Trends in dementia incidence and mortality, and dynamic changes in comorbidity and healthcare utilization from 2004 to 2017: A Taiwan national cohort study.

AIMS: This study aims to ascertain dementia incidence from 2004 to 2017 in Taiwan, and to examine the disease course in comorbidity, treatments, healthcare usage, and mortality among older people with incident dementia preceding the diagnosis of dementia and afterwards. METHODS: Taiwan National Health Insurance data on people aged ≥ 65 years with incident dementia from January 2004 to December 2017 were excerpted to estimate annual incidence rates and annualized percentage changes(APCs). For people diagnosed before 2013, annual mortality rates and causes of death during 5-years' follow-up were determined. Changes in 22 diseases/conditions, hospital visits and admissions, and psychotropic medication prescriptions commonly associated with dementia, were examined from 3 years preceding the index diagnosis until 5 years afterwards. RESULTS: From 2004 to 2017, the annual incidence of dementia in Taiwan increased from 30,606 to 50,651, and by > 90 % in women; age-standardized annual incidence increased significantly, with an APC of 0.4 %(p = 0.02). For 372,203 incident cases from 2004 to 2013, annual mortality was∼12 % during 5-years' follow-up. The prevalence of most comorbidities increased by 65-150 % after being diagnosed with dementia. People with incident dementia had increased healthcare usage 1 year before diagnosis, which peaked 1 year afterwards. Psychotropic medication prescriptions increased gradually over 3 years before diagnosis, peaked 3 months afterwards, gradually declined during the next 2 years, then remained stable. CONCLUSION: The incidence of dementia in Taiwan has increased gradually over time, with an annual mortality risk of∼12 %. Older people with dementia had more healthcare needs and comorbid conditions after dementia diagnosis, highlighting the exigency of person-centered dementia care.

The burden of frailty in heart failure: Prevalence, impacts on clinical outcomes and the role of heart failure medications.

BACKGROUND: Frailty often coexists with heart failure (HF), which significantly aggravates the clinical outcomes of older adults. However, studies investigating the interplay between frailty and HF in older adults are scarce. We aimed to assess the prevalence of frailty using the cumulative deficit approach and evaluate the impacts of frailty on health utilization, use of HF-related medications and adverse clinical outcomes (all-cause mortality, all-cause readmissions and HF readmissions) among older HF patients. METHODS: A total of 38 843 newly admitted HF patients were identified from Taiwan's National Health Insurance Research Database and categorized into three frailty subgroups (fit, mild frailty and severe frailty) based on the multimorbidity frailty index. Cox regression models and Fine and Gray subdistribution hazard models were used to estimate the impacts of frailty on clinical outcomes at 1 and 2 years of follow-up. Generalized estimating equation models were further conducted to evaluate the associations between longitudinal and time-varying use of HF-related medications and clinical outcomes among distinct frailty subgroups. RESULTS: Of 38 843 older HF patients (mean age 80.4 ± 8.5 years, 52.3% females) identified, 68.3% were categorized as frail (47.5% of mild frailty and 20.8% of severe frailty). The median number of readmissions (fit: 1 [inter-quartile range-IQR 2], mild frailty: 1 [IQR 2] and severe frailty: 2 [IQR 3]) increased with the severity of frailty. Only 27.3% of HF patients died of cardiovascular diseases regardless of their frailty status. Compared with the fit group, the severe frailty group was associated with increased risk of all-cause mortality (adjusted hazard ratio 1.16, 95% confidence interval [CI] 1.11-1.21), all-cause readmissions (subdistributional hazard ratio (sHR) 1.21, 95% CI 1.16-1.25) and HF-related readmissions (sHR 1.14, 95% CI 1.09-1.20) at 2 years of follow-up. Those who used triple or more HF-related medications were at lower risk for all-cause readmissions (adjusted odds ratio [aOR] 0.49, 95% CI 0.44-0.54) and HF-related readmissions (aOR 0.42, 95% CI 0.37-0.47) at 2 years of follow-up even in the severe frailty group. CONCLUSIONS: Frailty is highly prevalent and associated with increased risk of all-cause mortality, all-cause readmissions and HF readmissions among older HF patients. Those who were using triple or more HF-related medications were at lower risk of adverse clinical outcomes across distinct frailty subgroups. Further studies are needed to optimize the treatment strategies for older HF patients with distinct frailty status.

The incidences and clinical outcomes of cryptococcosis in Taiwan: A nationwide, population-based study, 2002-2015.

Large-scale epidemiological data on cryptococcosis other than cryptococcal meningitis (CM), human immunodeficiency virus (HIV)- or solid organ transplantation (SOT)-associated cryptococcosis are limited. This study investigated the disease burden of cryptococcosis in Taiwan over 14 years. Incident episodes of cryptococcosis, comorbidities, treatment, and outcomes were captured from Taiwan's National Health Insurance Research Database and National Death Registry between 2002 and 2015. Of 6647 episodes analyzed, the crude incidence rate per 100 000 population increased from 1.48 in 2002 to 2.76 in 2015, which was driven by the growing trend in the non-CM group (0.86-2.12) but not in the CM group (0.62-0.64). The leading three comorbidities were diabetes mellitus (23.62%), malignancy (22.81%), and liver disease (17.42%). HIV accounted for 6.14% of all episodes and was associated with the highest disease-specific incidence rate (269/100 000 population), but the value dropped 16.20% biennially. Within 90 days prior to cohort entry, 30.22% of episodes had systemic corticosteroid use. The in-hospital mortality of all episodes was 10.80%, which varied from 32.64% for cirrhosis and 13.22% for HIV to 6.90% for SOT. CM was associated with a higher in-hospital mortality rate than non-CM (19.15% vs. 6.33%). At diagnosis, only 48.53% of CM episodes were prescribed an amphotericin-based regimen. The incidence rate of cryptococcosis was increasing, especially that other than meningitis and in the non-HIV population. A high index of clinical suspicion is paramount to promptly diagnose, treat, and improve cryptococcosis-related mortality in populations other than those with HIV infection or SOT.

This nationwide study showed that the incidence rate of cryptococcosis doubled from 2002 to 2015. Non-meningeal cryptococcosis and non-HIV/nontransplant (NHNT)-associated cryptococcosis contributed to this increase. Our study highlighted the underestimated burden of cryptococcosis in the NHNT hosts.

HDGF stimulates liver tumorigenesis by enhancing reactive oxygen species generation in mitochondria.

Hepatoma-derived growth factor (HDGF) overexpression and uncontrolled reactive oxygen species (ROS) accumulation are involved in malignant transformation and poor prognosis in various types of cancer. However, the interplay between HDGF and ROS generation has not been elucidated in hepatocellular carcinoma. Here, we first analyzed the profile of HDGF expression and ROS production in newly generated orthotopic hepatomas by ultrasound-guided implantation. In situ superoxide detection showed that HDGF-overexpressing hepatomas had significantly elevated ROS levels compared with adjacent nontumor tissues. Consistently, liver tissues from HDGF-deficient mice exhibited lower ROS fluorescence than those from age- and sex-matched WT mice. ROS-detecting fluorescent dyes and flow cytometry revealed that recombinant HDGF (rHDGF) stimulated the production of superoxide anion, hydrogen peroxide, and mitochondrial ROS generation in cultured hepatoma cells in a dose-dependent manner. In contrast, the inactive Ser103Ala rHDGF mutant failed to promote ROS generation or oncogenic behaviors. Seahorse metabolic flux assays revealed that rHDGF dose dependently upregulated bioenergetics through enhanced basal and total oxygen consumption rate, extracellular acidification rate, and oxidative phosphorylation in hepatoma cells. Moreover, antioxidants of N-acetyl cysteine and MitoQ treatment significantly inhibited HDGF-mediated cell proliferation and invasive capacity. Genetic silencing of superoxide dismutase 2 augmented the HDGF-induced ROS generation and oncogenic behaviors of hepatoma cells. Finally, genetic knockdown nucleolin (NCL) and antibody neutralization of surface NCL, the HDGF receptor, abolished the HDGF-induced increase in ROS and mitochondrial energetics. In conclusion, this study has demonstrated for the first time that the HDGF/NCL signaling axis induces ROS generation by elevating ROS generation in mitochondria, thereby stimulating liver carcinogenesis.

Risk of thromboembolic events associated with different multiple myeloma regimens in Taiwan: a nested case-control study.

Although novel agents for multiple myeloma (MM) have a better response rate and survival in both newly diagnosed and relapsed/refractory MM patients, concerns regarding the association between MM treatments and thromboembolic events have been raised. The aim of this population-based study was to examine the association between different combinations of MM treatments and the risk of thromboembolic events. We conducted a nested case-control study using the Taiwan Cancer Registry (TCR) and National Health Insurance Research Database (NHIRD). Adult patients newly diagnosed with MM and treated with at least one of the immunomodulatory agents between 2008 and 2016 were identified. Among them, we further identified patients who developed thromboembolic events as cases and selected controls matched by age, sex and duration of MM diagnosis at a ratio of 1:5. The index date was defined as the day one year before the diagnosis date of thromboembolic events in the case group and the corresponding date in the control group. Conditional logistic regression was used to examine the association between different MM treatment regimens and the risk of thromboembolic events. A total of 4,180 newly diagnosed MM patients treated with at least one of the immunomodulatory agents were identified (mean age: 67.2 years; male: 55.7%). In this MM cohort, we further identified 388 cases and 1,940 matched controls (mean age: 71 years; male: 64.2%). The use of a thalidomide/bortezomib/steroid combination (odds ratio (OR) 2.95 [95% confidence interval (CI) 1.47-5.95]), thalidomide monotherapy (OR 3.33; 95% CI, 1.59-6.94), and a thalidomide/steroid combination (OR 4.24; 95% CI, 2.00-8.98) were associated with an increased risk of thromboembolic events. Other risk factors, particularly a history of thromboembolic events, including ischemic heart disease and pulmonary embolism, were significantly associated with increased risk of thromboembolic events. We found that the use of thalidomide alone and in specific combinations was associated with an increased risk of thromboembolic events.

Longitudinal impact of distinct infection trajectories on all-cause mortality of older people in Taiwan: a retrospective, nationwide, population-based study.

BACKGROUND: Infectious diseases are the leading cause of deaths in adults aged 65 years or older. Studies of adverse infection outcomes have been limited to specific infections and acute episodes and have not investigated longitudinal trends of cumulative infections. We aimed to identify distinct trajectories of longitudinal infection episodes in older adults and to assess their corresponding risk of all-cause mortality. METHODS: In this retrospective cohort study, we included people aged 65 years or older who were admitted to hospital between Jan 1 and Dec 31, 2011, with one of the following infections: urinary tract, pneumonia, sepsis, cellulitis, cholecystitis, peritonitis, endocarditis, and meningitis. Participants were identified from Taiwan's National Health Insurance Research Database. We analysed infection episodes on a quarterly basis during a 5-year period (2011-15) and used group-based trajectory modelling to identify distinct trajectories. We examined the associations between infection trajectories and all-cause mortality using Kaplan-Meier curves and the Cox proportional hazard model. FINDINGS: Among 79 666 eligible older adults, we identified four distinct infection trajectories over the 5-year follow-up: infrequent (58 619 [73·6%]), increasing (9746 [12·2%]), decreasing (9069 [11·4%]), and frequent (2232 [2·8%]). Compared with people with infrequent infections, the adjusted hazard ratios for all-cause mortality were 2·96 (95% CI 2·82-3·11) in participants with frequent infections, 2·15 (2·09-2·22) in those with increasing infections, and 1·85 (1·80-1·91) in those with decreasing infections. INTERPRETATION: Older adults with multiple infection episodes, irrespective of type, pathogens, and distinct infection pattern, had greater risk of all-cause mortality compared with those with infrequent infections. Further research to define the overall infection burden in older adults is needed for risk stratification and to inform prevention strategies. FUNDING: The Interdisciplinary Research Center for Healthy Longevity of National Yang Ming Chiao Tung University from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education, the National Science and Technology Council, and the Ministry of Science and Technology in Taiwan.

Clinical impacts of frailty on 123,172 people with diabetes mellitus considering the age of onset and drugs of choice: a nationwide population-based 10-year trajectory analysis.

AIMS: Frailty substantially increased the risk of adverse clinical outcomes, which was also critical in diabetes management. This study aimed to investigate the interrelationships between the age of onset, frailty, anti-diabetic medications and clinical outcomes in people with diabetes mellitus (DM). METHODS: A total of 123,172 people aged 40 years and older who were newly diagnosed with DM were identified and categorised into four frailty subgroups (robust, mild, moderate and severe) based on the multimorbidity frailty index (mFI). Cox proportional hazards models were used to examine associations between frailty and clinical outcomes at different ages of DM onsets (40-64, 65-74, 75-84 and 85+ years). Outcomes of interest included generic outcomes (mortality and unplanned hospitalisation) and DM-related outcomes (cardiovascular disease-related mortality, major adverse cardiovascular events (MACEs), diabetes-related hospitalisation and hypoglycaemia). RESULTS: The proportion of frailty increased with age at diagnosis amongst people with incident DM and the mFI scores increased significantly during the 10-year follow-up. Amongst people with diabetes, those with mild, moderate and severe frailty were associated with greater risks of all-cause mortality (mild: adjusted hazard ratio (aHR) 1.69 [95% confidence interval (CI) 1.60-1.80], P < 0.01; moderate: aHR 2.46 [2.29-2.65], P < 0.01; severe frailty: aHR 3.40 [3.16-3.65], P < 0.01) compared with the robust group. Similar results were found in unplanned hospitalisations, cardiovascular disease-related mortality, MACEs and hypoglycaemia. CONCLUSIONS: Our study quantified the prevalence of frailty, captured its dynamic changes and examined its impacts on various clinical outcomes amongst people with diabetes at different ages at onset. Frailty assessment and management should be implemented into routine diabetes care.

Using Hypothesis-Led Machine Learning and Hierarchical Cluster Analysis to Identify Disease Pathways Prior to Dementia: Longitudinal Cohort Study.

BACKGROUND: Dementia development is a complex process in which the occurrence and sequential relationships of different diseases or conditions may construct specific patterns leading to incident dementia. OBJECTIVE: This study aimed to identify patterns of disease or symptom clusters and their sequences prior to incident dementia using a novel approach incorporating machine learning methods. METHODS: Using Taiwan's National Health Insurance Research Database, data from 15,700 older people with dementia and 15,700 nondementia controls matched on age, sex, and index year (n=10,466, 67% for the training data set and n=5234, 33% for the testing data set) were retrieved for analysis. Using machine learning methods to capture specific hierarchical disease triplet clusters prior to dementia, we designed a study algorithm with four steps: (1) data preprocessing, (2) disease or symptom pathway selection, (3) model construction and optimization, and (4) data visualization. RESULTS: Among 15,700 identified older people with dementia, 10,466 and 5234 subjects were randomly assigned to the training and testing data sets, and 6215 hierarchical disease triplet clusters with positive correlations with dementia onset were identified. We subsequently generated 19,438 features to construct prediction models, and the model with the best performance was support vector machine (SVM) with the by-group LASSO (least absolute shrinkage and selection operator) regression method (total corresponding features=2513; accuracy=0.615; sensitivity=0.607; specificity=0.622; positive predictive value=0.612; negative predictive value=0.619; area under the curve=0.639). In total, this study captured 49 hierarchical disease triplet clusters related to dementia development, and the most characteristic patterns leading to incident dementia started with cardiovascular conditions (mainly hypertension), cerebrovascular disease, mobility disorders, or infections, followed by neuropsychiatric conditions. CONCLUSIONS: Dementia development in the real world is an intricate process involving various diseases or conditions, their co-occurrence, and sequential relationships. Using a machine learning approach, we identified 49 hierarchical disease triplet clusters with leading roles (cardio- or cerebrovascular disease) and supporting roles (mental conditions, locomotion difficulties, infections, and nonspecific neurological conditions) in dementia development. Further studies using data from other countries are needed to validate the prediction algorithms for dementia development, allowing the development of comprehensive strategies to prevent or care for dementia in the real world.

Medication overload: A closer look at polypharmacy and potentially inappropriate medications among older people in Taiwan and Japan.

BACKGROUND: Polypharmacy and potentially inappropriate medications (PIM) are widely recognized as vital quality indicators of pharmacotherapy in older adults. As Taiwan and Japan grapple with the ongoing challenges of population aging, obtaining an accurate understanding of the prevalence of these indicators is crucial for developing effective strategies to optimize pharmacotherapy in older populations. The present study aims to comprehensively evaluate the prevalence of polypharmacy and PIMs in Taiwan and two Japanese cohorts, shedding light on the similarities and differences in prescribing practices across these populations. METHODS: This study employed a cross-sectional design to investigate individuals aged ≥65 years in Taiwan, as well as two Japanese cohorts: Japan Cohort 1 (dispensing data from chain pharmacies; year 2014 and 2019) and Japan Cohort 2 (claims data; year 2017 and 2019). The prescription records of these participants were collected from the national claims database in Taiwan for the years 2014, 2017, and 2019. To identify polypharmacy and hyper-polypharmacy, the study defined the use of 5-9 and 10+ drugs, respectively. Furthermore, the study identified PIMs based on the STOPP-J criteria. Notably, the study further explored the most frequently used PIMs (by categories) in Taiwan. RESULTS: In the year 2019, the prevalence of polypharmacy exhibited similar rates in Taiwan (35.4%) and Japan Cohort 2 (33.1%), while surpassing that of Japan Cohort 1 (25.6%). Nonetheless, the incidence of PIMs in Taiwan was the highest (66.5%), exceeding those of the two Japanese cohorts (Cohort 1: 43.7% and Cohort 2: 40.2%) in the same year. Notably, the top three categories of commonly used PIMs in Taiwan comprised non-steroidal anti-inflammatory drugs (NSAIDs), antithrombotic drugs, and benzodiazepines. CONCLUSIONS: This study highlights the varying prevalence of polypharmacy and PIMs between Taiwan and Japan, but emphasizes the need for collaborative efforts towards optimizing pharmacotherapy in older adults.

Association between maternal benzodiazepine or Z-hypnotic use in early pregnancy and the risk of stillbirth, preterm birth, and small for gestational age: a nationwide, population-based cohort study in Taiwan.

BACKGROUND: Benzodiazepines and Z-hypnotics are commonly prescribed for anxiety and insomnia during pregnancy, but the evidence regarding potential adverse neonatal outcomes is insufficient because of poor control for confounding factors in previous studies. We therefore aimed to evaluate the association between the use of benzodiazepines or Z-hypnotics during early pregnancy and adverse neonatal outcomes (stillbirth, preterm birth, and small for gestational age). METHODS: We did a nationwide, population-based cohort study in Taiwan using three data sources: Taiwan's National Birth Certificate Application database, the National Health Insurance database, and the Maternal and Child Health Database. The study cohort included all singleton pregnancies of females aged 15-50 years who gave birth between Jan 1, 2004, and Dec 31, 2018. Pregnancies without valid information were excluded. Benzodiazepine and Z-hypnotic use was defined as at least one benzodiazepine or Z-hypnotic prescription during early pregnancy (the first 20 weeks of pregnancy). The primary outcomes were stillbirth (fetal death at or after 20 weeks' gestation), preterm birth (<37 weeks' gestation), and small for gestational age (birthweight below the 10th percentile for gestational age by sex). Logistic regression models with propensity score fine stratification weighting were used to control for potential confounders and examine the association between benzodiazepines or Z-hypnotics use during early pregnancy and the risk of adverse neonatal outcomes. Odds ratios (ORs) and 95% CIs were reported. We used confounding by indication control analyses, a sibling control study, and a paternal negative control design to account for unmeasured confounders. The risk associated with exposure during late pregnancy was also assessed. FINDINGS: Between Oct 7, 2021, and June 10, 2022, we analysed the study data. The cohort included 2 882 292 singleton pregnancies; of which, 75 655 (2·6%) of the mothers were dispensed one or more benzodiazepines or Z-hypnotics during early pregnancy. Women exposed during pregnancy were older (mean age at delivery was 31·0 years [SD 5·3] for exposed women vs 30·6 years [4·9] for unexposed women), had a higher prevalence of psychiatric disorders, and were more likely to have unhealthy lifestyle behaviours than unexposed women. Information about ethnicity was not available. Early pregnancy exposure was associated with adverse neonatal outcomes compared with non-exposure. The propensity score-weighted OR was 1·19 (95% CI 1·10-1·28) for stillbirth, 1·19 (1·16-1·23) for preterm birth, and 1·16 (1·13-1·19) for small for gestational age. After controlling for confounding by indication, there was no significant association between drug exposure and stillbirth risk; however, this attenuation was not observed for preterm birth and small for gestational age. In models with sibling controls that accounted for familial confounding and genetic factors, early exposure to benzodiazepines or Z-hypnotics was not associated with an increased risk of stillbirth and preterm birth, but it remained significantly associated with small for gestational age. The paternal negative control analyses with point estimates close to the null indicated no strong evidence of unmeasured confounding shared by the mother and the father. Substantially increased risks of stillbirth and preterm birth were observed for late pregnancy exposure. INTERPRETATION: Benzodiazepine or Z-hypnotic use in early pregnancy is not associated with a substantial increase in the risk of stillbirth and preterm birth after accounting for unmeasured confounding factors. Clinicians should be aware of the increased risk of small for gestational age and caution should be taken when prescribing these medications during late pregnancy. FUNDING: National Science and Technology Council, Taiwan. TRANSLATION: For the Taiwanese translation of the abstract see Supplementary Materials section.

Health care utilization and potentially preventable adverse outcomes of high-need, high-cost middle-aged and older adults: Needs for integrated care models with life-course approach.

PURPOSE OF THE RESEARCH: The success of modern health care increases life expectancy and prolongs the days of having multimorbidity and functional limitations; the so-defined "high need, high cost (HNHC)" state represents the extreme scenarios of care burden and complexity. This study aims to explore health care utilization and the risk of preventable adverse outcomes stratified by age and HNHC state. MATERIALS AND METHODS: We conducted a retrospective cohort study using the National Health Insurance (NHI) database. People aged ≥40 years were included and further stratified by age (middle-aged: 40-64 and older adults: 65) and HNHC state (top 10% of spending). Health care utilization and drug consumption across different groups were obtained. The multimorbidity frailty index (mFI) was developed for further analysis. Cox regression models were used to examine the associations between HNHC and adverse clinical outcomes (preventable hospitalizations, preventable emergency department visits, and mortality). RESULTS: HNHC participants were older, had a higher mFI and drug consumption, and had higher health care utilization. Compared with non-HNHC participants, HNHC participants exhibited a 4.4-fold and 2.4-fold higher risk of preventable hospitalizations in middle-aged (HR=4.41; 95% CI, 4.17-4.65, p<0.01) and older adults (HR=2.44; 95% CI, 2.34-2.55, p<0.01). Similar risks were observed for preventable emergency department visits and mortality (all p<0.01). CONCLUSIONS: The HNHC state substantially increased health care utilization, polypharmacy, and potentially preventable adverse outcomes after adjustment for frailty. Intervention studies developing integrated care models using the life-course approach are needed to improve the quality of health care systems in super-aged societies.

Detection of Trichomonas vaginalis Infection in Chronic Prostatitis/Chronic Pelvic Pain Syndrome Patients by Rapid Immunochromatographic Test.

This study aims to evaluate associations between the immunochromatographic rapid test technique and Trichomonas vaginalis (TV) infection in patients with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) in Taiwan. All patients received post-prostate massage urine (VB3) Trichomonas rapid tests. The demographic characteristics and urogenital symptoms of CP/CPPS were recorded. Routine urinalysis of VB3 was also performed, and laboratory examination results of semen were recorded if available. A total of 29 patients with TV infection and 109 without TV infection were enrolled, which reflected that the prevalence in patients with TV infection was approximately 21%. Patients with TV infection displayed a significantly higher frequency of suprapubic/lower abdominal pain (p = 0.034), semen leukocyte > 5/high-power field (HPF) (p = 0.020), and an inflammatory type (category IIIA) (p = 0.005) than patients without TV infection. A higher prevalence of TV infection was found in patients with category IIIA (47.37%). No significant difference was found in the symptom duration and other clinical symptoms. In conclusion, the high prevalence of TV infection was revealed in CP/CPPS patients using the VB3 rapid Trichomonas test, especially in CP/CPPS patients with category IIIA. Thus, rapid TV testing might be vital for CP/CPPS patients in the hospital.

Impacts of Catch-Up Immunization program with the 13-Valent pneumococcal Conjugate vaccine in Taiwan: Focus on age-stratified differences and high-risk population (2001-2015).

BACKGROUND: Taiwan commenced a national catch-up immunization program with a 13-valent pneumococcal conjugate vaccine (PCV13) in 2013 for children aged 2-5 years old and in 2014 for children aged 1-5 years old. However, real-world nationwide evidence of both the direct protection and indirect protection of all-cause pneumonia and pneumococcal pneumonia has been scarce, especially among high-risk populations, defined as patients with chronic diseases or immunosuppression. The aim of this study was to examine the impact of the national PCV13 catch-up program on all-cause pneumonia and pneumococcal pneumonia among overall and high-risk populations using interrupted time series analysis. METHODS: Using the National Health Insurance Research Database (NHIRD) from January 2001 to December 2015, we assessed the impact of this catch-up program by interrupted time-series analyses age-stratified (0-1, 2-4, 5-9, 10-17, 18-34, 35-49, 50-64, 65 + years old) incidence of pneumococcal pneumonia and all-cause pneumonia (100,000 person-quarter) among the overall and high-risk populations. RESULTS: The impact of this program was most profound on the incidence of pneumococcal pneumonia in children aged 2-4 years old (level change -10.56 per 100,000 person-quarters, p = 0.04; trend change -2.93, p less than 0.01). Indirect protection among unvaccinated children (0-1 years old: trend change -1.19, p = 0.01; 5-9 years old: trend change -1.04, p = 0.03; 10-17 years old: level change -1.42 per 100,000 person-quarters, p = 0.03) was also found. The incidence of all-cause pneumonia also decreased in children aged 2-4 (level change -234.91 per 100,000 person-quarter, p = 0.058) and 5-9 years old (level change -173.96 per 100,000 person-quarter, p = 0.0424). However, we did not find a significant impact among most high-risk populations. CONCLUSIONS: Our study suggests that the introduction of this catch-up program with PCV13 was associated with significant declines in the incidence of pneumococcal pneumonia and all-cause pneumonia in vaccinated children, and indirect protection from the program was also found in unvaccinated children.

Comparative Effectiveness and Safety of Different Combinations of Antithrombotic Regimens in Atrial Fibrillation Patients With Stent Insertions.

This study aims to compare the risks of major adverse cardiac events (MACEs), including cardiovascular death, myocardial infarction, ischemic stroke and transient ischemic attack, and major bleeding across different antithrombotic regimens in Asian patients with atrial fibrillation (AF) with stent insertions. We conducted a retrospective cohort study using Taiwan's National Health Insurance Research Database and National Mortality Registry. A total of 10,208 patients with nonvalvular AF who had undergone percutaneous coronary intervention with stents for the first time in 2007-2017 were identified. Most patients (68.4%) were prescribed dual antiplatelet therapy (DAPT) at discharge. During follow-up, the use of anticoagulants increased, and double therapy (an antiplatelet plus an anticoagulant) was the most frequently prescribed therapy. The risks of MACEs were comparable in double therapy and had a similar risk of MACEs compared with DAPT (adjusted hazard ratio (aHR) 0.86, 95% confidence interval (CI) 0.67-1.11). Triple therapy (DAPT plus an anticoagulant) also had similar effectiveness to double therapy (aHR 1.23, 95% CI 0.84-1.80) or DAPT (aHR 1.06, 95% CI 0.77-1.45). However, triple therapy was associated with a nearly twofold higher major bleeding risk than DAPT and double therapy (aHR 1.97, 95% CI 1.31-2.94 and aHR 1.80, 95% CI 1.10-2.95, respectively). DAPT was the most frequently prescribed antithrombotic regimen at discharge for Asian patients with AF who had undergone stent insertions. DAPT and double and triple therapy had comparable effectiveness, but triple therapy had a significantly higher major bleeding risk than either DAPT or double therapy.

Biological Features of the Outcome-Based Intrinsic Capacity Composite Scores From a Population-Based Cohort Study: Pas de Deux of Biological and Functional Aging.

Introduction: This study aims to develop and validate an integrative intrinsic capacity (IC) scoring system, to investigate its associations with a wide spectrum of biomarkers and to explore the predictive value of the integrative IC score on 4-year mortality among community dwelling people aged 50 years and older. Methods: We included 839 adults aged ≥50 years from the Social Environment and Biomarkers of Aging Study (SEBAS) and randomly divided them into derivation and validation cohorts to develop the IC scoring system. The multivariate logistic regression model was used to weight each subdomain (locomotion, sensory, vitality, psychological, and cognition) of IC according to its association with impairments in instrumental activities of daily living (IADL) and to construct the integrative IC score. Age-related biomarkers and genetic markers were compared between IC groups by ordinal logistic regression. A Cox proportional hazard model was used to examine the association between IC and mortality, and subgroup analysis was used to assess the robustness of the results among participants aged 60 years and older. Results: A 12-score IC scoring system (AUROC = 0.83; Hosmer-Lemeshow goodness-of-fit test p = 0.17) was developed, and higher scores indicated better intrinsic capacity. High interleukin (IL)-6, high E-selectin, low serum albumin and low folate were significantly associated with low IC in the whole sample. However, high IL-6, low serum albumin, low folate, high allostatic load, and APOE ε4 genotype were significantly associated with low IC in those aged 60 years old and older. Compared to the high IC group, the low IC group was significantly associated with all-cause mortality (HR: 2.50, 95% CI: 1.22-5.11, p = 0.01 for all participants; HR 2.19, 95% CI 1.03-4.64, p = 0.04 for participants aged 60 years and older). Conclusions: The conceptually proposed IC can be easily transformed into a scoring system considering different weights of individual subdomains, which not only predicts mortality but also suggests different pathophysiologies across the life course of aging (inflammation, nutrition, stress, and ApoE4 genotype). An intervention study is needed using the composite IC score to promote healthy aging and determine the underlying pathophysiology.

Development of frailty index using ICD-10 codes to predict mortality and rehospitalization of older adults: An update of the multimorbidity frailty index.

OBJECTIVE: This study aims to develop an updated mFI (multimorbidity frailty index) using ICD-10-CM codes and to examine the association between frailty and all-cause mortality, unplanned hospitalization, and ICU admission by adopting the updated mFI in the contemporary ICD-10-CM era. METHODS: From NHIRD, subjects aged 65-100 years with full National Health Insurance coverage in 2017 were included. We constructed the renewed mFI using ICD-10 CM codes (mFI-v10) by the cumulative deficit approach and categorized the study subjects according to the mFI-v10 quartiles: fit, mild frailty, moderate frailty, and severe frailty. Outcomes of interests (1-year mortality, unplanned hospitalization, and intensive care unit (ICU) admission) were assessed using Cox regression analyses, adjusted by sex and age. RESULTS: Compared with the fit group, those with severe frailty were associated with a 4-fold (adjusted HR 3.86, 95% CI 3.54-4.20) higher risk for death at one year. Subjects with moderate frailty or mild frailty were associated with a 2.4-fold (adjusted HR 2.35, 95% CI 2.18-2.55) or 1.6-fold (adjusted HR 1.57, 95% CI 1.47-1.69) higher risk for death at one year than the fit group. Similar risk trends can also be observed in unplanned hospitalization and intensive care unit (ICU) admission among the study population. CONCLUSION: The renewed multimorbidity frailty index constructed from ICD-10 codes is associated with an increased risk of 1-year of all-cause mortality, unplanned hospitalization, and ICU admission. It can provide updated information contributing to risk stratification using frailty index in the ICD-10 era.

Age and sex differences in associations between self-reported health, physical function, mental function and mortality.

OBJECTIVES: To explore how age and sex affect the impacts of self-rated health, self-reported physical activities, physical function, and depressive symptoms on long-term mortality among community-dwelling middle-aged and older adults using a nationally representative population-based cohort study. METHODS: Data from 1550 study participants from the Social Environment and Biomarkers of Aging Study (SEBAS) were retrieved for analysis, and all participants were divided into four groups based on their age and gender. Middle aged participants were aged 53 to 64 years, and elderly subjects were ≥ 65 years old. Multivariate logistic regression models were applied to investigate the associations between age, sex, and self-reported disabilities of physical activities, physical function (activities of daily living (ADL) and instrumental activities of daily living (IADL) and depression. RESULTS: Although the self-reported health status was similar across different age- and sex-stratified subgroups, older women were at the highest risk in self-reported difficulty with physical activities (aOR 2.58 [1.55-4.28]) and difficulty with IADL (aOR 3.32 [2.20-5.03]) compared to men. After adjusting for living arrangement, residence locale, education levels, occupation, socioeconomic status, self-reported health, multimorbidity, impairments in daily activities, and depressive symptoms, older men were found to display the highest risk of mortality (aHR 2.06 [95% CI 1.45-2.93]). CONCLUSIONS: Although self-reported health was similar across different age and sex stratified subgroups, women (particularly older women) are significantly more likely to have worse physical and functional health than men. After adjusting for all confounding factors, men are at substantially greater risk for mortality despite reporting better health and functional performance.

Detecting Suspected Prescribing Cascades by Prescription Sequence Symmetry Analysis of Nationwide Real-World Data.

OBJECTIVE: A prescription cascade is a subsequent event that occurs when an adverse drug event is misinterpreted as a new medical condition, resulting in the prescription of a potentially unnecessary medication to treat this new condition. This study was designed to test the hypothesis of whether prescribing cascades exist and their magnitude among older individuals by using prescription sequence symmetry analysis (PSSA). DESIGN: A retrospective population-based cohort study based on data from Taiwan's National Health Insurance Research Database (NHIRD), a nationwide claims-based database that covers 99% of the population in Taiwan. SETTING AND PARTICIPANTS: Patients receiving newly initiated index and marker drugs in the outpatient setting between 2014 and 2016 were included. Those who received index and marker drugs on the same date were excluded. MEASURES: PSSA measures the propensity for a marker drug (eg, thyroxine) to be prescribed after an index drug (eg, amiodarone) has been initiated, where the index drug is suspected of inducing a side effect (eg, hypothyroidism) and the marker drug is used to treat the side effect. We evaluated 14 PSSA sets as potential prescription cascade-related drug pairs (index and marker drug), including 2 confirmatory analyses (eg, amiodarone and thyroxin), to check the validity of the PSSA results and 12 exploratory analyses of cardiovascular medication-related prescribing cascades (eg, statins and antidepressants). The observation periods for sequences of incident marker drug use were 1 year before and 1 year after the use of the incident index drug, and the symmetry of prescriptions filled for the 2 periods was examined. The results of the PSSA were performed as the crude sequence ratio (SR), defined as the ratio of patients initiating the marker drug after the index drug (causal group) to those initiating the marker drug before the index drug (noncausal group), and the adjusted SR (aSR) with 95% confidence intervals (CIs). RESULTS: Among 12 potential prescription cascade-related drug pairs in exploratory analysis, 9 of them reached statistical significance, and aSR ranged from 1.02 to 1.46. Dihydropyridine calcium channel blocker-induced edema showed the highest aSR (1.46, 95% CI 1.45-1.48), and statin-induced muscle pain showed the lowest aSR (1.02, 95% CI 1.02-1.03). CONCLUSIONS AND IMPLICATIONS: Our study supported the application of PSSA in detecting prescribing cascades using a nationwide claims database. Nevertheless, most previously reported prescribing cascades among cardiovascular medications were shown to have a low effect size of sequence ratios among older individuals.

All-cause mortality, cardiovascular mortality, major cardiovascular events and hypoglycaemia of patients with diabetes onset at an older age: results from the 10-year nationwide cohort study.

BACKGROUND: Longitudinal adverse outcomes are unclear among adults with diabetes according to the age of onset. OBJECTIVE: To investigate the longitudinal diabetes-related outcomes in adults with new-onset diabetes stratified by age. DESIGN: Retrospective cohort study. SETTING: Taiwan National Health Insurance Research Database claims data from 2000 to 2015. SUBJECTS: In total, 115,751 participants aged ≥40 years with new-onset diabetes in 2003 were recruited and stratified by the ages 40-64 (64.3%), 65-74 (21.2%), 75-84 (11.8%) and ≥85 years (2.7%) at the time of diagnosis. METHODS: Time-varying multivariate Cox proportional hazards model adjusted for covariates was used to examine the associations between the ages of the patients at diabetes onset and the outcomes of interest [all-cause mortality, cardiovascular (CV) mortality, major cardiovascular events (MACE) and hypoglycaemia] during a 10-year follow-up period. RESULTS: The results showed that compared with those patients aged 40-64 at diagnosis, patients with older-onset diabetes had significantly higher comorbidities (P < 0.01) and a higher diabetes severity (P < 0.01). Patients with older-onset diabetes had a higher risk of all-cause mortality [adjusted hazard ratio (aHR) 2.28, 4.48 and 10.07 in 65-74, 75-84 and ≥85 years old, respectively], CV mortality (aHR = 2.82, 6.06 and 15.91), MACE (aHR = 2.19, 3.01 and 4.15) and hypoglycaemia (aHR = 2.41, 3.59 and 4.62) than patients aged 40-64 during a 10-year follow-up period. CONCLUSIONS: Patients with diabetes onset at an older age was associated with increased risks of all-cause mortality, CV mortality, MACE and hypoglycaemia after adjusting for the severity of diabetes and anti-diabetic treatment.

Tyrosine Kinase Inhibitors and Vascular Adverse Events in Patients with Chronic Myeloid Leukemia: A Population-Based, Propensity Score-Matched Cohort Study.

BACKGROUND: Tyrosine kinase inhibitors (TKIs) have shown long-term survival benefits in patients with chronic myeloid leukemia (CML). Nevertheless, significant concern has been raised regarding long-term TKI-associated vascular adverse events (VAEs). The objective of this retrospective cohort study was to investigate the incidence of VAEs in Taiwanese patients with CML treated with different TKIs (imatinib, nilotinib, and dasatinib) as well as potential risk factors. MATERIALS AND METHODS: We conducted a retrospective cohort study using the Taiwan Cancer Registry Database and National Health Insurance Research Database. Adult patients diagnosed with CML from 2008 to 2016 were identified and categorized into three groups according to their first-line TKI treatment (imatinib, nilotinib, and dasatinib). Propensity score matching was performed to control for potential confounders. Cox regressions were used to estimate the hazard ratio (HR) of VAEs in different TKI groups. RESULTS: In total, 1,111 patients with CML were included in our study. We found that the risk of VAEs in nilotinib users was significantly higher than that in imatinib users, with an HR of 3.13 (95% confidence interval (CI), 1.30-7.51), whereas dasatinib users also showed a nonsignificant trend for developing VAEs, with an HR of 1.71 (95% CI, 0.71-4.26). In multivariable logistic regression analysis, only nilotinib usage, older age, and history of cerebrovascular diseases were identified as significant risk factors. The annual incidence rate of VAEs was highest within the first year after the initiation of TKIs. CONCLUSION: These findings can support clinicians in making treatment decisions and monitoring VAEs in patients with CML in Taiwan. IMPLICATIONS FOR PRACTICE: This study found that patients with chronic myeloid leukemia (CML) treated with nilotinib and dasatinib may be exposed to a higher risk of developing vascular adverse events (VAEs) compared with those treated with imatinib. Thus, this study suggests that patients with CML who are older or have a history of cerebrovascular diseases should be under close monitoring of VAEs, particularly within the first year after the initiation of tyrosine kinase inhibitors.