results showed significantly increased HJV expression in brain tissues from AIS patients compare to non-stroke subjects. After adjusting for clinical variables, plasma levels of HJV within 48 h after stroke were an independent predictor of poor functional outcome three months post-stroke (OR:1.78, 95% CI: 1.03–3.07; P = 0.038). In basic part, Western blotting showed that HJV expression in mice brains was apparent at 3 h after middle cerebral artery occlusion (MCAO), and increased significantly at 72 h. In cultured cortical neurons, expression of HJV protein increased remarkably 24 h after oxygen glucose deprivation (OGD), and small interfering RNAs (siHJV) transfected OGD neurons had a lower apoptotic rate. Importantly, 72 h post-MCAO, HJV knockout mice had significantly smaller infarcts and less expression of cleaved caspase-3 protein compared with wild-type mice. In summary, HJV participates in the mechanisms of post-stroke neuronal injury, and that plasma HJV levels can be a potential early outcome indicator for AIS patients.

BACKGROUND AND AIM Gallstones and stroke are common diseases worldwide. The relationship between gallstones and stroke has been documented in the literature. In this work, to characterize the risk of stroke among gallstone patients with and without cholecystectomy, we investigated the effects of cholecystectomy in a nationwide population-based retrospective cohort study. METHODS Data were obtained from Taiwan's National Health Insurance Research Database. The study comprised 155 356 gallstone patients divided into two groups: those with and without cholecystectomy. RESULTS During the study period (2000-2012), 19 096 (17.8/1000 person-years) gallstone patients without cholecystectomy and 11 913 (10.6/1000 person-years) gallstone patients with cholecystectomy had a stroke. Following gallstone removal, the patients exhibited a significant decrease in the risk of overall stroke (hazard ratio [HR] = 0.60, 95% confidence interval [CI] = 0.59-0.61), ischemic stroke (HR = 0.59, 95% CI = 0.58-0.61), and hemorrhagic stroke (HR = 0.56, 95% CI = 0.53-0.59). Asymptomatic and symptomatic gallstone patients had lower overall stroke risk after cholecystectomy (HR = 0.64, 95% CI = 0.62-0.67 and HR = 0.57, 95% CI = 0.56-0.59) than did asymptomatic gallstone patients without cholecystectomy. CONCLUSIONS This population-based cohort study demonstrated that cholecystectomy is related to reduce the risk of overall stroke, ischemic stroke, and hemorrhagic stroke. Preventive measures for stroke may be considered for gallstone patients, particularly those presenting risk factor(s) for stroke.

Background Growing evidence shows links between septicaemia and non-multiple sclerosis demyelinating syndromes (NMSDS); nevertheless, epidemiological data are still very limited. This study aimed to explore the relationship between septicaemia and NMSDS in a general population. Methods The study included 482 781 individuals diagnosed with septicaemia and 1 892 825 age/sex-matched non-septicaemia patients for the comparison. Data were drawn from a population-based nationwide National Health Insurance Research Database Taiwan, from 1 January 2002 to 31 December 2011. The two cohorts of patients with and without septicaemia were followed up for the occurrence of NMSDS. The Cox-proportional hazard regression model was performed to estimate adjusted HR after multivariate adjustment. Results Individuals with septicaemia had a 4.17-fold (95% CI 3.21 to 5.4, p < 0.001) higher risk to develop NMSDS compared with those without septicaemia. Patients aged Conclusions Our results indicated that patients with septicaemia were likely to develop NMSDS. A possible contributing role of septicaemia in increasing the hazard of NMSDS is proposed, based on the outcome that individuals with higher severity of septicaemia carried elevated threat of encountering NMSDS.

Background: The natural history of vertebrobasilar artery (VBA) stenosis or occlusion remains understudied. Methods: Patients with diagnosis of ischemic stroke or transient ischemic attack (TIA) who were noted to have VBA stenosis based on computed tomography or magnetic resonance imaging or catheter-based angiogram were selected from Taiwan Stroke Registry. Cox proportional hazards model was used to determine the hazards ratio (HR) of recurrent stroke and death within 1 year of index event in various groups based on severity of VBA stenosis (none to mild: 0–49%; moderate to severe: 50–99%: occlusion: 100%) after adjusting for differences in demographic and clinical characteristics between groups at baseline evaluation. Results: None to mild or moderate to severe VBA stenosis was diagnosed in 6972 (66%) and 3,137 (29.8%) among 10,515 patients, respectively, and occlusion was identified in 406 (3.8%) patients. Comparing with patients who showed none to mild stenosis of VBA, there was a significantly higher risk of recurrent stroke (HR 1.21, 95% CI 1.01–1.45) among patients with moderate to severe VBA stenosis. There was a nonsignificantly higher risk of recurrent stroke (HR 1.49, 95% CI 0.99–2.22) and significantly higher risk of death (HR 2.21, 95% CI 1.72–2.83), among patients with VBA occlusion after adjustment of potential confounders. Conclusions: VBA stenosis or occlusion was relatively prevalent among patients with TIA or ischemic stroke and associated with higher risk of recurrent stroke and death in patients with ischemic stroke or TIA who had large artery atherosclerosis.

The association between pneumonia and neurodegenerative diseases (NDs) has never been reported in detail. We address this relationship with reference to the general population.Using Taiwan's National Health Insurance Research Database to identify a pneumonia cohort (including the typical and atypical), we established an ND cohort of 19,062 patients and a non-ND cohort of 76,227 people. In both cohorts, the risk of pneumonia was measured using multivariable Cox proportional hazards models.The adjusted hazard ratio (aHR) (95% confidence interval [CI]) for the pneumonia cohort was 2.10 (1.96-2.24), regardless of age, sex, comorbidities or drug use in the ND cohort. The aHR (95% CI) for adults aged 20-49 years was 2.08 (1.58-2.75), men 2.20 (2.01-2.40). However, older subjects were at greatest risk of pneumonia, (3.41 [2.99-3.88]) if the 20-49 years age group is used as the reference. For the ND and non-ND cohorts, those with comorbidities (with the exception of hyperlipidemia) had higher risk; aHR (95% CI) 2.35 (2.30-2.52). The aHR (95% CI) for those without comorbidities is 3.28 (2.52-4.26). No significant difference was observed in incidence of pneumonia between those who were and were not using statin medications; the aHR (95% CI) was 1.03 (0.93-1.14).The ND cohort had a higher risk of pneumonia, regardless of age, sex, comorbidities or statin use. The risk of pneumonia was higher in elderly and male patients in the ND cohort.

Background Patients with rheumatoid arthritis (RA) have a higher risk of coronary heart disease (CHD). Acupuncture, a commonly used treatment for patients with RA, has not been reported to prevent CHD in patients with RA. We aimed to assess the risk of developing CHD in acupuncture users and non-users of patients with RA. Methods We identified 29,741 patients with newly diagnosed RA from January 1997 to December 2010 from the Registry of Catastrophic Illness Patients Database from the Taiwanese National Health Insurance Research Database. Among them, 10,199 patients received acupuncture (acupuncture users), and 19,542 patients did not receive acupuncture (no-acupuncture users). After performing 1:1 propensity score matching by sex, age, baseline comorbidity, conventional treatment, initial diagnostic year, and index year, there were 9932 patients in both the acupuncture and no-acupuncture cohorts. The main outcome was the diagnosis of CHD in patients with RA in the acupuncture and no-acupuncture cohorts. Results Acupuncture users had a lower incidence of CHD than non-users (adjusted HR = 0.60, 95% CI = 0.55–0.65). The estimated cumulative incidence of CHD was significantly lower in the acupuncture cohort (log-rank test, p

Objectives Studies have suggested a possible autoimmune contribution in a subset of patients with schizophrenia. The purpose of this study was to determine if a history of autoimmune diseases (AD) is associated with an increased risk of later onset of schizophrenia. Methods Taiwan's National Health Insurance Research Database was used to identify a total of 64,817 AD patients and an equal number of age-matched control patients. The incidence rates of schizophrenia with a maximum follow-up period of 10 years between patients with and without AD were compared using a Cox proportional hazard model to estimate the hazard ratio (HR) and 95% confidence interval (95% CI). Results The main finding was the discovery of a higher incidence of subsequent schizophrenia in patients with AD (HR: 1.72, 95% CI: 1.23–2.4) after adjustment for other demographic characteristics. Specifically, the risk of schizophrenia was observed to be a significant increase in systemic lupus erythematosus (3.73, 2.07–6.72), rheumatoid arthritis (2.89, 1.97–4.23), dermatomyositis (5.85, 1.32–25.94) and autoimmune vasculitis (2.44, 1.17–5.06). Also, this study revealed some potential risk factors for developing schizophrenia, including younger age (less than or equal to 50 years) and some comorbidities (hypertension, chronic obstructive pulmonary disease, and alcohol use disorder). Conversely, this study found that steroid use was a potential protective factor for the development of schizophrenia. Conclusions This study found that AD were associated with an increased risk of developing schizophrenia, suggesting that the abnormal autoimmune process was associated with an increase in the expression of psychiatric disturbances.

Objective This research aimed to make statements regarding the reduction in atrial fibrillation (AF) risk due to acupuncture, stratified by CHA2DS2-VASc score. Methods The Kaplan–Meier method was performed to calculate cumulative incidence of outcomes for each group, and the log-rank test were performed to compare differences between groups. Incidences and hazard ratios (HRs) were estimated by univariate Cox proportional hazards models, and adjusted HRs (aHRs) were estimated by multivariate Cox proportional hazards models including demographic covariates and comorbid status. Results In CHA2DS2-VASc scores of 0–1, 2–3, 4–5 and >5, cases with acupuncture were all associated with decreased incidence of AF (aHR 0.46 with 95% CI 0.42–0.51, P 5). Conclusion Protective effect of acupuncture on AF was observed in this study, and the effect was more obvious for those with fewer comorbidities.

Background: Air pollution is speculated to affect the reproductive health of women. However, a longitudinal association between exposure to air pollution and dysmenorrhea has not been identified, which this study aimed to examine this point. Methods: Two nationwide databases, namely the Taiwan Air Quality Monitoring database and the Taiwan National Health Research Institutes database were linked. Women with a history of dysmenorrhea (International Classification of Disease, Ninth Revision, Clinical Modification code 625.3) before 2000 were excluded. All participants were followed from January 1, 2000 until the diagnosis of dysmenorrhea, withdrawal from National Health Insurance, or December 31, 2013. Furthermore, air pollutants were categorized into quartiles with three cut-off points (25th, 50th, and 75th percentiles). The Cox regression model was used to calculate the hazard ratios of dysmenorrhea. Results: This study enrolled 296,078 women. The mean concentrations of yearly air pollutants were 28.2 (±12.6) ppb for nitric oxides (NOx), 8.91 (±7.93) ppb for nitric oxide (NO), 19.3 (±5.49) ppb for nitrogen dioxide (NO2), 0.54 (±0.18) ppm for carbon monoxide (CO), and 31.8 (±6.80) μg/m3 for PM2.5. In total, 12,514 individuals developed dysmenorrhea during the 12-year follow-up. Relative to women exposed to Q1 concentrations of NOx, women exposed to Q4 concentrations exhibited a significantly higher dysmenorrhea risk [adjusted hazard ratio (aHR)= 27.9, 95% confidence interval (CI) = 21.6–31.3]; similarly higher risk was found for exposure to NO (aHR = 16.7, 95% CI = 15.4–18.4) and NO2 (aHR = 33.1, 95% CI = 30.9–37.4). For CO, the relative dysmenorrhea risk in women with Q4 level exposure was 28.7 (95% CI = 25.4–33.6). For PM2.5, women at the Q4 exposure level were 27.6 times (95% CI = 23.1–29.1) more likely to develop dysmenorrhea than those at the Q1 exposure level. Conclusion: Our results showed that women would have higher dysmenorrhea incidences while exposure to high concentrations of NO, NO2, NOx, CO, and PM2.5.

Background Few large-scale cohort studies have investigated the association between community acquired pneumonia and the use of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs). We aimed to study whether using ACEIs or ARBs had protective effects for community acquired pneumonia. Methods This database cohort study was conducted retrospectively in Taiwan. The hypertensive patients were the target population of this study. Patients with ARB use were defined as our first study cohort. The second study cohort comprised patients who used ACEI. Propensity-score matching at 1:1 was used between ARB users and non-ARB users. We recruited 67 944 participants for the ARB study and 58 062 participants for the ACEI study. The same matching was also performed between ACEI users and non-ACEI users. Cox proportional hazard regression was used to analyze the risk of the outcome of viral pneumonia. Results The hazard ratio of community acquired pneumonia for ARB users relative to non-ARB users was 0.33. The hazard ratio of community acquired pneumonia was 0.71 times in ACEI users compared with ACEI nonusers. In stratification analysis, both ARB and ACEI both exhibited a protective effect for community acquired pneumonia in each age and sex group. In the analysis of the effects of therapy duration, patients using ARB for fewer than 100 days exhibited a greater reduction in the risk of community acquired pneumonia (adjusted HR = 0.58) compared with the non-ARB cohort. For the ACEI study, patients who used ACEI for 121 to 450 days were more likely to exhibit reduced risks of community acquired pneumonia (adjusted HR = 0.5). Conclusion Both ACEI and ARB uses were associated with decreased risk of community acquired pneumonia infection.

Background: Fine air pollutant particles have been reported to be associated with risk of preeclampsia. The association between air pollutant exposure and preeclampsia risk in heavily air polluted Taiwan warrants investigation.Methods: We combined data from Taiwan National Health Insurance (NHI) Research Database (NHIRD) and Taiwan Air Quality Monitoring Database. Women aged 16–55 years were followed from January 1, 2000, until appearance of ICD-9 coding of preeclampsia withdrawal from the NHI program, or December 31, 2013. Daily concentration of NOx, NO, NO2, and CO was calculated by Kriging method. The Cox proportional hazard regression model was used for risk assessment.Results: For NOx, Relative to Quartile [Q] 1 concentrations, the Q2 (adjusted hazard ratio adjusted = 2.20, 95% CI = 1.50–3.22), Q3 (aHR = 7.28, 95% CI = 4.78–11.0), and Q4 (aHR = 23.7, 95% CI = 13.7–41.1) concentrations were associated with a significantly higher preeclampsia or eclampsia risk. Similarly, for NO, relative to Q1 concentrations, the Q2 (aHR = 1.82, 95% CI = 1.26–2.63), Q3 (aHR = 7.53, 95% CI = 5.12–11.0), and Q4 (aHR = 11.1, 95% CI = 6.72–18.3) concentrations were correlated with significantly higher preeclampsia or eclampsia risk. Furthermore, for NO2, relative to Q1 concentration, the Q2 (aHR = 1.99, 95% CI = 1.37–2.90), Q3 (aHR = 6.15, 95% CI = 3.95–9.57), and Q4 (aHR = 32.7, 95% CI = 19.7–54.3) concentrations also associated with a significantly higher preeclampsia or eclampsia risk.Conclusion: Women exposed to higher NOX, NO, NO2, and CO concentrations demonstrated higher preeclampsia incidence.

Background Several diseases are associated with herpes zoster (HZ). However, whether sciatica is a stressor leading to HZ development remains unclear. Here, we evaluated the occurrence of HZ in patients with sciatica. Methods The sciatica cohort consisted of patients first diagnosed as having sciatica between 2000 and 2012. All patients with sciatica were randomly age, sex and index year matched with control individuals without sciatica. The primary outcome was diagnosis of HZ. All individuals were followed until HZ diagnosis, withdrawal from the insurance, death, or December 31, 2013, whichever occurred first. HZ risk in the two cohorts was further analyzed with age, sex and comorbidity stratification. Results In total, 49,023 patients with sciatica and 49,023 matched controls were included. Female patients were more likely to have HZ development than were male patients [adjusted hazard ratio (HR) = 1.07, 95% confidence interval (CI) = 1.02–1.12]. After adjustments for all the covariates, HZ risk was significantly higher in the sciatica cohort than in the control cohort (adjusted HR = 1.19; 95% CI = 1.12–1.25). Conclusion Sciatica increased HZ risk. Thus, HZ risk should be addressed whenever physicians encounter patients with sciatica, HZ vaccination should be considered especially those aged over 50.

Tube feeding (TF) is commonly used for patients with severe swallowing disturbance, and patients with chronic dysphagia are often provided with a long-term nasogastric tube (NGT). However, nationwide epidemiological data on long-term NGT placement are limited. The present study identified the prevalence and outcomes of patients with long-term NGT placement in Taiwan. Data were obtained from the Longitudinal Health Insurance Database. Patients with NGT placement for more than 3 months between 2000 and 2012 were enrolled in this cohort study. An NGT cohort of 2754 patients was compared with 11,016 controls matched for age, sex, residential area, and comorbidities. The prevalence rate of long-term NGT reached 0.063% in 2005 and then remained stable at 0.05–0.06%. The major causes of NGT placement were stroke (44%), cancer (16%), head injury (14%), and dementia (12%). Men (63%) were more likely to have long-term NGT placement than women (37%). The adjusted hazard ratios were 28.1 (95% CI = 26.0, 30.3) for acute and chronic respiratory infections; 26.8 (95% CI = 24.1, 29.8) for pneumonia, 8.84 (95% CI = 7.87, 9.93) for diseases of the esophagus, stomach, and duodenum; and 7.5 (95% CI = 14.7, 20.8) for mortality. Patients with NGT placement for more than 6 months had a higher odds ratio (1.58, 95% CI = 1.13, 2.20) of pneumonia than those with NGT placement for less than 6 months. Only 13% and 0.62% of the patients underwent rehabilitation therapy and percutaneous endoscopic gastrostomy, respectively. Long-term NGT use was associated with a higher risk of comorbidities and mortality. Stroke was the main illness contributing to long-term NGT use. Further interventions are necessary to improve the negative effects of long-term TF.

Background: Abnormalities in the immune system of endometriosis has been demonstrated and may reflect the chronic inflammatory response or the autoimmune reaction to the presence of ectopic endometrial tissue. Rheumatoid arthritis (RA) is a chronic inflammatory joint disease of an autoimmune nature. The study aimed to investigate the risk of incident RA in patients with endometriosis. Materials and Methods: A total of 17,913 patients with endometriosis and 17,913 unaffected controls matched by age, index year, and Charlson Comorbidity Index (CCI) score were enrolled between 2000 and 2012. Patients were followed until the end of 2013 using Taiwan's National Health Insurance Research Database, at which time participants who developed RA were identified. Cox regression analysis was used to calculate the hazard ratio (HR) with a 95% confidence interval (CI) of RA incidence rate between patients with endometriosis and unaffected controls. Results: Patients with endometriosis were associated with an increased risk of incident RA compared with unaffected controls after adjusting for age, CCI score, and hormonal and surgical treatments (3.56 vs. 1.30 per 10,000 person-years, HR: 3.71, 95% CI: 2.91-5.73). Among these adjusted variables, hormonal and surgical treatments were treated as time-dependent covariates. Stratification analyses also revealed similar risk associations linking endometriosis to subsequent RA in all stratified age and CCI score subgroups (adjusted HR all >1, although not all were significant) Conclusions: Patients with endometriosis was associated with an increased risk of incident RA. Additional prospective studies that take into account genetic vulnerability and environmental exposures are warranted to confirm this relationship.

The CHAIn total, 3775 ESUS patients were enrolled from a nationwide hospital-based prospective study. Advanced renal dysfunction was defined as estimated glomerular filtration rate30 ml/min per 1.73 mAfter adjusting for confounding factors and CHAAdvanced renal dysfunction was significantly associated with clinical and functional outcomes in ESUS patients and may improve prognostic impact of the CHA