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Objective: To explore the prevalence and distinctive features of Xue-Fu-Zhu-Yu-Tang (XFZYT) prescriptions by analyzing the National Health Insurance Research Database (NHIRD) to identify the specific medical problems for which XFZYT is prescribed.Methods: This nationwide, population-based, cross-sectional study included 109,073 XFZYT users and 532,848 XFZYT non-users among Chinese herbal product (CHP) users in NHIRD. Chi-squared tests were used to analyze disparities between the XFZYT user and XFZYT non-user cohorts, and the mean age was evaluated using the Wilcoxon rank-sum test. Logistic regression was used to compute the odds ratios (ORs) and 95% confidence intervals (95% CIs).Results: XFZYT was frequently used to treat pain. The top five conditions for which the Taiwanese traditional Chinese medicine (TCM) practitioners would prescribe XFZYT were chest pain; headache; myalgia and myositis; lumbago; and neuralgia, neuritis, and radiculitis.Conclusion: This study represents an inaugural comprehensive survey conducted on the utilization of XFZYT prescriptions among patients with diverse diseases. XFZYT is mostly used to treat pain conditions in Taiwan. Combined with the combination use of other CHPs, XFZYT is used to treat symptoms of the chest and respiratory system, soft tissue conditions, menstruation disorders, and joint and back discomfort. These results suggest that further clinical trials are warranted to verify the effects of XFZYT in pain management.

IntroductionSchizophrenia increases the risk of mortality and cardiovascular disease (CVD) risk. However, the correlation between antipsychotics (APs) and CVD remains controversial. Hyperlipidemia is a significant risk factor for CVD.MethodsWe conducted a nationwide population-based retrospective cohort study to investigate the effects of APs on the risk of hyperlipidemia and lipid homeostasis gene expression. We used data from the Longitudinal Health Insurance Database of Taiwan on new-onset schizophrenia patients and a comparison cohort without schizophrenia. We used a Cox proportional hazards regression model to analyze the differences in hyperlipidemia development between the two cohorts. Furthermore, we examined the effects of APs on the hepatic expression of lipid homeostasis-related genes.ResultsAfter adjusting for potential interrelated confounding factors, the case group (N = 4,533) was found to have a higher hyperlipidemia risk than the control cohort (N = 4,533) [adjusted hazard ratio (aHR), 1.30, p

IntroductionA potential association between epilepsy and subsequent type 2 diabetes mellitus (T2DM) has emerged in recent studies. However, the association between epilepsy, anti-epileptic drugs (AEDs), and the risk of T2DM development remains controversial. We aimed to conduct a nationwide, population-based, retrospective, cohort study to evaluate this relationship.MethodsWe extracted data from the Taiwan Longitudinal Generation Tracking Database of patients with new-onset epilepsy and compared it with that of a comparison cohort of patients without epilepsy. A Cox proportional hazards regression model was used to analyze the difference in the risk of developing T2DM between the two cohorts. Next-generation RNA sequencing was used to characterize T2DM-related molecularchanges induced by AEDs and the T2DM-associated pathways they alter. The potential of AEDs to induce peroxisome proliferator-activated receptor γ (PPARγ) transactivation was also evaluated.ResultsAfter adjusting for comorbidities and confounding factors, the case group (N = 14,089) had a higher risk for T2DM than the control group (N = 14,089) [adjusted hazards ratio (aHR), 1.27]. Patients with epilepsy not treated with AEDs exhibited a significantly higher risk of T2DM (aHR, 1.70) than non-epileptic controls. In those treated with AEDs, the risk of developing T2DM was significantly lower than in those not treated (all aHR ≤ 0.60). However, an increase in the defined daily dose of phenytoin (PHE), but not of valproate (VPA), increased the risk of T2DM development (aHR, 2.28). Functional enrichment analysis of differentially expressed genes showed that compared to PHE, VPA induced multiple beneficial genes associated with glucose homeostasis. Among AEDs, VPA induced the specific transactivation of PPARγ.DiscussionOur study shows epilepsy increases the risk of T2DM development, however, some AEDs such as VPA might yield a protective effect against it. Thus, screening blood glucose levels in patients with epilepsy is required to explore the specific role and impact of AEDs in the development of T2DM. Future in depth research on the possibility to repurpose VPA for the treatment of T2DM, will offer valuable insight regarding the relationship between epilepsy and T2DM.

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.

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

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.

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.

Although the link between sugar-sweetened beverages (SSB) and pancreatic cancer has been suggested for its insulin-stimulating connection, most epidemiological studies showed inconclusive relationship. Whether the result was limited by sample size is explored. This prospective study followed 491,929 adults, consisting of 235,427 men and 256,502 women (mean age: 39.9, standard deviation: 13.2), from a health surveillance program and there were 523 pancreatic cancer deaths between 1994 and 2017. The individual identification numbers of the cohort were matched with the National Death file for mortality, and Cox models were used to assess the risk. The amount of SSB intake was recorded based on the average consumption in the month before interview by a structured questionnaire. We classified the amount of SSB intake into 4 categories: 0–

Objective: Lower serum low-density lipoprotein cholesterol (LDL-C) levels are associated with increased intracerebral hemorrhage (ICH) risk. However, reverse causality and residual confounding has not attracted public attention. Therefore, we assessed whether people with LDL-C have increased risk of mortality adjusting for potential confounders using two large Taiwan cohorts.Methods: The Mei-Jhao (MJ) cohort has 414,372 adults participating in a medical screening program with 378 ICH deaths within 15 years of follow-up (1994–2008). Cox proportional hazards regressions estimated hazard death ratios according to LDL-C levels. We identified 4,606 ICH patients from the Taiwan Stroke Registry (TSR) and analyzed the impact of LDL-C on 3-month mortality.Results: Low cholesterol (LDL-C

Objective: Stroke in young adults is uncommon, and the etiologies and risk factors of stroke in young adults differ from those in older populations. Smoker's paradox is an unexpected favorable outcome, and age difference is used to explain the association between smoking and the favorable functional outcome. This study aimed to investigate the existence of this phenomenon in young stroke patients.Methods: We analyzed a total of 9,087 young stroke cases registered in the nationwide stroke registry system of Taiwan between 2006 and 2016. Smoking criteria included having a current history of smoking more than one cigarette per day for more than 6 months. After matching for sex and age, a Cox model was used to compare mortality and function outcomes between smokers and non-smokers.Results: Compared with the non-smoker group, smoking was associated with older age, higher comorbidities, and higher alcohol consumption. Patients who report smoking with National Institutes of Health Stroke Scale scores of 11–15 had a worse functional outcome (adjusted odds ratio, 0.81; 95% confidence interval, 0.76 – 0.87).Conclusion: Smokers had a higher risk of unfavorable functional outcomes at 3 months after stroke, and therefore, we continue to strongly advocate the importance of smoking cessation.

Background: Gallstone disease (GD) is associated with a high risk of cardiovascular disease. However, it is unknown whether GD contributes to atrial fibrillation (AF). We aimed to investigate the association between GD and AF.Methods: We performed a population-based cohort study using data from the Taiwan National Health Insurance Research Database between 2001 and 2011. A GD cohort of 230,076 patients was compared with a control cohort consisting of an equal number of patients matched for age, sex, cardiovascular and gastrointestinal comorbidities.Results: In total, 5,992 (49.8/10,000 person-years) patients with GD and 5,804 (44.5/10,000 person-years) controls developed AF. GD increased AF risk with a hazard ratio (HR) of 1.20 [95% confidence interval (CI), 1.16–1.25]. In patients with GD but without cholecystectomy, the HR of AF reached 1.57 (95% CI = 1.50–1.63). After cholecystectomy, the HR of AF significantly decreased to 0.85 (95% CI = 0.81–0.90). Among the three age groups with GD (

Objective: While radix Salvia miltiorrhiza (Danshen; RSM) is commonly used in Chinese herbal medicine, its current usage has not yet been analyzed in a large-scale survey. This study aimed to investigate the conditions for which RSM is prescribed and the utilization of RSM in Taiwan.Methods: 1 million beneficiaries enrolled in the Taiwan National Health Insurance Research Database were sampled to identify patients who were prescribed RSM. Next, the diagnoses of these patients based on the International Classification of Diseases 9th Revision Clinical Modification code were analyzed. Logistic regression analysis was employed to estimate the odds ratio (OR) for RSM utilization.Results: Patients with disorders of menstruation and abnormal bleeding from the female genital tract due to other causes were the diagnostic group most commonly treated with RSM (9.48%), followed by those with general (9.46%) and cardiovascular symptoms (4.18%). Subjects treated with RSM were mostly aged 35–49 years (30.1%). The most common combination of diseases for which RSM was prescribed (0.17%) included menopausal disorders and general symptoms. Women were more likely to receive RSM than men (OR = 1.75, 95% confidence interval = 1.73–1.78). RSM was frequently combined with Yan-Hu-Suo and Jia-Wei-Xiao-Yao-San for clinical use.Conclusion: To date, this is the first study to identify the most common conditions for which RSM is used in modern Taiwan. The results indicate RSM as a key medicinal herb for the treatment of gynecological diseases, including menstrual disorders, female genital pain, menopausal disorders, etc. The most common combination for which RSM is prescribed is menopausal disorders and general symptoms. Further research is needed to elucidate the optimal dosage, efficacy, and safety of RSM.

Objective: Combinations of Chinese herbal products (CHPs) are widely used for Parkinson’s disease (PD) in Taiwan. Thereby, we investigated the use of CHPs in patients with PD.Methods: This study was a population-based cohort study that analyzed the data of patients with PD from the National Health Insurance Research Database. A total of 9,117 patients were selected from a random sample of one million individuals included in this database. We used multiple logistic regression models to estimate the adjusted odds ratios of the demographic factors and analyzed the formula and single CHPs commonly used for PD.Results: Traditional Chinese medicine users were more commonly female, younger, of white-collar status, and residents of Central Taiwan. Chaihu-Jia-Longgu-Muli-Tang was the most commonly used formula, followed by Ma-Zi-Ren-Wan and then Shao-Yao-Gan-Cao-Tang. The most commonly used single herb was Uncaria tomentosa (Willd. ex Schult.) DC., followed by Gastrodia elata Blume and then Radix et Rhizoma Rhei (Rheum palmatum L., Rheum tanguticum Maxim. ex Balf., and Rheum officinale Baill.). Chaihu-Jia-Longgu-Muli-Tang and U. tomentosa (Willd. ex Schult.) DC. have shown neuroprotective effects in previous studies, and they have been used for managing non-motor symptoms of PD.Conclusion: Chaihu-Jia-Longgu-Muli-Tang and U. tomentosa (Willd. ex Schult.) DC. are the most commonly used CHPs for PD in Taiwan. Our results revealed the preferences in medication prescriptions for PD. Further studies are warranted to determine the effectiveness of these CHPs for ameliorating the various symptoms of PD, their adverse effects, and the mechanisms underlying their associated neuroprotective effects.

BackgroundSulpiride is a highly selective dopamine D2 receptor antagonist and is commonly used in psychiatric disorders, Tourette syndrome, peptic ulcer disease (PUD), and gastroesophageal reflux disease (GERD). However, sulpiride has been recognized as a potential cause of drug-induced parkinsonism (DIP) for a long time. In this study, we aimed to focus on analysis of sulpiride-induced parkinsonism (SIP) in PUD and GERD patients based on a nationwide population.MethodsData were obtained from the Taiwan’s National Health Insurance Research Database. The study enrolled 5,275 PUD or GERD patients, of whom were divided into two groups, based on their exposure (1,055 cases) or non-exposure (4,220 cases) to sulpiride.ResultsDuring the study period (2000–2012), the incidence rate of parkinsonism was 261.5 and 762.2 per 100,000 person-years in the control and sulpiride-treated groups, respectively. For patients with at least 14 days of prescription for sulpiride, the adjusted hazard ratio (aHR) was 2.89, 95% confidence interval (CI): 2.04-4.11. Patients with age more than 65 years (aHR = 4.99, 95% CI = 2.58-9.65), hypertension (aHR = 2.39, 95% CI = 1.49-3.82), depression (aHR = 2.00, 95% CI = 1.38-2.91), and anxiety (aHR = 1.45, 95% CI = 1.01-2.09) had significant higher risk of developing parkinsonism. An average annual cumulative sulpiride dose > 1,103 mg was accompanied by the greatest risk of SIP; sulpiride use for ≥ 9 days is a cut-off point for predicting future SIP.ConclusionAt the population level, sulpiride may be frequently prescribed and apparently effective for PUD and GERD. SIP is associated with older age, hypertension, depression or anxiety comorbidities. Physicians should be aware of the neurogenic adverse effects, even when the drug is only used in low-dose or a short duration.

Background: Flunarizine (Fz) is a first-line prophylactic medication that is widely used in migraine. However, Fz has been recognized as a potential cause of drug-induced parkinsonism for a long time. However, to our knowledge, there has been no population-based subgroup analyses for Fz-induced parkinsonism (FIP) in migraine patients.Methods: Data were obtained from the Taiwan’s National Health Insurance Research Database. The study comprised 6,470 migraine patients who were divided into two groups, based on their exposure or non-exposure to Fz.Results: During the study period (2000–2012), the incidence rate of parkinsonism was 1.92 and 8.72 per 1,000 person-years in the control and Fz -treated groups, respectively. In the study population, the adjusted hazard ratio was 4.07 (95% confidence interval CI: 2.84–5.85). In 45–64-year old subjects and ≥ 65-year old subjects, the risk of FIP was 3.18 times (95% CI = 1.63–6.20) and 4.89 times (95% CI = 3.09–7.72) more than that in the controls. The Fz-treated subjects with comorbidities also had a higher risk (4.54, 95% CI: 3.14-6.57). An average annual cumulative Fz dose > 445 mg was accompanied by the greatest risk of FIP; Fz use for >60 days is a cut-off point for predicting future FIP.Conclusion: At the population level, this study showed a complete picture of FIP in migraine patients. FIP is associated with older age, history of comorbidities, exposure to high-dose of Fz, and longer duration of exposure to Fz.

Background: To determine the effects of bronchodilator, steroid, and anti-arrhythmia drug use on the risk of heart disease/stroke (HDS) in patients with bronchiectasis–chronic obstructive pulmonary disease overlap syndrome (BCOS).Methods: We retrospectively enrolled patients with BCOS (BCOS cohort, n = 1,493) and patients without bronchiectasis and chronic obstructive pulmonary disease (COPD) (non-BCOS cohort, n = 5,972). The cumulative incidence of HDS was analyzed through Cox proportional regression. We calculated adjusted hazard ratios (aHRs) and their 95% confidence intervals (CIs) for HDS after adjustments for sex, age, comorbidities, long-acting β2-agonist or long-acting muscarinic antagonist (LABAs/LAMAs) use, short-acting β2-agonist or short-acting muscarinic antagonist (SABAs/SAMAs) use, oral steroid (OSs) or inhaled corticosteroid steroid (ICSs) use, and anti-arrhythmia drugs use.Results: The aHR (95% CI) for HDS was 1.08 (0.28–4.06) for patients using LAMAs compared with those not using drugs. Regarding drug use days, the aHRs (95% CIs) were 32.2 (1.79–773.0), 1.85 (1.01–3.39), and 31.1 (3.25–297.80) for those with recent SABAs use, past ICSs use, and past anti-arrythmia drugs use, respectively. Regarding cumulative drug dose, the aHRs (95% CIs) were 2.12 (1.46–3.10), 3.48 (1.13–10.6), 3.19 (2.04–4.99), 28.1 (1.42–555.7), 2.09 (1.32–3.29), 2.28 (1.53–3.40), and 1.93 (1.36–2.74) for those with a low dose of SABAs, medium dose of SABAs, low dose of SAMAs, low dose of ICSs, medium dose of ICSs, low dose of OSs, and medium dose of OSs, respectively.Conclusions: Compared with patients without bronchiectasis and COPD, BCOS patients with recent SABAs, past ICSs, and past anti-arrhythmia drugs use; a low or medium SABAs ICSs, and OSs dose; and a low SAMAs dose had a higher risk of HDS. LAMAs were not associated with HDS.

Objective: The effects of statins on the risk of hepatic, renal, respiratory, and heart failure among patients with asthma–chronic obstructive pulmonary disease overlap (ACO) have not been reported.Design: Time-dependent population-based study.Setting: Patient data from 2000 to 2010 were retrieved from the Taiwan National Health Insurance Research Database.Patients: We divided patients with ACO into cohorts of statin use (N = 1,211) and nonuse (N = 7,443).Measurements and Main Results: The cumulative incidence rates of hepatic, renal, respiratory, and heart failure were analyzed through Cox proportional regression analysis with time-dependent variables. After adjustment for multiple confounding factors, including age, sex, comorbidities, and medications [statins, inhaled corticosteroid (ICS), or oral steroid (OS)], the adjusted hazard ratios (aHRs) [95% confidence intervals (CIs)] for hepatic, renal, respiratory, and heart failure were 0.50 (0.40–0.64), 0.49 (0.38–0.64), 0.61 (0.27–2.21), and 0.47 (0.37–0.60), respectively. The aHRs (95% CIs) for statin use with [ICS, OS] for hepatic, renal, and heart failure were [0.36 (0.20–0.66), 0.52 (0.39–0.70)]; [0.82 (0.51–1.34), 0.46 (0.33–0.63)]; and [0.66 (0.40–1.07), 0.48 (0.37–0.64)], respectively.Conclusions: The ACO cohort with statin use exhibited lower risk of hepatic, renal, and heart failure than any other cohort, regardless of age, sex, comorbidities, or ICS or OS use. Regarding the combined use of statins and ICS, the risks of hepatic failure were lower. For the combined use of statins and OS, hepatic, renal, and heart failure were less frequent.

Background: Earlier studies have indicated a relatively higher risk of occurring meningioma among female breast cancer survivors and have suggested that tamoxifen might decrease this risk. The present study evaluated whether tamoxifen use in breast cancer patients can reduce the risk of meningioma.Methods: We designed a population-based cohort study by using data from the National Health Insurance system of Taiwan to assess this issue. Between January 1, 2000, and December 31, 2008, women with breast cancer and of age ≥20 years were included. They were divided into two groups: those who had not received tamoxifen therapy and those who had. The Cox’s proportion hazard regression analysis was conducted to estimate the effects of tamoxifen treatment and the subsequent meningioma risk.Results: We identified a total of 50,442 tamoxifen users and 30,929 non-tamoxifen users. Tamoxifen users had a borderline significantly lower overall risk of meningioma than non-tamoxifen users [adjusted hazard ratio (aHR) = 0.64, 95% confidence interval (95% CI) = 0.40–1.02]. A statistically significant difference was found in those patients with tamoxifen treatment duration longer than 1,500 days (aHR = 0.42, 95% CI = 0.19–0.91) or with cumulative dosage exceeding 26,320 mg (aHR = 0.44, 95% CI = 0.22–0.88). Furthermore, no statistically significant joint effect of aromatase inhibitors and tamoxifen on the occurrence of meningioma among breast cancer patients was seen.Conclusion: Tamoxifen users had a non-significantly (36%) lower risk of developing meningioma than did tamoxifen non-users; however, our data indicated that tamoxifen therapy is associated with a reduced meningioma risk for Taiwanese breast cancer patients receiving long duration or high cumulative dosage treatment with tamoxifen.

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.

Background: Whether diabetes mellitus (DM) patients with chronic kidney disease (CKD) can glean individual renal benefit from dihydropyridine calcium channel blockers (DCCBs) remains to be determined. We conducted a nationwide, population-based, propensity score matching cohort study to examine the effect of DCCBs on CKD progression in DM patients with CKD.Methods: One million individuals were randomly sampled from Taiwan’s National Health Insurance Research Database. The study cohort consisted of DM patients with CKD who used DCCBs. The comparison cohort was propensity-matched for demographic characteristics and comorbidities. The endpoint was advanced CKD or end-stage renal disease (ESRD). The Cox proportional hazards model was used to calculate the risks.Results: In total, 9,761 DCCB users were compared with DCCB nonusers at a ratio of 1:1. DCCB users had lower risk of advanced CKD and ESRD than nonusers—with adjusted hazard ratio [aHR; 95% confidence interval (CI)] of 0.64 (0.53–0.78) and 0.59 (95% CI, 0.50–0.71) for advanced CKD and ESRD, respectively. DCCB users aged ≥65 years had the lowest incidence rates of advanced CKD and ESRD—with aHR (95% CI) of 0.47 (0.34–0.65) and 0.48 (0.35–0.65) for advanced CKD and ESRD, respectively. Finally, cumulative DCCB use for >1,100 days was associated with the lowest advanced CKD and ESRD risks [(aHR, 0.29 (95% CI, 0.19–0.44)].Conclusion: DM patients with CKD who used DCCBs had lower risk of progression to advanced CKD and ESRD than nonusers did.

Background: It is sometimes difficult to distinguish between asthma and bronchiectasis as their symptoms overlap, and these two diseases are associated with pulmonary tuberculosis (PTB) or pneumonia.Objective: The purpose of this study is to determine the effects of bronchodilator drugs, steroids, antidepressants drugs, and antianxiety drugs on the risks of PTB or pneumonia in patients with bronchiectasis–asthma combination or bronchiectasis–asthma–chronic obstructive pulmonary disease combination—BCAS cohort.Methods: After propensity score matching, we retrospectively studied patients with BCAS (N = 620) and without BCAS (N = 2,314) through an analysis. The cumulative incidence of PTB or pneumonia was analyzed through Cox proportional regression. After adjustment for sex, age, comorbidities, and medications [including long-acting beta2 agonist/muscarinic antagonists (LABAs/LAMAs), short-acting beta2 agonist/muscarinic antagonists (SABAs/SAMAs), leukotriene receptor antagonist, montelukast, steroids (inhaled corticosteroids, ICSs; oral steroids, OSs), anti-depressants (fluoxetine), and anti-anxiety drugs (benzodiazepines, BZDs)], we calculated the adjusted hazard ratios (aHR) and their 95% confidence intervals (95% CI) for these risks. Similar to OSs, ICSs are associated with an increased risk of PTB or pneumonia, lumping these two as steroids (ICSs/OSs).Results: For the aHR (95% CI), with non-LABAs/non-OSs as the reference 1, the use of LABAs [0.70 (0.52–0.94)]/OSs [0.35 (0.29–0.44)] was associated with a lower risk of PTB or pneumonia. However, the current use of LABAs [2.39 (1.31–4.34)]/SABAs [1.61 (1.31–1.96)], steroids [ICSs 3.23 (1.96–5.29)]/OSs 1.76 (1.45–2.14)], and BZDs [alprazolam 1.73 (1.08–2.75)/fludiazepam 7.48 (1.93–28.9)] was associated with these risks. The current use of LAMAs [0.52 (0.14–1.84)]/SAMAs [1.45 (0.99–2.11)] was not associated with these risks.Conclusion: The current use of LAMAs/SAMAs is relatively safe with respect to PTB or pneumonia risks, but LABAs/SABAs, steroids, and BZDs could be used after evaluation of the benefit for the BCAS cohort. However, we must take the possible protopathic bias into account.

ObjectiveWe investigated the effects of medication on heart disease and ischemic stroke (HDS) risk in patients with predominant bronchiectasis-asthma combination (BCAS).MethodsBCAS and non-BCAS cohorts (N = 588 and 1,118, respectively) were retrospectively enrolled. The cumulative incidence of HDS was analyzed using Cox proportional regression; propensity scores were estimated using non-parsimonious multivariable logistic regression. Adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for HDS were calculated, adjusting for sex, age, comorbidities, and medication {long- and short-acting β2 agonists and muscarinic antagonists (LABAs/SABAs and LAMAs/SAMAs), steroids [inhaled corticosteroid steroids (ICSs), oral steroids (OSs)], antiarrhythmics, antidepressants (fluoxetine), benzodiazepines (alprazolam, fludiazepam), statins and antihypertensive drugs (diuretics, cardioselective beta blockers, calcium channel blockers (CCBs) and angiotensin converting enzyme inhibitors (ACEi), angiotensin II blockers)}.ResultsCompared with the non-BCAS cohort, the BCAS cohort taking LABAs, SABAs, SAMAs, ICSs, OSs, antiarrhythmics, and alprazolam had an elevated HDS risk [aHRs (95% CIs): 2.36 (1.25–4.33), 2.65 (1.87–3.75), 2.66 (1.74–4.05), 2.53 (1.61–3.99), 1.76 (1.43–2.18), 9.88 (3.27–30.5), and 1.73 (1.15–2.58), respectively except fludiazepam 1.33 (0.73–2.40)]. The aHRs (95% CIs) for LABAs ≤ 30 days, DDDs 30 DDDs, fludiazepam >20 DDDs, ICSs ≦415 DDDs, and OSs DDDs ≦15 were 1.60 (0.78–3.29), 2.43 (0.90–6.55), 5.02 (1.76–14.3), and 2.28 (1.43–3.62), respectively.ConclusionThe bronchodilators, steroids, and antiarrhythmics were associated with higher risk of HDS, even low dose use of steroids. However, the current use of LABAs/ICSs were not associated with HDS. Benzodiazepines were relatively safe, except for current or recent alprazolam use. Notably, taking confounders into account is crucial in observational studies.

Objective: To evaluate the association between radiation exposure from repeated nuclear medicine (NM) examinations and the subsequent risk of neoplasm in pediatric patients.Methods: From 2000 to 2017, participants under 18 years of age who underwent NM scanning were identified using the Health and Welfare Data Science Center (HWDC) dataset, which was extracted from the Taiwan National Health Insurance Research Database (NHIRD). Both the exposed cohort and unexposed subjects were followed up with until the presence of any malignancy arose, including malignant brain, lymphoid and hematopoietic tumors and benign brain or other central nervous tumors.Results: There were 35,292 patients in the exposed cohort and 141,152 matched subjects in the non-exposed group. The exposed cohort had an overall higher IR (IR: incidence rate, per 100,000 person-years) of any malignancy and benign central nervous tumor than the non-exposed group [IR, 16.9 vs. 1.54; adjusted hazard ratio (HR), 10.9; 95% CI, 6.53–18.2]. Further stratifying the number of NM examinations into 1-2, 3-4, and 5 or more times revealed that the IR of pediatric neoplasms increased gradually with the increased frequency of NM examinations (IR, 11.5; adjusted HR, 7.5; 95% CI, 4.29–13.1; IR, 25.8; adjusted HR, 15.9; 95% CI, 7.00–36.1; IR, 93.8; adjusted HR, 56.4; 95% CI, 28.8–110.3).Conclusion: NM examination is significantly associated with a higher risk of pediatric neoplasms, according to our population-based data. Thorough radiation protection and dose reduction in pediatric NM procedures should be an issue of concern.

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.

Objective: To assess the association of type 1 diabetes (T1DM) and type 2 diabetes (T2DM) with the subsequent development of gallbladder stone disease (GSD).Setting: Cohort Study.Participants: We identified two study cohort groups to evaluate the association of T1DM and T2DM with the development of GSD. The first group comprised a T1DM cohort of 7015 patients aged ≤ 40 years and a non-diabetes cohort randomly matched with the study cohort (4:1). The second group comprised a T2DM cohort of 51,689 patients aged ≥20 years and a non-diabetes cohort randomly matched with the study cohort (1:1). All patients were studied from 1996 to the end of 2011 or withdrawal from the National Health Insurance program to determine the incidence of GSD.Results: Compared with patients without diabetes, those with T1DM had a decreased risk of GSD [adjusted hazard ratios (aHR) = 0.48, 95% confidence interval (CI) = 0.25–0.92]. Those with T2DM had an increased risk of GSD (aHR = 1.55, 95% CI = 1.41–1.69), after adjustment for age, sex, comorbidities, and number of parity. The relative risk of GSD in the T2DM cohort was higher than that in the non-diabetes cohort in each group of age, sex, and patients with or without comorbidity. However, the relative risk of GSD in the T1DM cohort was lower than that in the non-diabetes cohort only in the age group of 20–40 years.Conclusion: Our population-based cohort study reveals a strong association between T2DM and GSD. However, an inverse relationship exists between T1DM and GSD in patients aged 20–40 years.