Trends of drug expenditure in Taiwan National Health Insurance before and during COVID-19 pandemic.

Background: The Taiwanese government adopted the National Health Insurance (NHI) system in March 1995. This study aimed to understand the difference in medication costs before (year 2019) and during the COVID-19 pandemic (2020-2021) among different hospitals for treating their patients. Methods: The NHI claims database consisting of claims of prescription drugs for inpatients (IPD) and outpatients (OPD) in Taiwan was used to determine drug expenditure in different hospitals, particularly the top 10 prescription Anatomical Therapeutic Chemical (ATC) categories. Results: In medical centers, L01X (other antineoplastic agents) showed the highest drug expenditure, followed by L04A (immunosuppressants) and J05A (direct-acting antivirals). The drug expenditure pattern in regional hospitals was similar to that in medical centers, with L01X (other antineoplastic agents) showing the highest drug expenditure. L01X (other antineoplastic agents) also showed the highest drug expenditure in district hospitals, followed by N05A (antipsychotics) and A10B (blood glucose-lowering drugs, excluding insulin). In clinics, A10B (blood glucose-lowering drugs, excluding insulin) showed the highest drug expenditure. The total medication costs in 2021 were lower or similar to those in 2019. The use of systemic use anti-infectives decreased over time in OPDs among all hospita1 levels but increased in IPDs in medical centers and district hospitals. Furthermore, our analysis revealed that the trend in drug expenditure closely mirrored the trend in drug prescription volume for the highest annual sum cost item among the top 10 drug subgroups across different hospital levels. Conclusion: Our analysis found that annual drug expenditures in 2021 were lower or similar to those in 2019, suggesting that the COVID-19 pandemic has contributed to this reduction in drug expenditure.

Healthcare utilization and expenditures in patients with tricuspid regurgitation: A population-based cohort study.

Background: Tricuspid regurgitation (TR) is the most common tricuspid valve (TV) condition. However, little is known about the prevalence, clinical significance, or economic impact of TR, including TR with comorbid heart failure (HF). Materials and Methods: Taiwan's National Health Insurance Research Database was used to perform a retrospective cohort study about patients with TR. The study included patients over the age of 18 with TR who provided data from January 2017 to December 2019. The cohorts were divided into six groups based on whether significant TR was present (sTR) or not (nsTR), and whether HF was present (HF) or not present (noHF), or inconclusive (incHF). Results: This study included 21,051 patients with TR. Patients with nsTR-noHF had an annualized healthcare burden of 0.36 all-cause hospitalizations, 3.26 days length of stay (LOS), and NTD 66,834 in expenses. sTR led to significant increases in healthcare utilization and expenditures. The annualized economic burden for sTR-noHF patients increased to 1.03 all-cause hospitalizations, 10.75 days LOS, and NTD 210,842 in expenses. Patients with sTR and HF had significantly higher healthcare utilization and expenditures; patients with sTR-HF had an annualized economic burden of 2.46 all-cause hospitalizations, 33.18 days LOS, and NTD 480,711 in spending. Conclusion: TR patients with HF or sTR are more likely to be hospitalized, use more healthcare resources, and face higher financial burdens.

Epidemiology of Hepatocellular Carcinoma in Taiwan.

BACKGROUND: Hepatocellular carcinoma (HCC) is a major contributor to the world's cancer burden. Understanding the HCC incidence rate in Taiwan is thus an interesting avenue of research. METHODS: From an NHI database, those patients who had been newly diagnosed with HCC and who had been listed on a registry in a catastrophic illness dataset during the years 2013-2021 were enrolled in this study. Antineoplastic agent usage and comorbidities were also studied. RESULTS: The incidence rate of HCC decreased from 57.77 to 44.95 in 100,000 from 2013 to 2021. The average age of patients with HCC increased from 65.54 years old with a CCI score of 4.98 in 2013 to 67.92 years old with a CCI score of 5.49 in 2021. Among these HCC patients, the patients under antineoplastic agent treatment decreased from 53.47% to 31.41% from 2013 to 2021. The presence of comorbidities in HCC patients was about 55.77-83.01% with mild liver disease and 29.93-37.30% with diabetes (without complications) in the period 2013-2021. CONCLUSIONS: The incidence rate of HCC slightly decreased in Taiwan. Due to antineoplastic agent usage decreasing over time, these results may indicate that more early-stage HCC patients detected in recent years were mainly treated with surgeries.

Psychiatric disorders in term-born children with marginally low birth weight: a population-based study.

BACKGROUND: Marginally low birth weight (MLBW) is defined as a birth weight of 2000 ~ 2499 g. Inconsistent findings have been reported on whether children with low birth weight had higher rates of neurological, attention, or cognitive symptoms. No studies have explored the occurrence of clinically diagnosed psychiatric disorders in term- born MLBW infants. We aimed to investigate the risk of subsequent psychiatric disorders in term-born children with MLBW. METHODS: This is a nationwide retrospective cohort study, by analysing the data from Taiwan's National Health Insurance Research Database from 2008 to 2018. The study population includes propensity-score-matched term-born infants with MLBW and those without MLBW (birth weight ≥ 2500 g). Cox proportional hazard analysis was used after adjustment for potential demographic and perinatal comorbidity confounders. Incidence rates and hazard ratios (HR) of 11 psychiatric clinical diagnoses were evaluated. RESULTS: A total of 53,276 term-born MLBW infants and 1,323,930 term-born infants without MLBW were included in the study. After propensity score matching for demographic variables and perinatal comorbidities, we determined that the term-born MLBW infants (n = 50,060) were more likely to have attention deficit and hyperactivity disorder (HR = 1.26, 95% confidence interval (CI) [1.20, 1.33]), autism spectrum disorder (HR = 1.26, 95% CI [1.14, 1.40]), conduct disorder (HR = 1.25, 95% CI [1.03, 1.51]), emotional disturbance (HR: = 1.13, 95% CI [1.02, 1.26]), or specific developmental delays (HR = 1.38, 95% CI [1.33, 1.43]) than term-born infants without MLBW (n = 50,060). CONCLUSION: MLBW was significantly associated with the risk of subsequent psychiatric disorder development among term-born infants. The study findings demonstrate that further attention to mental health and neurodevelopment issues may be necessary in term-born children with MLBW. However, possibilities of misclassification in exposures or outcomes, and risks of residual and unmeasured confounding should be concerned when interpreting our data.

Investigation of the Therapeutic Potential of Organic Nitrates in Mortality Reduction Following Acute Myocardial Infarction in Hyperlipidemia Patients: A Population-Based Cohort Study.

BACKGROUND: Dyslipidemia is a known risk factor for cardiac dysfunction, and lipid-lowering therapy with statins reduces symptoms and reduces hospitalization related to left ventricular heart failure. Acute myocardial infarction (AMI) is a cause of morbidity and mortality worldwide. In this study, we aimed to determine the real-world AMI treatment drug combination used in Taiwan by using the NHI database to understand the treatment outcomes of current clinical medications prescribed for hyperlipidemia patients with AMI. METHODS: Using the NHI Research Database (NHIRD), we conducted a retrospective cohort study that compared different treatments for AMI in hyperlipidemia patients in the period from 2016 to 2018. We compared the survival outcomes between those treated with and without organic nitrates in this cohort. RESULTS: We determined that most hyperlipidemia patients were aged 61-70 y (29.95-31.46% from 2016 to 2018), and the annual AMI risk in these patients was <1% (0.42-0.68% from 2016 to 2018). The majority of hyperlipidemia patients with AMI were women, and 25.64% were aged 61-70 y. Receiving organic nitrates was associated with lower all-cause mortality rates (HR, 95% CI, p-value = 0.714, 0.674-0.756, p < 0.0001). After multivariate analysis, the overall survival in four groups (beta-blockers, beta-blocker + diuretics, diuretics, and others) receiving an organic nitrate treatment was significantly higher than in the groups that were not treated with organic nitrates (beta-blockers HR = 0.536, beta-blocker + diuretics HR = 0.620, diuretics HR = 0.715, and others HR = 0.690). CONCLUSIONS: The survival benefit was significantly greater in patients treated with organic nitrates than in those treated without organic nitrates, especially when combined with diuretics. A combination of organic nitrates could be a better treatment option for hyperlipidemia patients with AMI.

S-Nitrosylation of Tissue Transglutaminase in Modulating Glycolysis, Oxidative Stress, and Inflammatory Responses in Normal and Indoxyl-Sulfate-Induced Endothelial Cells.

Circulating uremic toxin indoxyl sulfate (IS), endothelial cell (EC) dysfunction, and decreased nitric oxide (NO) bioavailability are found in chronic kidney disease patients. NO nitrosylates/denitrosylates a specific protein's cysteine residue(s), forming S-nitrosothios (SNOs), and the decreased NO bioavailability could interfere with NO-mediated signaling events. We were interested in investigating the underlying mechanism(s) of the reduced NO and how it would regulate the S-nitrosylation of tissue transglutaminase (TG2) and its substrates on glycolytic, redox and inflammatory responses in normal and IS-induced EC injury. TG2, a therapeutic target for fibrosis, has a Ca2+-dependent transamidase (TGase) that is modulated by S-nitrosylation. We found IS increased oxidative stress, reduced NADPH and GSH levels, and uncoupled eNOS to generate NO. Immunoblot analysis demonstrated the upregulation of an angiotensin-converting enzyme (ACE) and significant downregulation of the beneficial ACE2 isoform that could contribute to oxidative stress in IS-induced injury. An in situ TGase assay demonstrated IS-activated TG2/TGase aminylated eNOS, NFkB, IkBα, PKM2, G6PD, GAPDH, and fibronectin (FN), leading to caspases activation. Except for FN, TGase substrates were all differentially S-nitrosylated either with or without IS but were denitrosylated in the presence of a specific, irreversible TG2/TGase inhibitor ZDON, suggesting ZDON-bound TG2 was not effectively transnitrosylating to TG2/TGase substrates. The data suggest novel roles of TG2 in the aminylation of its substrates and could also potentially function as a Cys-to-Cys S-nitrosylase to exert NO's bioactivity to its substrates and modulate glycolysis, redox, and inflammation in normal and IS-induced EC injury.

Long-term survival and renal outcomes of thrombotic microangiopathy in pregnancy: A retrospective cohort study.

OBJECTIVE: Thrombotic microangiopathy (TMA) in pregnancy can rapidly progress, leading to severe morbidities. This study aimed to compare baseline demographics and clinical outcomes between pregnant women with and without TMA. METHODS: Using the National Health Insurance Research Database, 207 patients with pregnancy-related TMA from January 1, 2006 to December 31, 2015 were enrolled. Their data were compared with a 1:4 propensity score-matched cohort of 828 pregnant women without TMA to evaluate mortality and end-stage renal disease (ESRD) risks. Cox proportional hazards models were used to estimate the adjusted hazard ratio and 95% confidence intervals. RESULTS: A total of 1035 participants were included. The risks of mortality and ESRD were 4.46 and 5.97 times higher for the TMA cohort, respectively. Subgroup analysis revealed higher mortality and ESRD risks in patients with TMA aged >40 years with a history of hypertension, stroke, cancer, concomitant stroke, malignant hypertension, or gastroenterocolitis than in the matched cohort. CONCLUSION: Pregnant patients with TMA, especially those older and with comorbidities and organ involvement, faced increased mortality and ESRD risks. Physicians should collaborate with obstetricians throughout the prenatal and postpartum periods for these patients.

Respiratory Syncytial Virus Outbreak in Infants and Young Children during COVID-19 Pandemic in Taiwan.

Respiratory syncytial virus (RSV) is a major burden of disease in babies and young children, including hospitalizations and deaths. RSV is a seasonal disease that peaks when temperatures decrease in temperate zones and humidity increases in tropical regions. Existing research reveals that RSV hospitalization activity is year-round in Taiwan, which is a subtropical region with small peaks in spring and fall. The monthly distribution and COVID-19 pandemic impact were unclear. The aim of this study was to investigate Taiwan's RSV hospitalization seasonality and the COVID-19 pandemic effects. The National Health Insurance Database and Death Registration Files from the Center for Health and Welfare Data Science Center were connected to birth data for this study. RSV hospitalization (RSVH) in infants aged 0-1 years ranged from 0.9518% (2009) to 1.7113% (2020), substantially higher than in children aged 1-5. Most years had 2 or 3 RSV epidemic seasons in 0-5-year-olds over the 13-year follow-up. RSVH incidence was low until the autumn of 2020, when a major rise occurred after September and lasted until December 2020. We detected RSVH peaks in February-May and July-August. The 2020 RSV outbreak was found at the end of 2020.

Transcatheter aortic valve implantation vs. surgical aortic valve replacement for aortic stenosis in Taiwan: A population-based cohort study.

OBJECTIVE: Aortic stenosis (AS) is a heart valve disease characterized by left ventricular outflow fixed obstruction. It can be managed by surgical aortic valve replacement (SAVR) or transcatheter aortic valve implantation (TAVI). However, real-world evidence for TAVI or SAVR outcomes is lacking in Taiwan. This study aimed to compare the clinical outcomes of TAVI and SAVR for treating of AS in Taiwan. MATERIALS AND METHODS: The National Health Insurance Research Database is a nationally representative cohort that contains detailed registry and claims data from all 23 million residents of Taiwan. This retrospective cohort study used this database to compare patients who underwent SAVR (bioprosthetic valves) or TAVI from 2017 to 2019. Survival outcomes and length of hospital stay (LOS) and intensive care unit (ICU) stay between TAVI and SAVR in the matched cohort. A Cox proportional hazards model was performed to identify the effect of treatment type on survival rates while controlling variables including age, gender, and comorbidities. RESULTS: We identified 475 and 1605 patients who underwent TAVI and SAVR with a bioprosthetic valve, respectively. Patients who underwent TAVI were older (82.19 vs. 68.75 y/o) and more likely to be female (55.79% vs. 42.31%) compared with patients who underwent SAVR. Propensity score matching (PSM) on age, gender, and Elixhauser Comorbidity Index (ECI) score revealed that 375 patients who underwent TAVI were matched with patients who underwent SAVR. A significant difference was found in survival rates between TAVI and SAVR. The 1-year mortality rate was 11.44% with TAVI and 17.55% with SAVR. Both the mean total LOS (19.86 vs. 28.24 days) and mean ICU stay (6.47 vs. 11.12 days) for patients who underwent TAVI were shorter than those who underwent SAVR. CONCLUSION: Patients who had undergone TAVI had better survival outcomes and shorter LOS compared with patients who had undergone SAVR in Taiwan.

One-Year Healthcare Utilization and Expenditures Among Patients with Clinically Significant Mitral Regurgitation in Taiwan.

INTRODUCTION: Mitral regurgitation (MR) is characterized by systolic blood flow reversal from the left ventricle to the left atrium. A 2019 study indicated that in the USA, clinically significant MR (sMR) is associated with a substantial healthcare cost burden. In Taiwan, few data are available to describe the clinical characteristics, treatment patterns, and economic burden of patients with sMR. METHODS: Using the National Health Insurance Research Database (NHIRD), a national, detailed claims database of all 23 million residents of Taiwan, we conducted a retrospective cohort study to identify patients with sMR and quantify the impact of the disease on Taiwan's healthcare system. We classified patients with sMR into three cohorts based on disease etiology: functional MR (sFMR), degenerative MR (sDMR), and uncharacterized MR (sUMR). RESULTS: We compared patient characteristics across cohorts and estimated attributable healthcare utilization and costs during the 12-month follow-up period. Our research shows that in Taiwan, patients with sFMR were older, sicker, and presented at casualty (emergency department) more frequently than those with sDMR and sUMR. Meanwhile, patients with sDMR had the highest 12-month healthcare expenditures across the cohorts. CONCLUSION: These findings are inconsistent with what has been shown in the USA, which warrants further investigation.

Trends in pharmaceutical expenditure in the Taiwan National Health Insurance database at different hospital levels.

Aim: This study aimed to understand the medication usage among different hospitals in Taiwan. Materials & methods: The NHI claims database consisting of claims prescription drugs in Taiwan was used to determine drug prescriptions in different hospitals. Results: In the medical center, L01X showed the highest drug expenditure and the drug prescription pattern in regional hospitals was similar to that in the medical center. The highest drug expenditure in the district hospital and clinics was A10B. Conclusion: Our analysis suggests that the annual pharmaceutical expenditures from 2016 to 2018 were increasing over time in all hospitals. The generic drug usage in medical centers/regional hospitals was lower than district hospitals/clinics.

Acute and Subacute Toxicity of Fluorescent Gold Nanoclusters Conjugated with α-Lipoic Acid.

Fluorescent gold nanoclusters conjugated with α-lipoic acid (FANC) is a promising biocompatible fluorescent nanomaterial with a high potential for drug development. However, there is still no FANC-related research on toxicology, which is very important for future research and the development of healthy food supplements or drugs. This study uses oral administration of FANC to determine the most appropriate dose range in ICR mice for further evaluation. The in vivo acute and subacute toxicity study was conducted by oral administration of FANC to male and female ICR mice. Animal survival, body weight, daily food consumption, hematological profile, organ coefficient, serum biochemistry profile, and histopathological changes were analyzed. FANC did not show any form of morbidity or mortality at acute and subacute toxicity in both male and female ICR mice. Animal behavior, daily food consumption, hematological profile, organ coefficient, and histopathology showed no treatment-related malignant changes at single and repeated doses. Furthermore, serum glutamic-oxaloacetic transaminase (GOT), glutamic-pyruvic transaminase (GPT), lactate dehydrogenase (LDH), blood urea nitrogen (BUN), and creatinine (CRE) levels showed no significant malignant changes, which indicated that FANC does not cause liver and renal damage. The only change observed in this study was the change in body weight. The body weight of the FANC-treated group was slightly decreased in female mice but increased in male mice; however, the body weight decreases were below the threshold of concern, and there was no dose-response effect. In conclusion, no observed adverse effect level (NOAEL) in repeated doses was considered in 20 µM/100 µL/25 g male and female ICR mice.

4-Acetylantroquinonol B Suppresses Prostate Cancer Growth and Angiogenesis via a VEGF/PI3K/ERK/mTOR-Dependent Signaling Pathway in Subcutaneous Xenograft and In Vivo Angiogenesis Models.

Prostate cancer is a major cause of cancer-related mortality in men in developed countries. The compound, 4-acetylantroquinonol B (4AAQB), is isolated from Antrodia cinnamomea (commonly known as Niu-Chang-Chih), which has been shown to inhibit cancer growth. However, the anticancer activity of 4AAQB has not previously been examined in prostate cancer. This study aimed to investigate the effect of 4AAQB on cancer and angiogenesis, as well as to explore its mechanism of action. Human prostate cancer cells (PC3) and human umbilical vein endothelial cells (HUVEC) were used in cell viability, cell migration, and cell cycle functional assays to evaluate the anticancer and antiangiogenic efficacy of 4AAQB in vitro. The effects of 4AAQB in vivo were determined using xenograft and angiogenesis models. The signaling events downstream of 4AAQB were also examined. The 4AAQB compound inhibited PC3 cell growth and migration, and reduced in vivo cancer growth, as shown in a subcutaneous xenograft model. Furthermore, 4AAQB inhibited HUVEC migration, tube formation, and aortic ring sprouting; it also reduced neovascularization in a Matrigel implant angiogenesis assay in vivo. The 4AAQB compound also decreased metastasis in the PC3 prostate cancer model in vivo. Serum or vascular endothelial growth factor (VEGF)-induced VEGF receptor 2 (VEGFR2), phosphoinositide 3-kinase (PI3K)/Ak strain transforming (Akt), and extracellular signal-regulated kinase ½ (ERK ½) phosphorylation were attenuated by 4AAQB in both PC3 and HUVEC. In conclusion, 4AAQB is a potential candidate for prostate cancer therapy.

Atherosclerosis amelioration by allicin in raw garlic through gut microbiota and trimethylamine-N-oxide modulation.

Cardiovascular disease (CVD) is strongly associated with the gut microbiota and its metabolites, including trimethylamine-N-oxide (TMAO), formed from metaorganismal metabolism of ʟ-carnitine. Raw garlic juice, with allicin as its primary compound, exhibits considerable effects on the gut microbiota. This study validated the benefits of raw garlic juice against CVD risk via modulation of the gut microbiota and its metabolites. Allicin supplementation significantly decreased serum TMAO in ʟ-carnitine-fed C57BL/6 J mice, reduced aortic lesions, and altered the fecal microbiota in carnitine-induced, atherosclerosis-prone, apolipoprotein E-deficient (ApoE-/-) mice. In human subjects exhibiting high-TMAO production, raw garlic juice intake for a week reduced TMAO formation, improved gut microbial diversity, and increased the relative abundances of beneficial bacteria. In in vitro and ex vivo studies, raw garlic juice and allicin inhibited γ-butyrobetaine (γBB) and trimethylamine production by the gut microbiota. Thus, raw garlic juice and allicin can potentially prevent cardiovascular disease by decreasing TMAO production via gut microbiota modulation.

Epidemiology of Heart Valve Disease in Taiwan.

Studies conducted in developed nations have shown that increase in life expectancy has brought with it a rise in the incidence and treatment of degenerative aortic and mitral heart valve diseases. Current standards recommend valve replacement among even some asymptomatic patients. In this research, we examine the epidemiology of valvular heart disease and rate of valve replacement in Taiwan, where life expectancy now stands at 80.69 years. Patients were enrolled based on claims from a widely used national database and categorized into cohorts defined by type of valve disease and, further, by valve replacements and type of valve (mechanical, porcine, or bovine). Data, including disease type, age, and gender, were analyzed to determine annual and cumulative incidence rates and prosthetic usage from 2000 to 2017. Results showed that across the cohorts, the cumulative incidence rate in 2017 was 3.59%, and in the aortic valve cohort, the percentage of surgical valve replacement for those ≥60 years was 6.99%. Compared with other developed nations, this demonstrates that incidence rates are slightly higher, yet surgical replacements are less than half that of other developed nations. This under-treatment of patients with valvular heart disease presents an important public health challenge in Taiwan.

Clinical characteristics, triggering etiologies, and response of plasmapheresis in thrombotic microangiopathy in Taiwan.

ABSTRACT: Thrombotic microangiopathy (TMA) syndromes are extraordinarily diverse in clinical presentations and etiologies. However, there are still a limited number of large cohort studies focusing on the underlying causes, outcomes, and response to plasmapheresis.A retrospective study was designed to understand trigger etiologies, organ dysfunctions, clinical outcomes, and efficacy of plasmapheresis in patients with TMA. The whole population of Taiwan was set up into 2 cohorts: 875 patients with TMA in the 2006 cohort (2006-2010) and 1352 patients with TMA in the 2011 cohort (2011-2015). One hundred ninety-five patients in the 2006 cohort and 272 patients in the 2011 cohort were under plasmapheresis treatment.The common underlying etiologies were pregnancy, followed by systemic lupus erythematosus, rheumatoid arthritis, transplantation and drugs, which were significantly higher than the control group. Stroke, seizure, arterial thrombosis, vascular stenosis, hypertension, myocardial infarction, and pancreatitis were the main clinical signs and extra-renal involvements. In the multivariate regression analysis, stroke, arterial thrombosis, peripheral arterial disease, and uremia were significantly higher compared with the control group. The mortality rate in TMA under plasmapheresis was significantly higher than all TMA cases (39.33% vs 15.39% in the 2006 cohort and 39.27% vs 15.06% in the 2011 cohort).This study indicated the spectrum of underlying causes, extra-renal characteristics, and the response to plasmapheresis of patients with TMA in Taiwan. Of note, the poor clinical outcomes of plasmapheresis in patients with TMA might highlight the masked underlying etiology or worse disease condition that should be noticed.