Impact on carbamazepine usage and cutaneous adverse reactions before and after the reimbursement of HLA-B*1502 genotyping in Taiwan, 2000-2017: A nationwide longitudinal study.

OBJECTIVE: The HLA-B*1502 allele is strongly associated with carbamazepine (CBZ)-induced Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) in the Han Chinese population. This study investigated the impact of HLA-B*1502 screening on CBZ utilization and rates of severe cutaneous allergic reactions (SCARs) and SJS/TEN over time in Taiwan, where screening for HLA-B*1502 genotyping before prescribing CBZ was reimbursed in June 2010. METHODS: Using the Taiwan National Health Insurance Research Database, we analyzed 13 277 457 episodes of seeking treatment for epilepsy or neuralgia between 2000 and 2017. Episodes were categorized into quarters based on treatment time. Propensity score-based stabilized weighting (PSSW) ensured well-balanced covariates. The difference in 3-month SCAR and SJS/TEN rates between phase 2 (2011-2017) and phase 1 (2000-2009) was examined using a one-sample Z-test. Pearson correlation coefficients assessed the association between screening rate, the number of CBZ users and nonusers, and SCAR and SJS/TEN rates after HLA-B*1502 genotyping. RESULTS: CBZ prescriptions reduced from 7% (2000-2003) to 6% (2004-2010) and 4% (2011-2017). The screening rates of CBZ nonusers and CBZ users increased from 0%, .5% in 2011 to .8%, 16% in 2017, respectively. After PSSW, the mean 3-month SCAR incidence rates (per 10 000 episodes) significantly decreased from phase 1 to phase 2 for CBZ users (6.91 vs. 3.09, p < .0001) and nonusers (1.96 vs. 1.65, p < .0001). SJS/TEN incidence rates (per 10 000 episodes) significantly decreased from phase 1 to phase 2 for CBZ users (2.94 vs. 1.93, p < .0001) but not for nonusers (.71 vs. .74, p = .1492). In phase 2, SCAR incidence rates were significantly and negatively correlated with the screening rate for both CBZ users (r = -.38, p = .0342) and nonusers (r = -.80, p < .001). No significant correlation was found between SJS/TEN incidence rates and screening rates. SIGNIFICANCE: Recognizing HLA-B*1502 allele and avoiding CBZ therapy in HLA-B*1502-positive patients is critical for preventing CBZ-induced severe adverse events.

Clinical Outcomes in Atrial Fibrillation Patients With a History of Cancer Treated With Non-Vitamin K Antagonist Oral Anticoagulants: A Nationwide Cohort Study.

Background and Purpose: Data on clinical outcomes for nonvitamin K antagonist oral anticoagulant (NOACs) and warfarin in patients with atrial fibrillation and cancer are limited, and patients with active cancer were excluded from randomized trials. We investigated the effectiveness and safety for NOACs versus warfarin among patients with atrial fibrillation with cancer. Methods: In this nationwide retrospective cohort study from Taiwan National Health Insurance Research Database, we identified a total of 6274 and 1681 consecutive patients with atrial fibrillation with cancer taking NOACs and warfarin from June 1, 2012, to December 31, 2017, respectively. Propensity score stabilized weighting was used to balance covariates across study groups. Results: There were 1031, 1758, 411, and 3074 patients treated with apixaban, dabigatran, edoxaban, and rivaroxaban, respectively. After propensity score stabilized weighting, NOAC was associated with a lower risk of major adverse cardiovascular events (hazard ratio, 0.63 [95% CI, 0.50­0.80]; P=0.0001), major adverse limb events (hazard ratio, 0.41 [95% CI, 0.24­0.70]; P=0.0010), venous thrombosis (hazard ratio, 0.37 [95% CI, 0.23­0.61]; P<0.0001), and major bleeding (hazard ratio, 0.73 [95% CI, 0.56­0.94]; P=0.0171) compared with warfarin. The outcomes were consistent with either direct thrombin inhibitor (dabigatran) or factor Xa inhibitor (apixaban, edoxaban, and rivaroxaban) use, among patients with stroke history, and among patients with different type of cancer and local, regional, or metastatic stage of cancer (P interaction >0.05). When compared with warfarin, NOAC was associated with lower risk of major adverse cardiovascular event, and venous thrombosis in patients aged <75 but not in those aged ≥75 years (P interaction <0.05). Conclusions: Thromboprophylaxis with NOACs rather than warfarin should be considered for the majority of the atrial fibrillation population with cancer.

Gonadotropin-releasing hormone antagonist associated with lower cardiovascular risk compared with gonadotropin-releasing hormone agonist in prostate cancer: A nationwide cohort and in vitro study.

BACKGROUND: We aimed to determine whether cardiovascular (CV) risk in patients with prostate cancer (PCa) differs between those who receive gonadotropin-releasing hormone (GnRH) agonist (GnRHa) therapy and those who receive GnRH antagonist therapy. METHODS: Using the Taiwan National Health Insurance Research Database, we analyzed data by comparing 666 participants receiving GnRH antagonists and 1332 propensity score-matched participants treated with GnRHa in a 1:2 fashion during the period from May 1, 2015, to September 30, 2018. Cox proportional-hazards models were used to estimate the treatment effect on CV outcomes. Furthermore, we conducted an in vitro study to investigate the effect of a GnRHa (leuprolide) or a GnRH antagonist (degarelix) on matrix metalloproteinase-9 (MMP-9) expression and invasion ability in THP-1 differentiated macrophages. RESULTS: GnRH antagonist therapy was associated with a lower risk of composite CV events of myocardial infarction, ischemic stroke, or CV death (hazard ratio [HR], 0.48; 95% confidence interval [CI], 0.25-0.90) than GnRHa therapy, with a mean follow-up period of 1.21 years. Significantly lower risks of CV death (HR, 0.21; 95% CI, 0.06-0.70) and all-cause mortality (HR, 0.77; 95% CI, 0.61-0.97) were observed in the GnRH antagonist group. In the in vitro study, leuprolide, but not degarelix, significantly increased the expression of MMP-9 activity and the invasive ability of THP-1 differentiated macrophages through gelatin zymography and the matrix invasion assay, respectively. CONCLUSION: GnRH antagonists were associated with reduced risk CV events compared with the GnRHa among patients with PCa, which may be through effects on macrophages.

Effectiveness and Safety of Direct Oral Anticoagulants in an Asian Population with Atrial Fibrillation Undergoing Dialysis: A Population-Based Cohort Study and Meta-Analysis.

PURPOSE: Whether direct oral anticoagulants (DOACs) are more effective and safer than warfarin among Asian patients with non-valvular atrial fibrillation (NVAF) undergoing dialysis remains unclear. METHODS: We first compared the risks of ischemic stroke/systemic embolism (IS/SE) and major bleeding associated with DOACs compared with warfarin, in NVAF Asians undergoing dialysis using the Taiwan National Health Insurance Research Database (NHIRD) (Aim 1). Next, we searched PubMed and Medline from January 1, 2010 until January 31, 2020, to perform a systematic review and meta-analysis of all observational real-world studies comparing DOACs with warfarin specifically focused on NVAF patients with stage 4 or 5 chronic kidney disease undergoing dialysis (Aim 2). Finally, we tested the hypothesis whether AF patients undergoing dialysis treated with OACs (warfarin and DOACs) would be associated with lower risk of adverse clinical outcomes as compared to those without OACs using the Taiwan NHIRD (Aim 3). RESULTS: From June 1, 2012, to December 31, 2017, a total of 3237 and 9263 NVAF patients comorbid with ESRD receiving oral anticoagulant (OACs) (490 on DOAC, 2747 on warfarin) or no OACs, respectively, were enrolled. Propensity score matching was used to balance covariates across the study groups. For the comparison of DOAC vs. warfarin (Aim 1), DOACs had comparable risks of IS/SE and major bleeding to warfarin in our present cohort. From the original 85 results retrieved, nine studies (including our study) with a total of 6490 and 22,494 patients treated with DOACs and warfarin were included in the meta-analysis, respectively. There were 5343 (82%) and 20,337 (90%) patients treated with DOACs and warfarin undergoing dialysis, respectively. The pooled meta-analysis also indicated no difference of the effectiveness (HR:0.90; [95%CI:0.74-1.10]; P = 0.32) and safety outcomes (HR:0.75; [95%CI:0.54-1.05]; P = 0.09) between DOACs and warfarin (Aim 2). For the comparison of OAC (+) vs. OAC (-) (Aim 3), OAC-treatment was associated with a higher risk of IS/SE (hazard ratio (HR):1.54; [95% confidential interval (CI):1.29-1.84];P < 0.0001) and comparable risk of major bleeding compared to those without OAC treatment. CONCLUSIONS: DOACs did not provide benefit over warfarin regarding effectiveness and safety in AF patients undergoing dialysis. The use of OAC was not associated with a lower risk of IS/SE in ESRD AF patients when compared to those without OAC use.

[Construction of yeast cell factories for production of azadirachtin precursor tirucalla-7,24-dien-3ß-ol].

Azadirachtin, as a botanical insecticide, is a highly oxidized limonoid triterpenoid existing in the seeds of Azadirachta indica. However, due to the low content in the seeds, the production of azadirachtin by seed extraction has low yield. Chemical synthesis of azadirachtin is characterized by complex process and low yield. Synthetic biology provides an alternative for the supply of azadirach-tin. In this study, two oxidosqualene cyclases AiOSC1 and MaOSC1 respectively derived from A. indica and Melia azedarach were identified in yeast. A yeast strain producing tirucalla-7,24-dien-3ß-ol was constructed by integration of AiOSC1, Arabidopsis thaliana-derived squalene synthase gene(AtAQS2), and Saccharomyces cerevisiae-derived truncated 3-hydroxy-3-methyl-glutaryl coenzyme A reductase gene(PgtHMGR) into the delta site of yeast. Then, the function of MaCYP71BQ5 was successfully verified in yeast after this gene was introduced into the constructed yeast strain. This study not only laid a foundation for the biosynthesis of tirucalla-7,24-dien-3ß-ol, but also provided a chassis cell for the functional identification of cytochrome oxidases(CYP450 s) in azadirachtin biosynthesis pathway.

Major adverse cardiovascular and limb events in patients with diabetes and concomitant peripheral artery disease treated with sodium glucose cotransporter 2 inhibitor versus dipeptidyl peptidase-4 inhibitor.

BACKGROUND: Whether sodium glucose co-transporter 2 inhibitors (SGLT2i) are associated with a lower risk of cardiovascular as well as adverse lower limb events in patients with type-2 diabetes mellitus (T2DM) and concomitant peripheral artery disease (PAD) is unclear. We aimed to evaluate the risk of cardiovascular and limb events, and death associated with the use of SGLT2i compared with dipeptidyl peptidase-4 inhibitors (DPP4i) among a longitudinal and national cohort of patients with T2DM. METHODS: In this nationwide retrospective cohort study based on the Taiwan National Health Insurance Research Database, we identified a total of 11,431 and 93,972 consecutive T2DM patients with PAD taking SGLT2i and DPP4i, respectively, from May 1, 2016, to December 31, 2017. We used 1:1 propensity score matching (PSM) to balance covariates across study groups. Patients were followed from the drug index date until the occurrence of clinical outcomes, death, discontinuation of the index drug, or the end of the study period, whichever occurred first. RESULTS: Overall, 56% and 44% of the patients were treated with dapagliflozin and empagliflozin, respectively. The use of SGLT2i had comparable risks of ischemic stroke and acute myocardial infarction, and was associated with lower risks of congestive heart failure (CHF) [hazard ratio (HR): 0.66; 95% confidence interval (CI) 0.49-0.89; p = 0.0062], lower limb ischemia requiring revascularization (HR: 0.73; 95% CI 0.54-0.98; p = 0.0367) or amputation (HR: 0.43; 95% CI 0.30-0.62; p < 0.0001), and cardiovascular death (HR: 0.67; 95% CI 0.49-0.90; p = 0.0089) when compared with the DDP4i group after PSM. The subgroup analysis revealed consistent results for CHF and major adverse limb outcomes for SGLT2i versus DPP4i among patients aged ≥ 75 years, the presence of chronic kidney disease and established cardiovascular disease was consistent with the main analysis. CONCLUSIONS: SGLT2i were associated with lower risks of CHF and adverse lower limb events compared with DPP4i among patients with T2DM and PAD in real-world practice.

Effectiveness, safety, and major adverse limb events in atrial fibrillation patients with concomitant diabetes mellitus treated with non-vitamin K antagonist oral anticoagulants.

BACKGROUND: Evidence of adverse clinical outcomes for non-vitamin K antagonist oral anticoagulant (NOACs) and warfarin in patients with atrial fibrillation (AF) and diabetes mellitus are limited. We investigated the effectiveness, safety, and major adverse limb events for NOACs versus warfarin among diabetic AF patients. METHODS: In this nationwide retrospective cohort study collected from Taiwan National Health Insurance Research Database, we identified a total of 20,967 and 5812 consecutive AF patients with diabetes taking NOACs and warfarin from June 1, 2012, to December 31, 2017, respectively. We used propensity-score stabilized weighting to balance covariates across study groups. RESULTS: NOAC was associated with a lower risk of major adverse cardiovascular events (MACE) (adjusted hazard ratio (aHR):0.88; [95% confidential interval (CI) 0.78-0.99]; P = 0.0283), major adverse limb events (MALE) (aHR:0.72;[95% CI 0.57-0.92]; P = 0.0083), and major bleeding (aHR:0.67;[95% CI 0.59-0.76]; P < 0.0001) compared to warfarin. NOACs decreased MACE in patients of ≥ 75 but not in those aged < 75 years (P interaction = 0.01), and in patients with ischemic heart disease (IHD) compared to those without IHD (P interaction < 0.01). For major adverse limb events, the advantage of risk reduction for NOAC over warfarin persisted in high risk subgroups including age ≥ 75 years, chronic kidney disease, IHD, peripheral artery disease, or use of concomitant antiplatelet drugs. CONCLUSION: Among diabetic AF patients, NOACs were associated with a lower risk of thromboembolism, major bleeding, and major adverse limb events than warfarin. Thromboprophylaxis with NOACs should be considered in the diabetic AF population with a high atherosclerotic burden.

Association of maternal ethnicity and urbanicity on severe pediatric disease: a nationwide cohort study.

BACKGROUND: A healthy migrant effect on birth outcomes has been reported, however, whether this protective effect persists throughout childhood is unknown. The effect of urbanicity on child health among an immigrant population is unclear. The objective of this study was to compare the incidence rate and cumulative incidence of severe diseases among urban children of Taiwan-born mothers, rural children of Taiwan-born mothers, urban children of foreign-born mothers, and rural children of foreign-born mothers. METHODS: A nationwide cohort study was conducted for children born in Taiwan during 2004-2011 and follow-up till age 4 to 11 years old by linkage the Taiwan Birth Registry 2004-2011, Taiwan Death Registry 2004-2015, and National Health Insurance Research Database 2004-2015. Cox proportional hazards model (multivariable) was used to examine differences among the four study groups. RESULTS: There were 682,982 urban children of Taiwan-born mothers, 662,818 rural children of Taiwan-born mothers, 61,570 urban children of foreign-born mothers, 87,473 rural children of foreign-born mothers. Children of foreign-born mothers had a lower incidence of vasculitis, mainly Kawasaki disease. The incidences of congenital disorders did not differ between children of foreign-born mothers and children of Taiwan-born mothers. The incidence of psychotic disorders was higher in urban children. However, children in rural areas had a higher incidence of major trauma/burn and a higher mortality rate. CONCLUSIONS: A healthy migrant effect was only seen for Kawasaki disease. The mental health of urban children born to immigrant mothers warrants concern.

End-stage renal disease patients using angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may reduce the risk of mortality: a Taiwanese Nationwide cohort study.

BACKGROUND: The association between the use of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) and mortality in end-stage renal disease (ESRD) patients lacks sufficient evidence. AIM: To investigate the efficacy of ACEI and ARB in ESRD patients. METHODS: This nationwide retrospective cohort study using data from the Taiwan National Health Insurance Research Database enrolled ESRD patients from January 1997 to December 2011. Propensity score matching provided two study groups (ACEI/ARB users vs non-users), balanced in sample size, with similar comorbidities and prescriptions. These patients were followed up from the first date of receiving dialysis until mortality, 5 years or 31 December 2013 (whichever came first). We analysed the association of the use of ACEI or ARB with cardiovascular (CV) death and all-cause mortality in patients with ESRD using the Kaplan-Meier method and time-dependent Cox models, with a robust sandwich variance method. RESULTS: After propensity score matching, all characteristics of the user of ACEI or ARB (n = 17 280) and non-user (n = 17 280) groups were appropriately balanced (P > 0.05). In the Cox proportional hazards model, the user group exhibited lower CV death and all-cause mortality with adjusted hazard ratios and 95% CI of 0.58 (0.55-0.62) and 0.47 (0.46-0.49) than the non-user group did. Furthermore, the association of ACEI/ARB use with low mortality risk was observed in all examined subgroups. CONCLUSION: In this large-scale, population-based cohort study, ESRD patients using ACEI/ARB had a lower risk of CV death and all-cause mortality than non-users did.

Dipeptidyl peptidase-4 inhibitor decreases the risk of atrial fibrillation in patients with type 2 diabetes: a nationwide cohort study in Taiwan.

BACKGROUND: Whether dipeptidyl peptidase-4 inhibitor (DPP4i) is associated with a lower risk of new-onset atrial fibrillation (AF) in patients with diabetes remains unclear. This study aimed to evaluate the risk of AF associated with use of DPP4i among a longitudinal cohort of patients with diabetes. METHODS: Over a 3-year period, 480,000 patients with diabetes were analyzed utilizing Taiwan's National Health Insurance Research Database and 90,880 patients taking metformin as first-line therapy were enrolled. Patients were further divided into two groups: (1) DPP4i users: those taking DPP4i and (2) non-DPP4i users: those prescribed other hypoglycemic agents (HAs) as second-line drug. Study end point was defined by diagnosis of AF, addition of any third-line HA, or the end of the study period (December 31, 2013), whichever came first. RESULTS: A total of 16,017 DPP4i users and 74,863 non-DPP4i users were eligible for the study. For the DPP4i group, most patients were prescribed sitagliptin (n = 12,180; 76%). Among the non-DPP4i group, most patients took sulfonylurea (n = 60,606; 81%) as their second-line medication. DPP4i users were associated with a lower risk of new-onset AF compared with non-DPP4i users after propensity-score weighting (hazard ratio 0.65; P < 0.0001). Subgroup analysis showed that DPP4i user were associated with a lower risk of new-onset AF compared with non-DPP4i users in most subgroups. Multivariate analysis indicated that use of DPP4i was associated with lower risk of new-onset AF and age > 65 years, presence of hypertension, and ischemic heart disease were independent risk factors for new-onset AF. CONCLUSIONS: Among patients with diabetes prescribed with metformin, the patients with DPP4i as second HA were associated with a lower risk of AF compared with the patients with other drugs as second HAs in real-world practice.

A comparison between angiotensin converting enzyme inhibitors and angiotensin receptor blockers on end stage renal disease and major adverse cardiovascular events in diabetic patients: a population-based dynamic cohort study in Taiwan.

BACKGROUND: Contemporary guidelines recommend angiotensin-converting-enzyme inhibitors (ACEi) or angiotensin-receptor blockers (ARB) for hypertensive patients with diabetes. However, there is limited data to evaluate the comparison between ACEi and ARB on end stage renal disease (ESRD) and major adverse cardiovascular events (MACE), in Asian diabetic patients. METHODS: We used the Taiwan Longitudinal Cohort of Diabetes Patients Database to perform a population-based dynamic cohort study. The comparison between ACEi and ARB on ESRD and MACE in diabetic patients was examined using the propensity score weighting method. We followed these patients until the occurrence of first study outcomes or end date of the study, whichever came first. RESULTS: There were 6898 and 12,758 patients in ACEi and ARB groups, respectively. The mean follow-up period was about 3.5 years in ESRD and 2.5 years in MACE. The incidence of ESRD was 0.44 % and 0.63 % per person-years in the ACEi and ARB group, respectively. The risk of ESRD was lower in the ACEi group than the ARB group [hazard ratio (HR) 0.69; 95 % confidence interval (CI) 0.54-0.88, P = 0.0025]. Among those without chronic kidney disease (CKD), the incidence of ESRD was 0.30 % and 0.37 % per person-years in the ACEi and ARB group, respectively. ACEi was similar to ARB in preventing ESRD for those without CKD (P = 0.11). Among those with CKD, the incidence of ESRD was 1.39 % and 2.34 % per person-years in the ACEi and ARB group, respectively. The ACEi group had a lower risk of ESRD than the ARB group (HR 0.61; 95 % CI 0.42-0.88, P = 0.008). The incidence of MACE was 9.33 % and 9.62 % per person-years in the ACEi and ARB group, respectively. There was no significant difference in the composite MACE outcome between the two groups (P = 0.42), but the ACEi group was associated with a higher risk of stroke than the ARB group (HR 1.12; 95 % CI 1.02-1.24, P = 0.02). CONCLUSIONS: ACEi compared with ARB was associated with a lower incidence of ESRD, especially in those with CKD. Though ACEi and ARB had a similar risk of composite MACE outcome, ACEi had a slightly higher incidence of stroke than ARB, among the Asian diabetic patients.

The Trend of Inflammatory Bowel Diseases in Taiwan: A Population-Based Study.

BACKGROUND AND AIM: The purpose of this study was to estimate the sex- and age-specific incidence rates of inflammatory bowel diseases (IBD) in Taiwan. Site-specific cancer occurred in patients with IBD would be reported, too. METHODS: A retrospective study by analyzing the data from the National Health Insurance Research Database of Taiwan. RESULTS: Between 2000 and 2010, the overall incidence rate of Crohn's disease (CD) and ulcerative colitis (UC) was 0.208 and 0.838 per 100,000 person-years. For male, the incidence rate of CD was 0.195 (95 % CI 0.113-0.276) per 100,000 persons in 2000 and increased to 0.318 (95 % CI 0.216-0.421) per 100,000 persons in 2010. For female, the incidence rate of CD was 0.092 (95 % CI 0.035-0.149) per 100,000 persons in 2000 and increased to 0.210 (95 % CI 0.128-0.293) per 100,000 persons in 2010. For male, the incidence rate of UC was 0.690 (95 % CI 0.537-0.843) per 100,000 persons in 2000 and increased to 1.351 (95 % CI, 1.140-1.562) per 100,000 persons in 2010. For female, the incidence rate of UC was 0.386 (95 % CI 0.269-0.503) per 100,000 persons in 2000 and increased to 0.858 (95 % CI 0.691-1.024) per 100,000 persons in 2010. Among the CD patients, 0.19 % had colorectal cancers (1/519). Among the UC patients, 0.24 % had colorectal cancers (5/2098). CONCLUSIONS: This nationwide population-based longitudinal epidemiological study of IBD in Taiwan provides data for future global comparisons.

Association of metformin with lower atrial fibrillation risk among patients with type 2 diabetes mellitus: a population-based dynamic cohort and in vitro studies.

BACKGROUND: Atrial fibrillation (AF), an inflammatory process involving arrhythmia, is associated with severe morbidity and mortality and commonly seen in patients with diabetes mellitus (DM). The effect of metformin, the most commonly used medication for patients with DM, on AF has not been investigated. The primary aim of this study was to examine whether metformin prevented the occurrence of AF in type 2 DM patients by analyzing a nationwide, population-based dynamic cohort. Additionally, we investigated the effect of metformin on tachycardia-induced myolysis and oxidative stress in atrial cells. METHODS: The study population included 645,710 patients with type 2 diabetes and not using other anti-diabetic medication from a subset of the Taiwan National Health Insurance Research Database. Of these patients, those who used metformin were categorized as the user group, and the remaining were classified as the non-user group. The time-dependent Cox's proportional hazard model was used to examine the effect of metformin on AF and the status of metformin use was treated as a time-dependent covariate. HL-1 atrial cells were paced with or without metformin, and then troponin and heavy-chain-myosin were measured as markers of myolysis. RESULTS: After 13 years of follow-up, 9,983 patients developed AF with an incidence rate of 1.5% (287 per 100,000 person-years). After adjusting for co-morbidities and medications, metformin independently protected the diabetic patients from new-onset AF with a hazard ratio of .81 (95% confidence interval 0.76-0.86, p < 0.0001). Metformin significantly decreased the extent of pacing-induced myolysis and the production of reactive oxygen species. CONCLUSION: Metformin use was associated with a decreased risk of AF in patients with type 2 DM who were not using other anti-diabetic medication, probably via attenuation of atrial cell tachycardia-induced myolysis and oxidative stress.

First-year outcomes of very low birth weight preterm singleton infants with hypoxemic respiratory failure treated with milrinone and inhaled nitric oxide (iNO) compared to iNO alone: A nationwide retrospective study.

BACKGROUND: Inhaled nitric oxide (iNO) has a beneficial effect on hypoxemic respiratory failure. The increased use of concurrent iNO and milrinone was observed. We aimed to report the trends of iNO use in the past 15 years in Taiwan and compare the first-year outcomes of combining iNO and milrinone to the iNO alone in very low birth weight preterm (VLBWP) infants under mechanical ventilation. METHODS: This nationwide cohort study enrolled preterm singleton infants with birth weight <1500g treated with iNO from 2004 to 2019. Infants were divided into two groups, with a combination of intravenous milrinone (Group 2, n = 166) and without milrinone (Group 1, n = 591). After propensity score matching (PSM), each group's sample size is 124. The primary outcomes were all-cause mortality and the respiratory condition, including ventilator use and duration. The secondary outcomes were preterm morbidities within one year after birth. RESULTS: After PSM, more infants in Group 2 needed inotropes. The mortality rate was significantly higher in Group 2 than in Group 1 from one month after birth till 1 year of age (55.1% vs. 13.5%) with the adjusted hazard ratio of 4.25 (95%CI = 2.42-7.47, p <0.001). For infants who died before 36 weeks of postmenstrual age (PMA), Group 2 had longer hospital stays compared to Group 1. For infants who survived after 36 weeks PMA, the incidence of moderate and severe bronchopulmonary dysplasia (BPD) was significantly higher in Group 2 than in Group 1. For infants who survived until one year of age, the incidence of pneumonia was significantly higher in Group 2 (28.30%) compared to Group 1 (12.62%) (p = 0.0153). CONCLUSION: Combined treatment of iNO and milrinone is increasingly applied in VLBWP infants in Taiwan. This retrospective study did not support the benefits of combining iNO and milrinone on one-year survival and BPD prevention. A future prospective study is warranted.

Effect of febuxostat on adverse events and mortality in gout in Taiwan: An interrupted time series analysis.

OBJECTIVES: To evaluate the influence of febuxostat on adverse events and mortality in gout. METHODS: We retrospectively enrolled patients with newly diagnosed gout and prescribed urate-lowering therapy between 2006 and 2017 from the Taiwan National Health Insurance Database. These patients were divided into 2 groups: with and without comorbidities (n = 294 847 and 194 539). An interrupted time series analysis with adjustments for demographics, comorbidities, and comedication by propensity score-based stabilized weights was used to compare the trend of adverse events and mortality before vs after febuxostat was introduced in 2012. RESULTS: The proportion of febuxostat use gradually increased from 0% in 2012 to 30% in those with comorbidities and 10% in those without comorbidities in 2017. Allopurinol use decreased from 30% in 2012 to 10% in 2017. The slope of the 1-year incidence rate of Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) (per 10 000 patients) significantly reduced after 2012 in those with and without comorbidities (-0.375 per quarter, P = .015 and -.253 per quarter, P = .049). The slope of the 3-year incidence rate of acute myocardial infarction (AMI) (per 1000 patients), percutaneous coronary intervention (PCI) (per 1000 patients), and all-cause mortality (per 100 patients) significantly increased after 2012 in those with comorbidities (+0.207 per quarter, P = .013; +.389 per quarter, P = .002; +.103 per quarter, P = .001). CONCLUSIONS: Febuxostat may reduce SJS and TEN in all gout patients but increase AMI, PCI, and all-cause mortality in gout patients with comorbidities.

Pioglitazone reduces cardiovascular events and dementia but increases bone fracture in elderly patients with type 2 diabetes mellitus: a national cohort study.

The prevalence of type 2 diabetes (T2DM) in elderly people has expanded rapidly. Considering cognitive impairment and being prone to hypoglycemia of the elder, the pros and cons of oral hypoglycemic agents (OHA) should be reassessed in this population. Pioglitazone might be appropriate for elderly DM patients because of its insulin-sensitizing effect and low risk of hypoglycemia. By using Taiwan's National Health Insurance Research Database, 191,937 types 2 diabetes patients aged ≥65 years under treatment between 2005 and 2013 were identified and further divided into two groups according to whether they received pioglitazone (pioglitazone group) or other OHAs (non-pioglitazone group) in the 3 months preceding their first outpatient visit date after 65 years of age, with a diagnosis of T2DM. Propensity score stabilization weight (PSSW) was used to balance the baseline characteristics. In results, the pioglitazone group (n = 17,388) exhibited a lower rate (per person-years) of major advanced cardiovascular events MACCE (2.76% vs. 3.03%, hazard ratio [HR]: 0.91, 95% confidence interval [CI]: 0.87-0.95), new- diagnosis dementia (1.32% vs. 1.46%, HR: 0.91, 95% CI: 0.84-0.98) but a higher rate of new-diagnosis bone fractures (5.37% vs. 4.47%, HR: 1.24, 95% CI: 1.19-1.28) than the non-pioglitazone group (n = 174,549). In conclusion, using pioglitazone may reduce the risks of MACCE and dementia but increases the probability of bone fractures in the elderly DM population.

Trends of adverse events and mortality after DMARDs in patients with rheumatoid arthritis: Interrupted time-series analysis.

OBJECTIVES: Patients with rheumatoid arthritis (RA) experience adverse events because of the characteristics of the disease and the side effects of medications. We investigated the trends of adverse events and mortality associated with disease-modifying antirheumatic drugs (DMARDs). METHODS: We used the Taiwan National Health Insurance Database to enroll patients with incident RA between 2000 and 2017. The 1-year incident rate of gastrointestinal (GI) bleeding and 3-year incident rates of other adverse events and mortality for each calendar-quarter cohort were computed and adjusted using propensity score-based stabilized weights for fair comparisons. Levels and trends of the conventional DMARD era (2000-2002, Phase 1) were compared with those of the TNFi era (2003-2012, Phase 2) and OMA era (2013-2017, Phase 3) by using interrupted time series (ITS) analysis. RESULTS: All patients with RA were prescribed cDMARDs in Phase 1 (2000-2002), and 1%-3% were prescribed either TNFi in phase 2 (2003-2012) or OMAs in phase 3 (2013-2017). The cancer incidence rate was 1.90%, and its mortality rate was 4.19%. After the introduction of TNFi from 2003 to 2012, the main outcomes, except TKA, exhibited a steady or mild decrease in trends. ITS analysis revealed that the slope mildly increased in 2003-2012 compared with that in 2000-2003 by 0.13% for total knee replacement (p = .0322). In 2012-2017 (the OMA era), the events became steady. CONCLUSION: In patients with RA, the introduction of DMARDs was associated with stable adverse events and mortality rates. Moreover, the introduced new treatment for RA exhibited a good safety profile.

Comparative safety of Janus kinase inhibitors and tumor necrosis factor inhibitors in patients undergoing treatment for rheumatoid arthritis.

OBJECTIVES: Since 2010, biological disease-modifying antirheumatic drugs (bDMARDs) have been the dominant mode of treatment for rheumatoid arthritis (RA). However, the safety of DMARDs, such as tumor necrosis factor inhibitors (TNFis) and Janus kinase inhibitors (JAKis), in treating patients with RA is a concern. We compared the safety outcomes of JAKis and TNFis in RA patients in clinical settings. METHODS: Patients diagnosed with RA between 2015 and 2017 were identified from the Taiwan National Health Insurance Research Database and followed till 2018. Propensity score stabilized weighting was used to balance the baseline characteristics of the JAKis and TNFis groups. The incidences of safety outcomes, namely cardiovascular (CV) events, tuberculosis (TB), total hip replacement (THR), total knee replacement (TKR), and all-cause mortality, were compared between the 2 study groups. RESULTS: A total of 3179 patients with RA who were administered JAKis (n = 822) and TNFis (n = 2357) were included in this study. The mean follow-up duration was 2.02 years in the JAKis group and 2.10 in the TNFis group. All-cause mortality had the highest incidence rate, followed by TKR, THR, CV events, and TB. A lower incidence rate of the study outcomes was observed in the JAKis group than in the TNFis group but without statistical significance. CONCLUSION: Comparable safety issues and mortality rates were observed for JAKis and TNFis in RA patients treated in real-world settings.

Sleep problems in preschool children at the child development center with different developmental status: A questionnaire survey.

Objective: To investigate the relationship between sleep problems and development in preschool children with suspected developmental delay. Methods: A total of 192 preschool children (mean age 4 years; 131 males, 61 females) were recruited from the Child Development Clinic, including 98 preterm children and 94 age- and sex-matched full-term children. All participants underwent evaluation of gross motor, fine motor and speech performance. All parents of all participants completed the Children's Sleep Habits Questionnaire (CSHQ). Some of the participants also underwent psychological evaluation. Correlation analysis and community network analysis were used to investigate the interactions. Results: The developmental status was: 75.5% developmental delay, 19.3% borderline development, and 5.2% normal development. Eighty-nine percent of the subjects had abnormal CSHQ scores. Age, gestational age, speech development, cognitive development, and socio-emotional development were significantly correlated with the CSHQ. Significant interactions between sleep problems and development were noted mostly in the preterm group. Conclusion: High prevalence of sleep disturbances in children at the Child Development Center was noted and associated with multiple factors. Therefore, during the multidisciplinary evaluation of children with possible developmental delay, inquiring about their sleep quality and habits is strongly recommended. Mitigating sleep problems enhances the efficacy of early intervention programs.

Major Adverse Cardiovascular Events in Patients With Renal Cell Carcinoma Treated With Targeted Therapies.

Background: The risk for major adverse cardiovascular events (MACE) with targeted therapies for patients with advanced renal cell carcinoma (RCC) in real-world practice remains unclear. Objectives: The aim of this study was to compare the risk for MACE associated with targeted cancer therapies with that associated with cytokine treatment in patients with advanced RCC. Methods: Using Taiwan's National Health Insurance Research Database, a retrospective nationwide cohort study was conducted involving patients with advanced RCC who had received targeted therapy (sunitinib, sorafenib, pazopanib, everolimus, or temsirolimus) or cytokine therapy (interleukin-2 or interferon gamma) from 2007 to 2018. Cox proportional hazards models were used to estimate the risk for MACE (a composite of myocardial infarction, ischemic stroke, heart failure, and cardiovascular death) in the cohort using the propensity score method of stabilized inverse probability of treatment weighting. Results: In this cohort of 2,785 patients with advanced RCC, 2,257 (81%) and 528 (19%) had received targeted and cytokine therapy, respectively. After stabilized inverse probability of treatment weighting, the incidence rates of MACE were 6.65 and 3.36 per 100 person-years in the targeted and cytokine therapy groups, respectively (HR: 1.80; 95% CI: 1.19-2.74). Baseline history of heart failure (HR: 3.88; 95% CI: 2.25-6.71), atrial fibrillation (HR: 3.60; 95% CI: 2.16-5.99), venous thromboembolism (HR: 2.50; 95% CI: 1.27-4.92), ischemic stroke (HR: 1.88; 95% CI: 1.14-3.11), and age ≥ 65 years (HR: 1.81; 95% CI: 1.27-2.58) were independent risk factors for targeted therapy-associated MACE. Conclusions: Among patients with advanced RCC, the risk for MACE associated with targeted cancer therapy is higher than that associated with cytokine therapy.