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Objectives: Nasopharyngeal cancer is a common cancer in East and South Asia. The radiotherapy and chemotherapy regimen has advanced in recent years. However, many patients still suffer from local recurrence and distant metastasis; thus, identifying medication that can be combined with standard treatment to improve the treatment outcomes in nasopharyngeal cancer patients is an unmet need. Methods: We included nasopharyngeal cancer patients from the Taiwan National Health Insurance Database (NHIRD). The primary endpoint was set as the cancer-specific mortality rate. Metformin cohorts and non-Metformin cohorts were matched by sex, age, and the year of the index date. Propensity score matching with a ratio of 1:1 was applied. Results: A total of 6078 subjects were included in the study, with 3039 patients in each group. Male participants outnumbered female participants. Most of the patients were aged 50 to 64; the mean age was 60.4 ± 10.4 years in Metformin non-users, and that of Metformin users was 59.9 ± 10.5 years. Metformin users had a lower risk of death due to nasopharyngeal cancer (adjusted HR = 0.80; 95% CI = 0.71, 0.90) than controls. Conclusions: We concluded that Metformin might be effective at reducing the cancer-specific mortality rate in nasopharyngeal cancer patients. Further randomized control trials should be completed.

This retrospective analysis aims to explore the risk of chronic kidney disease (CKD) among type 2 diabetes mellitus (DM) patients with different scores of adapted diabetes complications severity index (DCSI) who received sodium-glucose cotransporter-2 inhibitors (SGLT2Is).This study includes 113,449 DM patients from the Taiwan National Health Insurance Research Database (NHIRD). We analyzed the data collected from 107,440 patients showing a DCSI score change of 1 per year, 3720 patients with a score change of 1 to 2 per year and 2289 patients with a score change of 2 per year. Cox proportional hazard models were used to evaluate the CKD risk throughout the overall follow-up period, and were adjusted for sex, age, comorbidities and medications of a-glucosidase inhibitors, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, biguanides, dipeptidyl peptidase-4 inhibitors, glucagon like peptide-1 receptor agonists, insulin, meglitinides, sulphonylurea and thiazolidinedione.The incidence of CKD increased from 18.30 per 1000 person-years in patients with a score change of 1 per year to 137.55 per 1000 person-years for those with a score change of 2 per year. Patients with a higher score change ( 2 per year) and receiving SGLT2Is had a lower risk of developing CKD than patients who did not receive SGLT2Is.The use of SGLT2Is was significantly associated with the reduction in CKD incidence in diabetic patients with a higher DCSI.

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: Research investigating differences in the overall stroke risk between individuals with and without immune thrombocytopenia (ITP) is lacking. Methods: This real-world study used the National Health Insurance Research Database (NHIRD). Risk of stroke was compared between 13,085 individuals with ITP enrolled between 1 January 2000 and 31 December 2015 and a control cohort of 52,340 individuals without ITP (1:4 ratio propensity score–matched by age, sex, index year, relevant comorbidities, and medications). Sub-distribution hazards models were used to estimate adjusted sub-distribution hazard ratio (SHR) and 95% confidence intervals (CIs), with the non-ITP group as the control group. Results: Of the 65,425 participants, 13,085 had ITP, 63.3% were women, and the mean age was 52.59 years. The risk of both ischemic and hemorrhagic stroke was 1.14 times (adjusted SHR 1.14, 95% CI, 1.07–1.22) and 1.93 times (adjusted SHR 1.93, 95% CI, 1.70–2.20) higher in the ITP group than in controls. Patients with ITP in the 20- to 29-year subgroup had a higher risk of new-onset stroke (adjusted SHR, 4.06 (95% CI, 2.72–6.07), p value for interaction Conclusions: ITP is associated with increased risk of both ischemic and hemorrhagic stroke.

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.

Patients with chronic spontaneous urticaria (CSU) have a higher risk of developing hypertension. This study aimed to determine whether acupuncture could decrease the risk of hypertension in patients with CSU. We enrolled patients newly diagnosed with CSU between 1 January 2008, and 31 December 2018, from the Taiwanese National Health Insurance Research Database. The claims data were assessed from the index date to 31 December 2019. A Cox regression model was used to compare the hazard ratios (HRs) of the two cohorts. The cumulative incidence of hypertension was estimated using the Kaplan–Meier method. After propensity score matching with a 1:1 ratio, 43,547 patients with CSU who received acupuncture were matched with 43,547 patients with CSU who did not receive acupuncture in this study. After considering potential confounding factors, patients who received acupuncture had a significantly lower risk of hypertension than those in the control group (adjusted hazard ratio = 0.56, 95% confidence interval = 0.54–0.58). Patients who received medications combined with acupuncture tended to have the lowest risk of hypertension. This study revealed that acupuncture decreases the risk of hypertension in patients with CSU in Taiwan. The detailed mechanisms can be further clarified through prospective studies.

Aim: The risk factors for systemic autoimmune disease (SAD)s with antiarrhythmic drug(AAD)s in arrhythmia patients are still unclear. This study was discussed this risk factors for SADs with AADs in arrhythmia patients. Methods: This study was a retrospective cohort design and analyzed this relationship in an Asian population. Patients without a prior diagnosis of SADs were identified from Taiwan's National Health Insurance Research Database from January 1, 2000 to December 31, 2013. Cox regression models were estimated the hazard ratio (HR) with 95% confidence interval [CI] of SAD. Results: We estimated the data of participants aged ≧ 20 or ≦ 100 years old and free of SADs at baseline. AAD users (n = 138376) had a significantly increased risk of SADs over non-AAD users. There was a significant higher risk of developing SADs in all age and sex categories. The patients who received AADs, the autoimmune disease with the significantly higher risk was systemic lupus erythematous (SLE) (adjusted HR [aHR] 1.53, 95%CI, 1.04-2.26), Sjögren syndrome (SjS) (adjusted HR [aHR] 2.06, 95%CI, 1.59-2.66) and rheumatoid arthritis (RA) (aHR, 1.57, 95%CI, 1.26-1.94). Conclusion: We concluded that there were statistical associations between AADs and SADs, and the higher incidence was SLE, SjS and RA in arrhythmia patients.

Supplemental Table 1. Hazard ratios for cancer incidence for different serum iron levels by smoking status. Supplemental Table 2. Cancer mortality risk for different serum iron levels Supplemental Table 3. Comparison of results of first and second test of serum iron. Supplemental Figure 1. J-shaped relationship between serum iron and cancer risk.

INTRODUCTION: Vascular factors have been shown to be associated with increased risk of dementia. However, clinical trials have so far been unsuccessful, suggesting new approaches are needed. The aim of this study was to use population-based real world data to investigate risk factors and preventive factors for dementia, including the effects of traditional Chinese medicine. METHODS: This is a retrospective cohort study using LHID2000, a dataset randomly selected from Taiwan’s National Health Insurance Research Database (NHIRD). Subjects with occlusion and stenosis of precerebral and cerebral arteries, cerebral atherosclerosis without mention of cerebral infarction, and transient cerebral ischemia were included. Subjects with dementia at baseline were excluded. The primary endpoint was dementia. Data for demographic and clinical comorbid status and treatments administered at baseline in 2000 and at the end of follow-up in 2013 were included. RESULTS: A total of 4207 subjects with cerebral vascular disease and no cognitive impairment were included, of whom 392 converted to dementia during an average 5.15-year (SD: 3.79) follow-up. Depression, osteoporosis and the use of enalapril were risk factors for dementia, while nitroglycerin was a protecting factor, in subjects with cerebrovascular diseases without mention of cerebral infarction. In total, statins were shown to decrease the risk of dementia; however, no one statin subtype had such an effect. CONCLUSION: Depression, osteoporosis and the use of enalapril were associated with a higher risk of dementia, while nitroglycerin might be a protecting factor for dementia, in subjects with cerebrovascular diseases without mention of cerebral infarction.

Background Trials of tranexamic acid (TXA) in acute intracerebral hemorrhage (ICH) have focused on the imaging outcomes of intraparenchymal hematoma growth. However, intraventricular hemorrhage (IVH) growth is also strongly associated with outcome after ICH. Revised definitions of hematoma expansion incorporating IVH growth have been proposed. Aims We sought to evaluate the effect of TXA on IVH growth. Methods We analyzed data from the STOP-AUST trial, a prospective randomized trial comparing TXA to placebo in ICH patients presenting ≤ 4.5 h from symptom onset with a CT-angiography spot sign. New IVH development at follow-up, any interval IVH growth, and IVH growth ≥ 1 mL were compared between the treatment groups using logistic regression. The treatment effect of TXA against placebo using conventional (> 6 mL or 33%), and revised definitions of hematoma expansion (> 6 mL or 33% or IVH expansion ≥ 1 mL, > 6 mL or 33%, or any IVH expansion, and > 6 mL or 33% or new IVH development) were also assessed. Treatment effects were adjusted for baseline ICH volume. Results The analysis population consisted of 99 patients (50 placebo, 49 TXA). New IVH development at follow-up was observed in 6/49 (12%) who received TXA and 13/50 (26%) who received placebo (aOR: 0.38 [95% CI: 0.13–1.13]). Any interval IVH growth was observed in 12/49 (25%) who received TXA versus 26/50 (32%) receiving placebo (aOR: 0.69 [95% CI: 0.28–1.66]). IVH growth ≥ 1 mL did not differ between the two groups. Using revised definitions of hematoma expansion, no significant difference in treatment effect was observed between TXA and placebo. Conclusions IVH may be attenuated by TXA following ICH; however, studies with larger cohorts are required to investigate this further. Registration http://www.clinicaltrials.gov ; Unique identifier: NCT01702636.

Previous studies reported an increased risk of benign paroxysmal positional vertigo (BPPV) in patients with migraine. Hence, we aimed to assess the risk of migraine in patients with BPPV. This cohort study was conducted using the Taiwan National Health Insurance Research Database. The BPPV cohort consisted of patients aged

IntroductionWe conducted this study to compare the risk of pneumonia between thiazolidinedione (TZD) use and nonuse in persons with type 2 diabetes (T2D).MethodsWe identified 46,763 propensity-score matched TZD users and nonusers from Taiwan’s National Health Insurance Research Database between January 1, 2000, and December 31, 2017. The Cox proportional hazards models were used for comparing the risk of morbidity and mortality associated with pneumonias.ResultsCompared with the nonuse of TZDs, the adjusted hazard ratios (95% CI) for TZD use in hospitalization for all-cause pneumonia, bacterial pneumonia, invasive mechanical ventilation, and death due to pneumonia were 0.92 (0.88–0.95), 0.95 (0.91–0.99), 0.80 (0.77–0.83), and 0.73 (0.64–0.82), respectively. The subgroup analysis revealed that pioglitazone, not rosiglitazone, was associated with a significantly lower risk of hospitalization for all-cause pneumonia [0.85 (0.82–0.89)]. Longer cumulative duration and higher cumulative dose of pioglitazone were associated with further lower adjusted hazard ratios in these outcomes compared to no-use of TZDs.DiscussionThis cohort study demonstrated that TZD use was associated with significantly lower risks of hospitalization for pneumonia, invasive mechanical ventilation, and death due to pneumonia in patients with T2D. Higher cumulative duration and dose of pioglitazone were associated with a further lower risk of outcomes.

Background: Pulmonary tuberculosis (TB), a global health problem, is typically caused by the bacterium Mycobacterium tuberculosis. Herpes zoster (HZ) is caused by the reactivation of the varicella-zoster virus (VZV). The reactivation of VZV can be caused by stress. We investigated whether pulmonary TB increases the risk of HZ development. Methods: This study used data that sampled a population of 2 million people in 2000 from the National Health Insurance Research Database. This cohort study observed Taiwanese patients aged 20–100 years with pulmonary TB from 2000 to 2017 (tracked to 2018). Pulmonary TB was defined as having two or more outpatient diagnoses or at least one admission record. To address potential bias caused by confounding factors, the control cohort and pulmonary TB cohort were matched 1:1 by age, gender, index year, and comorbidities. Patients with HZ before the index date were excluded. Results: A total of 30,805 patients were in the pulmonary TB and control cohorts. The incidence rate of HZ in pulmonary TB and control cohorts were 12.00 and 9.66 per 1000 person-years, respectively. The risk of HZ in the pulmonary TB cohort (adjusted hazard ratios = 1.23; 95% confidence interval = 1.16–1.30) was significantly higher than that of in control cohort. Among patients without comorbidities, the patients with TB were 1.28-fold more likely to have HZ than those without TB. Conclusion: Patients with TB should be well treated to avoid the potential risk of HZ occurrence. Although we identified the association between pulmonary TB and HZ, further studies are needed to confirm the result.

ImportanceIt remains unknown whether Taiwanese veterans have a lower risk of subsequent cancer compared with non-veterans.ObjectiveTo examine whether veterans are associated with reduced cancer risk.MethodsFrom January 2004 to December 2017, this study included 957 veterans and 957 civilians who were propensity score (PS) matched by years of birth, sex, residence, index year, days in the hospital, frequency of outpatient visits, and relevant comorbidities at baseline. Multivariate Cox proportional hazards regression analysis was applied to compare the risks of cancer, overall and by subgroup, and mortality. All the participants were cancer free at the baseline.ExposuresVeterans retrieved from Taiwan National Health Insurance Research Database (NHIRD).Main outcomeCancer extracted from the Registry for Catastrophic Illness Patients Database (RCIPD).ResultsOverall, 1,914 participants were included, and 957 veterans with a mean (SD) age of 75.9 (6.79) years and 946 men (98.9%). The mean follow-up was about 10.5 (±4.51) years. Cancer was recorded in 6.68% (N = 64) and 12.12% (N = 116) of veterans and non-veterans, respectively. Veterans were associated with decreased risk [adjusted hazard ratio (aHR), 0.57; 95% CI: 0.41–0.78; P < 0.001] of cancer compared with civilians after controlling for age, sex, urbanization, hypertension, diabetes, hyperlipidemia, cardiovascular event, COPD, asthma, chronic liver disease, alcohol-related illness, and Parkinson’s disease. Cancer subgroup analyses verified this finding (HRs P < 0.05).ConclusionTaiwanese older veterans are associated with reduced overall cancer risk than individuals without veteran status.

Ischemic cardiac or cerebrovascular disease (ICCD) survivors represent a subpopulation with a high cancer risk. Antiplatelet medications, such as aspirin, remain a fundamental therapy for the secondary prevention of ischemic attack in these patients. We conducted a population-based cohort study to investigate the association of long-term low-dose aspirin use with the risk of primary cancer in ICCD survivors. Patients aged ≥20 years with newly diagnosed ICCD (n = 98,519) between January 2000 and December 2013 were identified from the Taiwan National Health Insurance Research Database. The aspirin user and nonuser groups (each n = 24,030) were propensity-matched (1:1) for age, sex, comorbidities, prior medications, ICCD diagnosis year, and year of index dates. The incidence rate of primary cancer was significantly lower in the user group (6.49/1000 person-years) than in the nonuser group (14.04/1000 person-years). Multivariate Cox regression analysis indicated that aspirin use was an independent factor associated with a reduced risk of primary cancer (aHR (95% confidence interval) = 0.42 (0.38–0.45)) after adjustment. Kaplan–Meier curve analysis revealed that the cumulative incidence rate of primary cancer was significantly lower (p < 0.0001) in the user group than in the nonuser group over the 14-year follow-up period. Subgroup analyses demonstrated that this anticancer effect increased with duration of treatment and with similar estimates in women and men. In addition, aspirin use was associated with a reduced risk for seven out of the ten most common cancers in Taiwan. These findings suggest the anticancer effect of aspirin in ICCD survivors and provide information for assessing the benefit-to-risk profile of aspirin as an antiplatelet medication in these patients.

Background: Adequate management of diabetes in patients with liver cirrhosis can be challenging. We conducted this study to investigate the liver-related long term outcomes of alpha-glucosidase inhibitors (AGIs) in patients with diabetes and cirrhosis.Methods: From National Health Insurance Research Database (NHIRD) in Taiwan, we recruited propensity-score matched alpha-glucosidase inhibitor users and non-users from a cohort of type 2 diabetes mellitus (T2DM) with compensated liver cirrhosis between 1 January 2000, and 31 December 2017, and followed them until 31 December 2018. Cox proportional hazards models with robust sandwich standard error estimates were used to assess the risk of main outcomes for alpha-glucosidase inhibitor users versus non-users.Results: The incidence rates of mortality during follow-up were 65.56 vs. 96.06 per 1,000 patient-years for alpha-glucosidase inhibitor users and non-users, respectively. The multivariable-adjusted model shows that alpha-glucosidase inhibitor users had significantly lower risks of all-cause mortality (aHR 0.63, 95% CI 0.56–0.71), hepatocellular carcinoma (aHR 0.55, 95% CI 0.46–0.67), decompensated cirrhosis (aHR 0.74 95% CI 0.63–0.87), hepatic encephalopathy (aHR 0.72, 95% CI 0.60–0.87), and hepatic failure (aHR 0.74, 95% CI 0.62–0.88) than alpha-glucosidase inhibitor non-users. Patients who received alpha-glucosidase inhibitors for a cumulative duration of more than 364 days had significantly lower risks of these outcomes than non-users.Conclusion: Alpha-glucosidase inhibitor use was associated with a lower risk of mortality, hepatocellular carcinoma, decompensated cirrhosis, and hepatic failure in patients with diabetes and compensated cirrhosis. alpha-glucosidase inhibitors may be useful for the management of diabetes in patients with compensated liver cirrhosis. Large-scale prospective studies are required to verify our results.

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.

Older adults are more likely to have influenza and respond less well to the flu vaccine. We conducted this study to investigate whether pre-influenza vaccination metformin use had an effect on influenza and relevant complications in older adults with type 2 diabetes mellitus. Propensity score matching was used to identify 28,169 pairs of metformin users and nonusers from Taiwan’s National Health Insurance Research Database from 1 January 2000 to 31 December 2018. We used Cox proportional hazards models to calculate the risks of hospitalization for influenza, pneumonia, cardiovascular disease, ventilation, and mortality between metformin users and nonusers. Compared with metformin nonusers, the aHRs (95% CI) for metformin users at risk of hospitalization for influenza, pneumonia, cardiovascular disease, invasive mechanical ventilation, death due to cardiovascular disease, and all-cause mortality were 0.60 (0.34, 1.060), 0.63 (0.53, 0.76), 0.41 (0.36, 0.47), 0.56 (0.45, 0.71), 0.49 (0.33, 0.73), and 0.44 (0.39, 0.51), respectively. Higher cumulative duration of metformin use was associated with lower risks of these outcomes than no use of metformin. This cohort study demonstrated that pre-influenza vaccination metformin use was associated with lower risks of hospitalizations for influenza, pneumonia, cardiovascular disease, mechanical ventilation, and mortality compared to metformin nonusers.

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.

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

BackgroundHypertension (HTN) is the leading preventable risk factor for cardiovascular disease worldwide. Patients with HTN are at higher risk for heart failure (HF). The currently available therapeutic approaches for HTN do not always optimally control blood pressure or are not suitable for hypertensive patients who have a higher number of comorbidities. This study aimed to determine whether Chinese herbal medicine (CMH)-based interventions could reduce the risk of HF in hypertensive patients.MethodsThis retrospective study randomly selected 2 million enrollees from the National Health Insurance Research Database and identified 507,608 patients who were newly diagnosed with HTN in 2000–2017. After 1:1 frequency-matching by age, sex, index year, income, urbanization, duration of HTN, comorbidities and antihypertensive medications, we selected 8,912 eligible patients in each group. During 16 years of follow-up, 380 CHM users and 426 CHM non-users developed HF, representing incidence rates of 6.29 and 7.43 per 1,000 person-years, respectively.ResultsCHM users had significantly lower HF risk compared with CHM non-users (adjusted HR = 0.85, 95% CI 0.74–0.98). The markedly predominant effect was observed in those receiving CHM products for more than 180 days (adjusted HR = 0.65). The frequently prescribed formula, Jia-Wei-Xiao-Yao-San, and the single herbs Ge Gen, Huang Qi, Du Zhong, Huang Qin, and Chuan Xiong were significantly associated with lower risk of HF.ConclusionsThis population-based study revealed decreased HF risk in hypertensive patients with CHM use. These findings may provide a reference for HF prevention strategies and support the integration of CHM into clinical intervention programs that provide a favorable prognosis for hypertensive patients.

Patients with inflammatory bowel disease (IBD) present a higher risk of developing cardiovascular diseases (CVDs) due to chronic inflammation, which plays an essential role in atherogenesis. Hyperlipidemia is another risk factor for CVDs; however, the association between IBD, IBD medications, and hyperlipidemia remains controversial. We conducted a nationwide, population-based, retrospective, cohort study to examine the effect of IBD and IBD medications on the risk of developing hyperlipidemia. The effects of IBD medications on the expression of lipogenesis-related hepatic genes were also evaluated. We obtained data from the Longitudinal Health Insurance Database of Taiwan from patients with new-onset IBD and a comparison cohort of patients without IBD. A Cox proportional hazards regression model was used to analyze the difference in the risk of developing hyperlipidemia between the two cohorts. We also examined the influence of IBD medications on the expression of lipogenesis-related hepatic genes. After adjusting for comorbidities and confounding factors, the case group (N = 14,524) had a higher risk for hyperlipidemia than the control group (N = 14,524) [adjusted hazards ratio (aHR), 2.18]. Patients with IBD that did not receive IBD medications exhibited a significantly higher risk of hyperlipidemia (aHR, 2.20). In those treated with IBD medications, the risk of developing hyperlipidemia was significantly lowered than those without such medications (all aHR ≤ 0.45). Gene expression analysis indicated that IBD medications downregulated the expression of lipogenesis-related genes. Screening blood lipids in IBD patients is needed to explore the specific role and impact of IBD medications in the development of CVD.

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.

BACKGROUND AND PURPOSE The CHA2 DS2 -VASc score has immense prognostic value in patients with embolic stroke of undetermined source (ESUS). We aimed to determine the usefulness of advanced renal dysfunction and its addition to the CHA2 DS2 -VASc score in improving predictive accuracy. METHODS In total, 3775 ESUS patients were enrolled from a nationwide hospital-based prospective study. Advanced renal dysfunction was defined as estimated glomerular filtration rate 2 at first-, third-, and sixth-month post-stroke. The renal (R)-CHA2 DS2 -VASc score was derived by including advanced renal dysfunction in the CHA2 DS2 -VASc score. Risk stratification improvement after including advanced renal dysfunction was assessed using C statistic, integrated discrimination improvement (IDI), and category-free net reclassification index (NRI). RESULTS After adjusting for confounding factors and CHA2 DS2 -VASc score, advanced renal dysfunction showed significant associations with all-cause mortality (HR: 2.88, 95% CI: 1.92-4.34) and poor functional outcome at third- (OR: 2.69, 95% CI: 1.47-4.94) and sixth-month post-stroke (OR: 2.67, 95% CI: 1.47-4.83). IDI and NRI showed that incorporating advanced renal dysfunction significantly improved risk discrimination over the original CHA2 DS2 -VASc score. R-CHA2 DS2 -VASc score ≥2 increased risk by 1.94-fold (95% CI: 1.15-3.27) for all-cause mortality, and ≥4 increased risk by 1.62-fold (95% CI: 1.05-2.50) of poor functional outcome at third-month post-stroke and by 1.81-fold (95% CI: 1.19-2.75) at sixth-month post-stroke. CONCLUSIONS Advanced renal dysfunction was significantly associated with clinical and functional outcomes in ESUS patients and may improve prognostic impact of the CHA2 DS2 -VASc score.

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.