BACKGROUND:Lung adenocarcinoma (LUAD) is the most common type of lung cancer. A recent genome-wide association study of lung adenocarcinoma in East Asia reported 28 independent susceptibility variants across 25 loci and identified 2 genes whose genetically predicted expression levels are associated with lung adenocarcinoma risk, using an ancestry-matched lung tissue expression quantitative trait loci (QTL) dataset. It is desirable to identify additional susceptibility loci and to understand their underlying biological mechanisms. METHODS:Using an expanded genome-wide association study of lung adenocarcinoma in East Asia and ancestry-matched lung tissue expression QTL and DNA methylation QTL datasets, we performed transcriptome-wide association studies and DNA methylome-wide association studies simultaneously and examined the association between measured expression of genes and DNA methylation of nearby CpGs. Genes and nearby CpGs are termed CpG-gene-LUAD trios if these 3 associations hold simultaneously. RESULTS:At a Bonferroni-corrected P value less than .05, we identified a new susceptibility locus (6p21.31; lead single-nucleotide polymorphism rs7772643), 10 lung adenocarcinoma-associated genes, and 86 lung adenocarcinoma-associated CpGs. At a false discovery rate q value less than 0.05, we identified 28 lung adenocarcinoma-associated genes, 220 lung adenocarcinoma-associated CpGs, and 45 CpG-gene-LUAD trios; among them, 43 were direction-matched regarding these 3 associations. These show that 23 of the known 28 susceptibility variants for lung adenocarcinoma in East Asia are near these genes or CpGs and MARCH3, ELF5, IKZF3, GSDMB, CCDC116, and DSP are putative novel candidate genes. Few of them were reported in lung adenocarcinoma in European populations. CONCLUSIONS:This study substantially advances our understanding of the etiology of lung adenocarcinoma in East Asia and could be useful in developing translational applications.

BACKGROUND AND AIMS:Poor physical performance (PPP) in terms of weakness and slow walking speed is closely associated with frailty during ageing. We aimed to analyse the associations between modifiable lifestyle factors, inflammation markers (hs-CRP, D-dimer, and fibrinogen), and the odds of PPP and state transitions between normal and PPP in older adults. METHODS:A total of 3756 participants ($\ge$ 55 years) in wave 1 (2009-2013) and wave 2 (2014-2019) of the Healthy Aging Longitudinal Study in Taiwan (HALST) were analysed. A logistic regression model was used to assess the associations between lifestyle factors (physical activity [PA], diet, and psychosocial health), inflammation markers, comorbidities, and PPP (two or more of the criteria: grip strength, 6-minute walking distance, or gait speed among the lowest 20%). RESULTS:In total, 229 and 149 of the 773 PPP participants at wave 1 reversed and persistent in PPP state at wave 2, respectively. Higher PA (OR 0.917, 95% CI 0.894-0.941), psychosocial health (OR 0.964, 95% CI 0.955-0.972), LDL-C, and education level had significant protective effects, whereas greater waist circumference, D-dimer, fibrinogen, longer sleeping time, and comorbidities were positively associated with PPP. Higher PA, psychosocial health, and diet scores were protective against conversion to PPP, and increased PA and higher psychosocial health score were significant for reversion. CONCLUSIONS:Older adults are encouraged to engage in various forms of PA and participate in societal events to increase their physical performance. To avoid further deterioration in physical frailty, screening for PPP may be adopted as a standard clinical practice for older adults.

Absolute risk prediction models are important tools for disease prevention and early detection. They are best studied in prospective cohorts. However, when the disease incidence rate is low, such as that of lung cancer in never smokers, synthesizing data and information from multiple sources is an important strategy. A recent study exemplified this strategy by proposing a two-stage procedure to estimate a logistic regression model for predicting lung cancer occurrence among never-smoking females in Taiwan on the basis of age-matched case–control studies and age-specific lung cancer incidence rates among this population. The latter were obtained from the Taiwan Cancer Registry, Cause of Death Database, age-specific female population size and smoking rates, life tables, and others. The risk factors considered in the logistic regression model included age, body mass index, chronic obstructive pulmonary disease, educational level, and genetic variants. With additional information on the age-specific population distribution of these risk factors, in this paper, we established an asymptotic theory, used it to construct confidence intervals, examined its numerical performance via simulation studies, and applied it to estimate the numbers and confidence intervals of Taiwanese never-smoking females whose lung cancer risk was higher than the thresholds discussed in the literature regarding low-dose computed tomography lung cancer screening. This information is useful for health policy decision making.

Home healthcare is a widely adopted health policy to address the needs of aging societies. This study examined Taiwan's home healthcare policy as a case example, assessing its implementation through the five dimensions of the RE-AIM framework (Reach, Effectiveness, Adoption, Implementation, and Maintenance). Taiwan's home healthcare policy, launched in 2016 as the "Integrated Home-Based Medical Care" (iHBMC) program, is reimbursed by the National Health Insurance. The study utilized data from the National Health Insurance Research Database and publicly available government sources. A total of 15,761 adults aged 50 years and above in the iHBMC program during its first year were identified, with 16% receiving home-based primary care (S1) and 84% receiving home-based advanced care (S2) (Reach). Prescriptions for chronic diseases and emergency department visits were significantly decreased among S1 and S2 patients after the iHBMC program (Effectiveness). Among all institutions delivering home healthcare, the majority were clinics (74%), followed by home nursing care agencies (18.3%) and hospitals (7.5%) (Adoption). Continuity of care was higher in S1 than in S2 (Implementation). More than 70% of participants engaged in the program for more than 6 months (Maintenance). These findings suggest the iHBMC program is feasible, improves healthcare utilization, and reduces hospital burden.

BACKGROUND:Lung adenocarcinoma (LUAD) in never-smokers is a major public health burden, especially among East Asian women. Polygenic risk scores (PRSs) are promising for risk stratification but are primarily developed in European-ancestry populations. We aimed to develop and validate single- and multi-ancestry PRSs for East Asian never-smokers to improve LUAD risk prediction. METHODS:PRSs were developed using genome-wide association study summary statistics from East Asian (8,002 cases; 20,782 controls) and European (2,058 cases; 5,575 controls) populations. Single-ancestry models included PRS-25, PRS-CT, and LDpred2; multi-ancestry models included LDpred2+PRS-EUR128, PRS-CSx, and CT-SLEB. Performance was evaluated in independent East Asian data from the Female Lung Cancer Consortium (FLCCA) and externally validated in the Nanjing Lung Cancer Cohort (NJLCC). We assessed predictive accuracy via AUC, with 10-year and (age 30-80) absolute risks estimates. RESULTS:The best multi-ancestry PRS, using East Asian and European data via CT-SLEB (clumping and thresholding, super learning, empirical Bayes), outperformed the best East Asian-only PRS (LDpred2; AUC = 0.629, 95% CI:0.618,0.641), achieving an AUC of 0.640 (95% CI : 0.629,0.653) and odds ratio of 1.71 (95% CI : 1.61,1.82) per SD increase. NJLCC Validation confirmed robust performance (AUC =0.649, 95% CI: 0.623, 0.676). The top 20% PRS group had a 3.92-fold higher LUAD risk than the bottom 20%. Further, the top 5% PRS group reached a 6.69% lifetime absolute risk. Notably, this group reached the average population 10-year LUAD risk at age 50 (0.42%) by age 41, nine years earlier. CONCLUSIONS:Multi-ancestry PRS approaches enhance LUAD risk stratification in East Asian never-smokers, with consistent external validation, suggesting future clinical utility.

The need for home healthcare (HHC) is increasing among people living with dementia (PLWD) to achieve their desire to age. This study aimed to investigate the determinants of hospitalization among PLWD receiving HHC. This retrospective cohort study used data from the National Health Insurance Research Database of Taiwan from 2007 to 2017. The primary outcome was subsequent hospitalization after HHC for PLWD. Using multivariate Poisson regression, baseline and follow-up HHC-related characteristics were examined as covariates and influencing factors. A total of 95,831 PLWD received HHC (mean age: 80.2 years), and 81.7% had at least one subsequent hospitalization during the follow-up period. Regarding baseline characteristics, prior admission was the strongest determinant of subsequent hospitalization, especially being admitted three to six months before HHC use (aRR = 1.47, 95% confidence interval [CI] 1.39-1.56, P < .001), followed by dementia duration from diagnosis to index date more than 3.5 years (aRR = 1.22, 95% CI 1.19-1.24). Among HHC-related characteristics, a higher frequency of HHC visits (more than 2 counts/month) (aRR = 4.81, 95% CI 4.63-5.00) and visits by both physicians and nurses (aRR = 2.03, 95% CI 1.98-2.07) were associated with a higher risk of hospitalization. Our findings suggest that prior admission, longer dementia duration from diagnosis to the index date, and frequency of HHC were positively associated with increased hospitalization. Future interventions and strategies can focus on these factors to decrease hospitalization among PLWD receiving HHC.

Background Type 2 diabetes mellitus (T2DM) is a complex, multifactorial disease with a significant global burden. Although genome-wide association studies (GWAS) have identified many T2DM-associated variants, most lie in non-coding regions, making it difficult to interpret their functional roles. Methods We aimed to identify genetically regulated Cytosine–phosphate–Guanine (CpG) sites associated with T2DM by conducting a methylome-wide association study (MWAS), followed by Mendelian randomization (MR) and functional validation using human pancreatic cells and mouse models. MWAS was performed using summary statistics from large-scale GWAS and a DNA methylation (DNAm) prediction model to test associations between genetically predicted DNAm and T2DM. Results We identified 111 CpG sites significantly associated with T2DM in Europeans, including 8 novel sites near genes not previously linked to T2DM. These findings were replicated in independent datasets. Many CpGs also showed associations with cardiometabolic traits, highlighting shared epigenetic mechanisms. Trans-ethnic MR analysis confirmed consistent effects for six CpGs in East Asians. Functional analysis revealed that several CpGs regulate gene expression in human pancreatic α- and β-cells. Among them, 2´-5´-oligoadenylate synthetase like (OASL) expression, regulated by a significant CpG, was differentially expressed in α-cells of T2DM cases compared to controls. Supporting evidence from mouse models suggests a role for OASL in glucose regulation. Conclusion Our study identifies novel genetically regulated CpG sites associated with T2DM risk and highlights OASL as a potential epigenetic regulator of glucose metabolism in α-cells. These findings provide mechanistic insights into the epigenetic architecture of T2DM and suggest potential targets for cross-ethnic biomarker development and therapeutic intervention.

Clonal hematopoiesis (CH) is defined by the expansion of a lineage of genetically identical cells in blood. Genetic lesions that confer a fitness advantage, such as leukemogenic point mutations or mosaic chromosomal alterations (mCAs), are frequent mediators of CH. However, recent analyses of both single cell-derived colonies of hematopoietic cells and population sequencing cohorts have revealed CH frequently occurs in the absence of known driver genetic lesions. To characterize CH without known driver genetic lesions, we use 51,399 deeply sequenced whole genomes from the NHLBI TOPMed sequencing initiative to perform simultaneous germline and somatic mutation analyses among individuals without leukemogenic point mutations (LPM), which we term CH-LPMneg. We quantify CH by estimating the total mutation burden. Because estimating somatic mutation burden without a paired-tissue sample is challenging, we develop a novel statistical method, the Genomic and Epigenomic informed Mutation (GEM) rate, that uses external genomic and epigenomic data sources to distinguish artifactual signals from true somatic mutations. We perform a genome-wide association study of GEM to discover the germline determinants of CH-LPMneg. We identify seven genes associated with CH-LPMneg (TCL1A, TERT, SMC4, NRIP1, PRDM16, MSRA, SCARB1).Functional analyses of SMC4 and NRIP1 implicated altered hematopoietic stem cell self-renewal and proliferation as the primary mediator of mutation burden in blood. We then perform comprehensive multi-tissue transcriptomic analyses, finding that the expression levels of 404 genes are associated with GEM. Finally, we perform phenotypic association meta-analyses across four cohorts, finding that GEM is associated with increased white blood cell count, but is not significantly associated with incident stroke or coronary disease events. Overall, we develop GEM for quantifying mutation burden from WGS and use GEM to discover the genetic, genomic, and phenotypic correlates of CH-LPMneg.

We assessed the association between a genome-wide polygenic risk score (PRS) developed for lung adenocarcinoma (LUAD) risk and mutation on the EGFR gene in 998 East Asian never-smoking female LUAD cases (518 EGFR-positive; 480 EGFR-negative) and 4544 never-smoking controls using case-case and multinomial regression analyses. We found that the PRS was more strongly associated with EGFR-positive LUAD compared with EGFR-negative LUAD, where the association between the fourth quartile of the PRS and EGFR-positive LUAD (odds ratio = 8.63, 95% confidence interval: 5.67-13.14) was significantly higher than the association between the fourth quartile of the PRS with EGFR-negative LUAD (odds ratio = 3.50, 95% confidence interval: 2.44-5.00) (p-heterogeneity = 3.66 × 10-3). Our findings suggest that germline genetic susceptibility may be differentially associated with LUAD in never-smoking female East Asian patients depending on the cancer's mutation status, which may have important public health and clinical implications.

Background: The Supportive and Palliative Care Indicators Tool (SPICT) was developed for identifying, in a timely manner, patients who may benefit from supportive and palliative care for better treatment review, care-plan discussion, and end-of-life care. Although the SPICT has been validated in different languages and for patients living in different settings, it has not been validated for patients receiving home-based medical care (HBMC), or in the context of using traditional Chinese characters. Objectives: The present study aimed to validate the Taiwanese version of the SPICT (SPICT-TW) and to measure its ability to predict six-month mortality in patients who received HBMC in Taiwan. Methods: Seven HBMC agents (five clinics and two hospitals) participated in this validation study. We recruited 129 patients aged ≥ 50 years who had been consistently receiving HBMC for >two months. Results: The results revealed that the SPICT-TW demonstrated similar reliability and validity compared to other language versions of the SPICT. It may be an appropriate tool for healthcare professionals to detect, in a timely manner, the needs for palliative care in older people who receive home healthcare. Furthermore, we found that a combination of four general indicators and one clinical indicator in the SPCIT-TW has the best prediction ability at predicting six-month mortality in these HBMC recipients. This multi-center study validated the SPICT-TW among HBMC recipients in Taiwan. Conclusions: The SPICT-TW demonstrated high reliability and validity through the Kuder–Richardson 20, an intraclass correlation coefficient, Cohen’s kappa, and receiver operating characteristic analysis, supporting its potential as a practical tool for identifying older adults at risk of dying within six months who have not yet received palliative care but may benefit from it.

Background and Objectives: Misconceptions of and cultural differences in aging influence older adults' medical decision-making self-efficacy and engagement in advance care planning (ACP). This study aims to investigate the association between current medical decision-making participation self-efficacy and ACP engagement among older individuals receiving home-based medical care (HBMC) in Taiwan.Design: Baseline data analysis of a nationwide cohort study.Setting and Participants: Patients aged >= 50 years who had been consistently receiving HBMC for > two months between November 2019 and December 2022 were recruited. Study recruitment took place at six hospitals and 12 community home care institutions.Measurement and Analysis: A structured questionnaire was used to collect data on sociodemographic characteristics, decision-making participation self-efficacy, and ACP engagement. Descriptive, stratified, and multivariate logistic regression analyses were performed.Results: In total, 408 HBMC recipients were enrolled (average age: 80.4 years; 55% women). The respondents reported moderate decision-making participation self-efficacy but low ACP engagement. In light of the transtheoretical model of behavior change, participants with moderate or high self-efficacy had a significantly higher chance of reaching the "contemplation stage" for ACP decisions (odds ratio or OR 4.06-27.13). Participants were more likely to reach the "preparation and action stages" for ACP decisions only when they had high self-efficacy (OR 2.76-14.73).Conclusions: Although participants with better current medical decision-making self-efficacy were more likely to contemplate ACP, many did not take action beyond appointing a medical surrogate(s). Strategies to enhance decisional self-efficacy, thereby increasing timely ACP discussions among older adults in home settings in Chinese culture, are warranted. Trial registration number: ClinicalTrials.gov Identifier is NCT04250103 which has been registered on 31st January 2020.

Purpose This study aimed to investigate the distinct yet interconnected aspects of social isolation, namely living alone and loneliness, and their individual and combined effects on predicting health-related quality of life (HRQoL). Methods A comprehensive analysis, encompassing both cross-sectional and longitudinal approaches, was conducted using a nationally representative sample of 5644 community-dwelling adults aged 55 and older from the Healthy Aging Longitudinal Study in Taiwan (HALST). Results Baseline data revealed that 9% of the sample reported living alone, while 10.3% reported experiencing loneliness, with 2.5% reporting both living alone and feeling lonely. Regression analyses consistently demonstrated that loneliness was significantly associated with concurrent and subsequent lower physical (PCS) and mental (MCS) component of HRQoL. Conversely, additional analyses indicated that living alone could indirectly exacerbate the adverse effects of loneliness or contribute to prolonged feelings of loneliness, subsequently predicting lower HRQoL after 3.2 year. Conclusion In terms of practical implications, interventions and policies aiming to enhance HRQoL in older adults should give particular attention to those who report feelings of loneliness, especially individuals living alone.

Fluconazole-resistant clade 4 Candida tropicalis causing candidemia in humans has been detected in tropical/subtropical areas, including those in China, Singapore, and Australia. We analyzed 704 individual yeasts isolated from fruits, soil, water, and farmers at 80 orchards in Taiwan. The most common pathogenic yeast species among 251 isolates recovered from farmers were Candida albicans (14.7%) and C. parapsilosis (11.6%). In contrast, C. tropicalis (13.0%), C. palmioleophila (6.6%), and Pichia kudriavzevii (6.0%) were prevalent among 453 environmental isolates. Approximately 18.6% (11/59) of C. tropicalis from the environment were resistant to fluconazole, and 81.8% (9/11) of those belonged to the clade 4 genotype. C. tropicalis susceptibility to fluconazole correlated with susceptibilities to the agricultural azole fungicides, difenoconazole, tebuconazole, and triadimenol. Tandem gene duplications of mutated ERG11 contributed to azole resistance. Agriculture environments are a reservoir for azole-resistant C. tropicalis; discontinuing agricultural use of azoles might reduce emergence of azole-resistant Candida spp. strains in humans.

Dietary patterns related to inflammation have garnered great interest in disease prevention. The aims of this study were to evaluate whether a proinflammatory diet affects the incidence of frailty and its reversal in a prospective follow-up study. Data were taken from 5663 community-dwelling individuals ≥ 55 years old in Taiwan. The energy-adjusted dietary inflammatory index (DII) and the Empirical Dietary Inflammatory Patterns-Healthy Aging Longitudinal Study in Taiwan (EDIP-HALT) at baseline were calculated using a food frequency questionnaire. Frailty was assessed with Fried’s criteria in 2008–2013 and 2013–2020. Associations with changes in frailty status were assessed with multinominal logistic regressions and adjusted for major confounders. Higher EDIP-HALST scores (proinflammatory) were associated with higher odds of frailty among baseline robust participants in men (OR = 2.44, 95% CI = 1.42–4.21, p-trend < 0.01) and broadline associated in women (OR = 1.96, 95% CI = 0.96–3.98, p-trend = 0.05), but associated with lower odds of reversing back to robust among baseline prefrail participants. However, the later association was only observed in women, and the relationships were stronger in the middle tertile (second vs. first tertile, OR = 0.40, 95% CI = 0.25–0.65). A pro-inflammatory diet pattern was associated with higher odds of frailty onset in baseline robust participants and lower odds of reversal in baseline prefrail female participants.

Background Taiwan was a coronavirus disease 2019 (COVID-19) outlier, with an extraordinarily long transmission-free record: 253 days without locally transmitted infections while the rest of the world battled wave after wave of infection. The appearance of the alpha variant in May 2021, closely followed by the delta variant, disrupted this transmission-free streak. However, despite low vaccination coverage (<1%), outbreaks were well-controlled. Methods This study analyzed the time to border closure and conducted one-sample t test to compare between Taiwan and Non-Taiwan countries prior to vaccine introduction. The study also collected case data to observe the dynamics of omicron transmission. Time-varying reproduction number,Rt, was calculated and was used to reflect infection impact at specified time points and model trends of future incidence. Results The study analyzed and compare the time to border closure in Taiwan and non-Taiwan countries. The mean times to any border closure from the first domestic case within each country were -21 and 5.98 days, respectively (P < .0001). The Taiwanese government invested in quick and effective contact tracing with a precise quarantine strategy in lieu of a strict lockdown. Residents followed recommendations based on self-discipline and unity. The self-discipline in action is evidenced in Google mobility reports. The central and local governments worked together to enact non-pharmaceutical interventions (NPIs), including universal masking, social distancing, limited unnecessary gatherings, systematic contact tracing, and enhanced quarantine measures. The people cooperated actively with pandemic-prevention regulations, including vaccination and preventive NPIs. Conclusions This article describes four key factors underlying Taiwan’s success in controlling COVID-19 transmission: quick responses; effective control measures with new technologies and rolling knowledge updates; unity and cooperation among Taiwanese government agencies, private companies and organizations, and individual citizens; and Taiwanese self-discipline.

Background Prognostic indices can enhance personalized predictions of health burdens. However, a simple, practical, and reproducible tool is lacking for clinical use. This study aimed to develop a machine learning-based prognostic index for predicting all-cause mortality in community-dwelling older individuals.Methods We utilized the Healthy Aging Longitudinal Study in Taiwan (HALST) cohort, encompassing data from 5 663 participants. Over the 5-year follow-up, 447 deaths were confirmed. A machine learning-based routine blood examination prognostic index (MARBE-PI) was developed using common laboratory tests based on machine learning techniques. Participants were grouped into multiple risk categories by stratum-specific likelihood ratio analysis based on their MARBE-PI scores. The MARBE-PI was subsequently externally validated with an independent population-based cohort from Japan.Results Beyond age, sex, education level, and BMI, 6 laboratory tests (low-density lipoprotein, albumin, aspartate aminotransferase, lymphocyte count, high-sensitivity C-reactive protein, and creatinine) emerged as pivotal predictors via stepwise logistic regression (LR) for 5-year mortality. The area under curves of MARBE-PI constructed by LR were 0.799 (95% confidence interval [95% CI]: 0.778-0.819) and 0.756 (95% CI: 0.694-0.814) for the internal and external validation data sets, and were 0.801 (95% CI: 0.790-0.811) and 0.809 (95% CI: 0.774-0.845) for the extended 10-year mortality in both data sets, respectively. Risk categories stratified by MARBE-PI showed a consistent dose-response association with mortality. The MARBE-PI also performed comparably with indices constructed with clinical health deficits and/or laboratory results.Conclusions The MARBE-PI is considered the most applicable measure for risk stratification in busy clinical settings. It holds potential to pinpoint older individuals at elevated mortality risk, thereby aiding clinical decision-making. Graphical Abstract