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Jai-Sing Yang,1,&ast; Ting-Yuan Liu,2,&ast; Yu-Chia Chen,2 Shih-Chang Tsai,3 Yu-Jen Chiu,4,5 Chi-Chou Liao,2 Fuu-Jen Tsai6– 8 1Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, 404327, Taiwan; 2Million-Person Precision Medicine Initiative, Department of Medical Research, China Medical University Hospital, Taichung, 404327, Taiwan; 3Department of Biological Science and Technology, China Medical University, Taichung, 406040, Taiwan; 4Division of Plastic and Reconstructive Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, 112201, Taiwan; 5Department of Surgery, School of Medicine, National Yang Ming Chiao Tung University, Taipei, 112304, Taiwan; 6School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, 404333, Taiwan; 7China Medical University Children’s Hospital, Taichung, 404327, Taiwan; 8Department of Medical Genetics, China Medical University Hospital, Taichung, 404327, Taiwan&ast;These authors contributed equally to this workCorrespondence: Fuu-Jen Tsai, Department of Medical Genetics, China Medical University Hospital, No. 2, Yude Road, Taichung City, 404332, Taiwan, Tel +886 422052121, Email d0704@mail.cmuh.org.twPurpose: Alopecia areata (AA) is one of the most prevalent autoimmune diseases affecting humans. Given that hair follicles are immune-privileged, autoimmunity can result in disfiguring hair loss. However, the genetic basis for AA in the Taiwanese population remains unknown.Materials and Methods: A genome-wide association study was conducted using a cohort of 408 AA cases and 8167 controls. To link variants to gene relationships, we used 882 SNPs (P< 1E-05) within 74 genes that were associated with AA group to build the biological networks by IPA software. HLA diplotypes and haplotypes were analyzed using Attribute Bagging (HIBAG)-R package and chi-square analysis.Results: Seven single nucleotide polymorphisms (SNPs) including LINC02006 (rs531166736, rs187306735), APC (rs112800832_C_CAT), SRP19 (rs139948960, rs144784670), EGFLAM (rs16903975) and LDLRAD3 (rs79874564) were closely associated with the AA phenotype (P< 5E-08). Examination of biological networks revealed that these genomic areas are associated with antigen presentation signaling, B cell and T cell development, Th1 and Th2 activation pathways, Notch signaling, crosstalk signaling between dendritic cells and natural killer cells, and phagosome maturation. Based on human leukocyte antigen (HLA) genotype analysis, four HLA genotypes (HLA-B&ast;15:01-&ast;40:01, HLA-DQA1&ast;01:02-&ast;03:03, HLA-DQA1&ast;01:02, and HLA-DQB1&ast;02:01) were found to be associated with AA (adjusted p-value< 0.05). HLA-DQA1&ast;01:02 is the most significantly related gene in the Taiwanese population (adjusted p-value = 2.09E-05).Conclusion: This study successfully identified susceptibility loci associated with AA in the Taiwanese population. These findings not only shed light on the origins of AA within the Taiwanese context but also contribute to a comprehensive understanding of the genetic factors influencing AA susceptibility.Keywords: alopecia areata, genome-wide association study, network analysis, HLA genotypes

The purpose of this study was to investigate the effects of different stretch amplitudes (angular displacements) on the performance and electromyographic (EMG) activity during drop jumps (DJs). The AMTI force platform, the Biovision electrical goniometer, and EMG system were used to record the ground reaction forces, knee angular displacement, and the EMG signals of the rectus femoris. The EMG data were treated by different data-processing methods: the biphase and triphase data-processing methods. The results revealed that the short-stretch DJs had a larger passive force, a higher eccentric end force, a higher concentric average force, and a faster eccentric angular velocity showing a more efficient stretch-shortening cycle (SSC) mechanism in using elastic energy and reactive properties than the long-stretch DJs. Therefore, the short-stretch DJs are recommended in training for the SSC movement. However, the results of biphase data-processing EMG method did not support this conclusion because there was no significant difference between long-stretch DJs and short-stretch DJs by using the biphase data-processing method, whereas the triphase method did support this conclusion and demonstrated that short-stretch DJs are more efficient. [ABSTRACT FROM AUTHOR]

Mevastatin (MVS) is known for its anti-inflammatory effects, potentially achieved by upregulating heme oxygenase-1 (HO-1), an enzyme involved in cytoprotection against oxidative injury. Nonetheless, the specific processes by which MVS stimulates HO-1 expression in human cardiac fibroblasts (HCFs) are not yet fully understood. In this study, we found that MVS treatment increased HO-1 mRNA and protein levels in HCFs. This induction was inhibited by pretreatment with specific inhibitors of p38 MAPK, JNK1/2, and FoxO1, and by siRNAs targeting NOX2, p47 phox , p38, JNK1, FoxO1, Keap1, and Nrf2. MVS also triggered ROS generation and activated JNK1/2 and p38 MAPK, both attenuated by NADPH oxidase or ROS inhibitors. Additionally, MVS promoted the phosphorylation of FoxO1 and Nrf2, which was suppressed by p38 MAPK or JNK1/2 inhibitor. Furthermore, MVS inhibited TNF-α-induced NF-κB activation and vascular cell adhesion molecule-1 (VCAM-1) expression via the HO-1/CO pathway in HCFs. In summary, the induction of HO-1 expression in HCFs by MVS is mediated through two primary signaling pathways: NADPH oxidase/ROS/p38 MAPK, and JNK1/2/FoxO1 and Nrf2. This research illuminates the underlying processes through which MVS exerts its anti-inflammatory effects by modulating HO-1 in cardiac fibroblasts., (© 2024 Wiley Periodicals LLC.)

Transthyretin (TTR) is a natively tetrameric thyroxine transporter in blood and cerebrospinal fluid whose misfolding and aggregation causes TTR amyloidosis. A rational drug design campaign identified the small molecule tafamidis (Vyndamax) as a stabilizer of the native TTR fold, and this aggregation inhibitor is regulatory agency approved for the treatment of TTR amyloidosis. Here we used cryo-EM to investigate the conformational landscape of this 55 kDa tetramer in the absence and presence of one or two ligands, revealing inherent asymmetries in the tetrameric architecture and previously unobserved conformational states. These findings provide critical mechanistic insights into negatively cooperative ligand binding and the structural pathways responsible for TTR amyloidogenesis, underscoring the capacity of cryo-EM to identify pharmacological targets suppressed by the confines of the crystal lattice, opening uncharted territory in structure-based drug design., Competing Interests: Competing interests: J.W.K. and E.T.P. discovered tafamidis and receive royalty payments for its sales. J.W.K. was a founder and shareholder in FoldRx, which first developed tafamidis as a therapeutic. J.W.K. is a paid consultant for and has received support for travel and accommodations from Pfizer, which sells tafamidis. The other authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Otitis media with effusion (OME) is associated with comorbidities such as allergic rhinitis, gastroesophageal reflux disease, asthma, and more. Many of these comorbidities can be caused by type 2 inflammation (T2I). This study aims to determine the risk of undergoing OME surgery in patients with and without T2I disease., Objective: To determine whether T2I disease is associated with an increased incidence of OME surgery., Methods: This retrospective, matched-cohort study involved the retrospective recruitment of patients with T2I disease (n = 31,603) and non-T2I disease (n = 31,603) from 2010 to 2019, using the Taiwan National Health Insurance Research Database. Statistical analyses were performed using t tests, Cox proportional regression models, Kaplan-Meier estimators, and log-rank tests., Results: Among patients with OME, those with T2I disease had a greater risk of undergoing OME surgery, with an adjusted hazard ratio of 9.84 (95% confidence interval [CI], 8.90-10.88), than those without T2I disease. The adjusted relative risk for the number of OME surgeries in patients with T2I disease was 11.14 (95% CI, 10.30-12.05). Kaplan-Meier analysis showed consistently higher cumulative incidence curves in patients with T2I disease throughout the follow-up period (log-rank test: P < .001)., Conclusions: OME patients with T2I disease had a significantly higher incidence of undergoing surgery due to failed conservative treatment, indicating that T2I may play an important role in middle ear disorders. Further research on this topic should be considered significant and worthy of investigation., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

We conducted the first genome-wide association study (GWAS) of colorectal cancer (CRC) in Taiwan with 5342 cases and 61,015 controls. Ninety-two SNPs in three genomic regions reached genome-wide significance (p < 5 × 10 -8 ). The lead SNPs in these three regions were: rs12778523 (OR = 1.18, 95% CI, 1.15-1.23, p = 4.51 × 10 -13 ), an intergenic SNP between RNA5SP299 and LINC02676 at chromosome 10p14; rs647161 (OR = 1.14, 95% CI, 1.09-1.19, p = 2.21 × 10 -9 ), an intronic SNP in PITX1 at 5q31.1, and rs10427139 (OR = 1.20, 95% CI, 1.14-1.28, p = 3.62 × 10 -9 ), an intronic SNP in GPATCH1 at 19q13.1. We further validated CRC susceptibility SNPs previously identified through GWAS in other populations. A total of 61 CRC susceptibility SNPs were confirmed in Taiwanese. The top validated putative CRC susceptibility genes included: POU2AF2, HAO1, LAMC1, EIF3H, BMP2, ZMIZ1, BMP4, POLD3, CDKN1A, PREX1, CDKN2B, CDH1, and LRIG1. The top enriched pathways included TGF-β signaling, BMP signaling, extracellular matrix organization, DNA repair, and cell cycle control. We could not validate SNPs in HLA-G at 6p22.1 and in NOTCH4 at 6p21.32. We generated a weighted genetic risk score (GRS) using the 61 SNPs and constructed receiver operating characteristic (ROC) curves using the GRS to predict CRC. The area under the ROC curve (AUC) was 0.589 for GRS alone and 0.645 for GRS, sex, and age. These susceptibility SNPs and genes provide important insights into the molecular mechanisms of CRC development and help identify high-risk individuals for CRC in Taiwan., (© 2024 Wiley Periodicals LLC.)

Introduction: This systematic review examines how extreme temperatures impact chronic obstructive pulmonary disease (COPD) morbidity and mortality, focusing on identifying vulnerable subpopulations., Methods: We conducted a systematic literature search from January 1, 2000, to November 6, 2024, across databases like PubMed, MEDLINE and EMBASE, Web of Science, and Scopus, focusing on observational studies that quantitatively defined extreme temperatures and their impacts on COPD morbidity and mortality. Out of 3140 records, 25 studies met the inclusion criteria. We extracted data on study characteristics, effect estimates, and confounders, employing methods to assess the risk of bias and synthesize results., Results: We observed that extreme heat increased the relative risk (RR) for COPD morbimortality by 1.16-fold (95 % CI: 1.08-1.26; p < 0.05), and extreme cold increased the RR by 1.32-fold (95 % CI: 1.20-1.46;). Extreme heat was associated with a 1.19-fold (95 % CI: 1.09-1.30; p < 0.05) increase in COPD mortality. In contrast, extreme cold was associated with both COPD morbidity and mortality, with morbidity increasing by 1.47-fold (95 % CI: 1.26-1.71; p < 0.05) and mortality by 1.23-fold (95 % CI: 1.10-1.38; p < 0.05). Extreme heat poses a higher risk for female COPD patients compared to males. Moreover, extreme heat and cold were associated with morbimortality risk among older adults. Asian populations were sensitive to both temperature extremes, whereas Europeans were predominantly susceptible to extreme cold., Conclusion: This variability in response to extreme temperatures affects COPD morbidity and mortality, emphasizing the need for tailored medical and emergency responses to effectively mitigate health risks during extreme weather events., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Several studies have proposed viral infection with herpes simplex virus (HSV) as a probable cause of vitiligo. We aimed to examine the association between HSV infection and vitiligo., Methods: We used the National Health Insurance Research Database of Taiwan to perform a comparative analysis of the study population with or without a diagnosis of HSV infection. The study period was from January 1st, 2008, to December 31st, 2019. The primary outcome was the date of first vitiligo diagnosis, death, withdrawal from the National Health Insurance Program, or end of the study., Results: We performed 1:1 propensity score matching based on age, sex, and comorbidities, resulting in 1,009,445 matched pairs of patients with and without HSV infections. The adjusted hazard ratio for developing vitiligo in the HSV cohort was 1.71 (95% confidence interval, 1.59 - 1.83; P < 0.001). An age-dependent pattern was also observed among HSV-infected patients with vitiligo (P for interaction < 0.001). Both sexes exhibited a significantly higher risk of developing vitiligo in the presence of HSV infection. The HSV cohort significantly increased cumulative vitiligo risk compared to the non-HSV cohort in a 12-year follow-up (log-rank P < 0.001). The result of sensitivity analysis was compatible with that of primary analysis. Patients with HSV infection had a considerably increased vitiligo risk within the 1-year follow-up than the non-HSV cohort (adjusted hazard ratio, 4.83; 95% confidence interval, 4.04 - 5.77, P < 0.001)., Conclusion: This nationwide population-based study demonstrated an association between HSV infection and an increased risk of vitiligo. Further investigation of HSV DNA in the affected regions of vitiligo lesions may help to establish causality., Competing Interests: Declarations. Ethics statement: The Institutional Review Board of China Medical University Hospital approved the study. The requirement for informed consent was waived because all included participants were deidentified. IRB approval status: The Institutional Review Board of China Medical University Hospital (ID number CMUH110-REC3-133(CR-1)) reviewed and approved this study. Conflict of interest: The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest or financial conflict with the subject matter or materials discussed in the manuscript., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Antimicrobial resistance (AMR) is a growing global concern, compromising the effectiveness of treatments for infections and being referred to as a silent pandemic. This study examines the factors associated with AMR awareness and capacities across 103 countries from 2017 to 2020. This cross-sectional study aimed to determine whether factors such as Human Development Index (HDI), Civil Liberties (CL), Gender Equality (GE), Universal Health Coverage (UHC), Healthcare Workforce Density (HWD), and State Party Self-Assessment Annual Report (SPAR) scores are significantly associated with countries' AMR awareness and capacities. The results identified that the majority of countries had Very High HDI, Full Freedom, Fair GE, Low UHC, High HWD, and Low SPAR scores. However, despite these generally favorable profiles, the majority still lack sufficient awareness and capacity to address AMR. This underscores the importance of strengthening AMR awareness and capacities globally, regardless of a country's characteristics. Significant associations were observed between these factors and AMR awareness and capacities (χ 2 ). UHC emerged as the only factor significantly associated with AMR capacities, where countries with low AMR capacities are more frequently found among countries that also have poor UHC (OR = 10.49, 8.96, and 12.92 across various models; all p < 0.05). This finding highlights the potential to improve the AMR capacities of countries through the achievement of UHC targets., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: Not applicable as this study did not involve direct use of human subjects and utilized publicly available data., (© 2024. The Author(s).)

The Natural Product Research Laboratory (NPRL) of China Medical University Hospital (CMUH) was established in collaboration with CMUH and Professor Kuo-Hsiung Lee from the University of North Carolina at Chapel Hill. The laboratory collection features over 6000 natural products worldwide, including pure compounds and semi-synthetic derivatives. This is the most comprehensive and fully operational natural product database in Taiwan. This review article explores the history and development of the NPRL of CMUH. We then provide an overview of the recent applications and impact of artificial intelligence (AI) in new drug discovery. Finally, we examine advanced powerful AI-tools and related software to explain how these resources can be utilized in research on large-scale drug data libraries. This article presents a drug research and development (R&D) platform that combines AI with the NPRL. We believe that this approach will reduce resource wastage and enhance the research capabilities of Taiwan's academic and industrial sectors in biotechnology and pharmaceuticals., Competing Interests: Conflict of interest: The authors declare that they have no competing interests., (© the Author(s).)

Introduction: In recent years, significant progress has been made in regenerative medicine, specifically in using mesenchymal stem cells (MSCs) due to their regenerative and differentiating abilities. An exciting development in this area is the utilization of exosomes derived from MSCs, which have shown promise in tissue restoration, immune system modulation, and cancer treatment., Objectives: This study aims to analyze global research trends and the academic impact of MSCs-derived exosomes from 2014 to 2023, providing a comprehensive overview of this emerging field., Materials and Methods: The Web of Science database selected 948 relevant publications from 2014 to 2023. Artificial intelligence (AI)-bibliometric tools, including Bibliometrix, CiteSpace, and VOSviewer, were employed to analyze and visualize the data. The focus was on publication quantity, research nations, institutional partnerships, keywords, and research focal points., Results: The study revealed that China, Japan, Taiwan, and the United States are the leaders in publication volume and impact in MSCs-derived exosome research. China has the highest number of publications, while the United States and Iran excel in research quality and influence. Primary research themes were identified through keyword and clustering analyses, including tissue repair, immune modulation, bone regeneration, and cancer treatment. The study also emphasized the importance of international collaboration, with China and the United States demonstrating the most robust cooperation., Conclusion: MSCs-derived exosome research rapidly expands worldwide, showing promising prospects in regenerative medicine and cell therapy. With continued research and international collaboration, MSCs-derived exosomes are expected to play a vital role in future therapeutic application., Competing Interests: Conflict of interest: The authors declare that they have no competing interests., (© the Author(s).)

Introduction: Although the HaCaT keratinocyte model has been used in previous research to study the effects of antipsoriatic agents, there is still a lack of comprehensive understanding of the mechanism of imiquimod (IMQ)-induced proliferation and signal transduction in psoriasis-like keratinocytes., Objectives: This study aimed to investigate the molecular mechanisms and pathways associated with psoriasis-like inflammation caused by IMQ in human keratinocytes., Materials and Methods: HaCaT cells were exposed to different concentrations of IMQ to induce inflammation similar to that observed in psoriasis. Cell viability was evaluated using the MTT assay and cell morphology was examined using phase-contrast microscopy. Gene expression profiles were analyzed through whole transcriptome sequencing, followed by bio-informatics network analysis using IPA software. The GSEA was conducted with the aim of identifying enriched pathways. The expression of key cytokines IL-6 and TNF-α was confirmed by QPCR. Artificial intelligence/machine learning (AI/ML) algorithms were used to predict potential diseases and phenotypes associated with the observed gene profiles., Results: IMQ treatment demonstrated a substantial positive impact on cell survival without any detectable alterations in the morphology of HaCaT cells. A comprehensive analysis of the entire set of transcribed genes identified 513 genes that exhibited differential expression. Bioinformatics analysis revealed key pathways associated with immune response, cellular proliferation, and cytokine signaling. GSEA identified significant enrichment in the IFN-γ response and JAK-STAT signaling pathways. QPCR analysis confirmed the increased mRNA expression levels of IL-6 and TNF-α in cells treated with IMQ. AI/ML algorithms have identified potential correlations with diseases, such as multiple sclerosis, lympho-proliferative malignancy, and autoimmune disorders., Conclusion: Our results highlight the importance of specific genes and pathways, particularly those associated with IFN-γ pathway and IL-6/JAK-STAT signaling. AI/ML predictions indicate potential associations with various diseases and provide valuable insights for the development of novel therapeutic approaches for psoriasis and related disorders., Competing Interests: Conflicts of interest: The authors declare that they have no competing interests., (© the Author(s).)

Background: Bone age (BA) and sexual maturity rating (SMR) are crucial measures in assessing adolescent growth and development. However, studies specifically focusing on the association between BA and SMR in the Taiwanese adolescent population are limited. This study aims to utilize AI-assessed BA results to establish a relationship between BA and SMR in the Taiwanese adolescent population, particularly regarding the initiation of puberty., Materials and Methods: The electronic medical records of bone age assessments conducted between January 1, 2019, and December 31, 2019, were reviewed retrospectively. For individuals with multiple records, only the latest entry within this period was retained. Records lacking a valid SMR or presenting significant medical conditions were excluded from the analysis. Males aged 7-17 years and females aged 6-16 years were included in the study., Results: The onset of puberty was observed to occur at a median bone age of 11.50 years (95% CI: 11.42-11.83) for males and 9.33 years (95% CI: 9.25-9.50) for females., Conclusion: The consistency between BA and SMR could serve as an alternative approach for assessing pubertal status in peripubertal children, providing a less intrusive evaluation regardless of chronological age (CA)., Competing Interests: Conflicts of interest: The authors declare that they have no conflicts of interest., (© the Author(s).)

Introduction: Our previous research demonstrated that a large language model (LLM) based on the transformer architecture, specifically the MegaMolBART encoder with an XGBoost classifier, effectively predicts the blood-brain barrier (BBB) permeability of compounds. However, the permeability coefficients of compounds that can traverse this barrier remain unclear. Additionally, the absorption, distribution, metabolism, and excretion (ADME) characteristics of substances obtained from the Natural Product Research Laboratory (NPRL) at China Medical University Hospital (CMUH) have not yet been determined., Objectives: The study aims to investigate the pharmacokinetic ADME properties and BBB permeability coefficients of NPRL compounds., Materials and Methods: A combined model using a transformer-based MegaMolBART encoder and XGBoost classifier was employed to predict BBB permeability. Machine learning (ML) tools from Discovery Studio were used to assess the ADME characteristics of the NPRL compounds. The CCK-8 assay was conducted to evaluate the cytotoxic effects of NPRL compounds on bEnd.3 brain endothelial cells after exposure to 10 μg/mL of the compounds. We assessed the permeability coefficient by subjecting bEnd.3 cell monolayers to the test compounds and measuring the permeability of FITC-dextran., Results: There were 4956 compounds that could cross the blood-brain barrier (BBB+) and 2851 that could not (BBB-) in the B3DB dataset that was utilized for training. A total of 2461 BBB+ and 2184 BBB- compounds were used in the NPRL-CMUH dataset for testing. The permeability coefficient of temozolomide (TMZ) and 21 other BBB + compounds exceeded 10 × 10 -7 cm/s. Computational analysis revealed that NPRL compounds exhibited a variety of ADME characteristics., Conclusion: Computer-based predictions for the NPRL of CMUH compounds regarding their capacity to traverse the BBB are verified by the findings. Artificial intelligence (AI) prediction models have effectively identified the potential ADME characteristics of various compounds., Competing Interests: Conflicts of interest: The authors declare that they have no competing interests., (© the Author(s).)

Background: The prevalence of diabetic dyslipidemia has gradually increased worldwide and individuals with hypertriglyceridemia often have a high polygenic burden of triglyceride (TG)-increasing variants. However, the contribution of genetic variants to dyslipidemia in patients with type 2 diabetes (T2D) remains limited. Therefore, in this study, we aimed to investigate the genetic characteristics of longitudinal changes in TG levels among patients with T2D and summarize the genetic effects of polygenic risk score (PRS) on TG trajectory and risk of diabetic complications., Methods: We conducted a case-control study. A total of 11,312 patients with T2D with longitudinal TG and genetic data were identified from a large hospital database in Taiwan. We then performed a genome-wide association study and calculated the relative PRS., Results: In total, 21 single-nucleotide polymorphisms (SNPs) related to TG trajectory were identified and yielded an area under the receiver operating characteristic curve (ROC) of 0.712 for high TG trajectory risk among Taiwanese patients with T2D. A cumulative genetic effect was observed for high TG trajectory, even when considering the adherence of a lipid-lowering agent in stratified analysis. An increased PRS increases high TG trajectory risk in a logistic regression model (odds ratio = 1.55; 95% confidence interval [CI] = 1.31-1.83 in the validation cohort). The TG-specific PRS was associated with the risk of diabetic microvascular complications, including diabetic retinopathy and nephropathy (with hazard ratios of 1.11 [95% CI = 1.01-1.21, P = 0.027] and 1.05 [95% CI = 1.01-1.1, P = 0.018], respectively)., Conclusions: This study may contribute to the identification of patients with T2D who are at risk of abnormal TG levels and diabetic microvascular complications using polygenic information., (© 2024. The Author(s), under exclusive licence to Italian Society of Endocrinology (SIE).)

Background: Whether erectile dysfunction (ED) leads to considerable stress for affected men remains unclear? In this study, we investigated whether organic ED (OED) is associated with increased risks of herpes zoster (HZ) and postherpetic neuralgia (PHN)., Methods: A representative subset of Taiwan's National Health Insurance Research Database was employed for this study. Enrollees with OED from the years 2000 to 2018 were selected. To ensure comparability between the case and control groups, we implemented 1:1 propensity score matching based on age, index year, comorbidities, and medications., Results: The case group included 20,808 patients with OED, while the control group consisted of 20,808 individuals without OED. The OED group exhibited a significantly elevated risk of HZ (adjusted hazard ratio [aHR] = 1.74) and PHN (aHR = 1.56) compared to the non-OED group., Conclusions: Men experiencing OED seem to face elevated risks of HZ and PHN compared to those without OED. ED may serve as a warning sign for individuals at HZ risk.

Objectives: To estimate the risk of Alzheimer's disease (AD) associated with long-term use of topical glaucoma medications among middle-aged and older glaucoma patients, and compare the AD risk among various glaucoma subtypes., Methods: This nationwide population-based cohort study utilized insurance claims data from Taiwan's National Health Insurance Research Database between 2008 and 2019. Participants were adults aged 45 years or older either with a diagnosis of glaucoma or without. Those with glaucoma must have received single antiglaucomatous medication (including α2-adrenergic agonists, cholinergic agonists, beta-blockers, prostaglandin analogs, and pilocarpine) for over 90 days. Those with pre-existing AD diagnoses prior to the index date were excluded., Results: A total of 202,000 participants were included in the study, with 101,000 in each group (glaucoma and control groups). Glaucoma patients on topical alpha-2 adrenergic agonist monotherapy exhibited a significantly higher AD risk (aHR 1.15, 95% CI = 1.01-1.31) compared to those on beta-blockers. Glaucoma was further categorized into primary open-angle glaucoma (POAG), normal-tension glaucoma (NTG), primary angle-closure glaucoma (PACG), and unspecified glaucoma. Irrespective of the type of glaucoma, individuals with glaucoma had a significantly higher risk of AD compared to those without glaucoma (POAG: aHR 1.23, 95% CI = 1.08-1.40; NTG: aHR 1.49, 95% CI = 1.19-1.85; PACG: aHR 1.35, 95% CI = 1.19-1.52; unspecified glaucoma: aHR 1.36, 95% CI = 1.23-1.50)., Conclusions: Topical alpha-2 adrenergic agonists might pose increased AD risk in individuals with glaucoma compared to beta-blockers. Accordingly, their utilization should be undertaken judiciously, especially in middle-aged and older populations. Our findings also indicate glaucoma may increase the risk of AD regardless of glaucoma subtype., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to The Royal College of Ophthalmologists.)

Background: Sjögren's syndrome (SS) is an autoimmune disorder that primarily affects the exocrine glands, leading to dryness of mucous membranes and systemic manifestations. This study aimed to identify genetic markers associated with primary SS (pSS) in the Taiwan Han population through a hospital-based genome-wide association study (GWAS) and polygenic risk score (PRS) analysis, addressing the lack of genetic research., Results: This study included 11,390 patients diagnosed with pSS and 113,900 controls. GWAS identified one known locus and eight novel loci. Known HLA alleles, including HLA-DRB1*15:01 and HLA-DQA1*03:01, were successfully replicated in a consistent effect direction. PRS analysis revealed that several autoimmune diseases share similar genetic backgrounds with pSS, including rheumatoid arthritis and systemic lupus erythematosus., Conclusion: This study represents the largest cohort to date on the genetics of pSS in the Taiwan Han population. Our findings provide valuable insights into the pathogenesis of pSS and emphasize the comorbidities associated with it as an autoimmune disease., Competing Interests: Declaration of competing interest The authors affirm that the research was conducted without any commercial or financial relationships that could be perceived as potential conflicts of interest., (Copyright © 2024. Published by Elsevier Inc.)

Background: Tourette syndrome (TS) is a neurodevelopmental disorder characterized by motor and vocal tics. Several susceptibility loci associated with TS have been identified previously in populations of European descent using genome-wide association studies (GWAS). However, the exact pathogenic mechanism underlying TS is unknown; additionally, the results of previous GWAS for TS were based on Western populations, which may not translate to other populations. Therefore, we conducted a GWAS in Taiwanese patients with TS and chronic tic disorders (CTDs), with an aim to elucidate the genetic basis and potential risk factors for TS in this population., Methods: GWAS was performed on a Taiwanese TS/CTDs cohort with a sample size of 1007 patients with TS and 25,522 ancestry-matched controls. Additionally, polygenic risk score was calculated and assessed., Results: Genome-wide significant locus, rs12313062 (p = 1.43 × 10 -8 ) and other 9 single nucleotide polymorphisms, were identified in chromosomes 12q23.2, associated with DRAM1 and was a novel susceptibility locus identified in TS/CTDs group. DRAM1, a lysosomal transmembrane protein regulated by p53, modulates autophagy and apoptosis, with potential implications for neuropsychiatric conditions associated with autophagy disruption., Conclusions: This study conducted the first GWAS for TS in a Taiwanese population, identifying a significant locus on chromosome 12q23.2 associated with DRAM1. These findings provide novel insights into the neurobiology of TS and potential directions for future research in this area., (© 2024 The Authors. Published by Elsevier B.V. on behalf of Chang Gung University. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)

The impact of sodium-glucose cotransporter 2 inhibitors (SLGT2i) usage on reducing the risk of dementia remains uncertain. Our research seeks to establish the association between dementia risk and SLGT2 inhibitors among individuals with diabetes. This study relied on data from the Taiwan National Health Insurance Database (NHIRD), which was established in 1995 coinciding with the launch of the National Health Insurance (NHI) program by the Taiwanese government. The NHI program was implemented to enhance the healthcare system and public health in Taiwan. Patients with type 2 diabetes mellitus (T2DM) administered SGLT2i between 2016 and 2019 were included in the SGLT2i cohort. The comparison cohort consisted of patients who did not receive SGLT2i, propensity score matching by sex, age (in 5-y intervals), index date year, insurance fee, urbanization, comorbidities, and medications, with a 1:1 ratio of the exposure group. SGLT2i users had a significantly lower risk of dementia than non-SGLT2i users after adjusting for age, sex, insurance fees, urbanization, comorbidities, and medications (adjusted HR = 0.53, 95%CI: 0.50-0.57). The results revealed that patients treated with SGLT2i have a lower risk of dementia in Taiwan., Competing Interests: Declarations. Ethics approval: The NHIRD secures patient personal data by employing encryption to safeguard privacy. It also provides researchers with anonymous identification numbers that are associated with relevant claims data, including details such as gender, date of birth, medical services, and prescriptions. As a result, patient consent is not required to access the NHIRD for this research project. This research project received approval for exemption from the Institutional Review Board (IRB) at China Medical University (Approval Number CMUH109-REC2-031 (CR2)), and the IRB explicitly waived the requirement for informed consent. All the procedures were followed by the relevant guidelines and regulations. Consent for publication: All authors agree to publish the article. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Endometriosis is a common gynecological disorder affecting around 10% of reproductive-age women. Although many hypotheses were proposed, genetic alteration has been considered as one of the key factors promoting pathogenesis. Due to racial/ethnic disparities in the process of hormone regulation and nutrition metabolism, a genome-wide association study (GWAS) with 2794 cases and 27,940 controls was conducted in a Taiwanese-Han population. Our study identified five significant susceptibility loci for endometriosis, and three of them, WNT4 (on the 1p36.12), RMND1 (6q25.1), and CCDC170 (6q25.1), have been previously associated with endometriosis across different populations, including European and Japanese descent cohorts. Other two including C5orf66/C5orf66-AS2 (5q31.1) and STN1 (10q24.33) are newly identified ones. Functional network analysis of potent risk genes revealed the involvement of cancer susceptibility and neurodevelopmental disorders in endometriosis development. In addition, long non-coding RNAs (lncRNAs) C5orf66 and C5orf66-AS2 can interact with many RNA-binding proteins (RBPs) which can influence RNA metabolic process, mRNA stabilization, and mRNA splicing, leading to dysregulation in tumor-promoting gene expression. Those findings support clinical observations of differences in the presentation of endometriosis in Taiwanese-Han population with higher risks of developing deeply infiltrating/invasive lesions and the associated malignancies., (© 2024. The Author(s), under exclusive licence to The Japan Society of Human Genetics.)

Background: Atrial fibrillation (AF), the most common atrial arrhythmia, presents with varied clinical manifestations. Despite the identification of genetic loci associated with AF, particularly in specific populations, research within Asian ethnicities remains limited. In this study we aimed to develop predictive models for AF using AF-associated single-nucleotide polymorphisms (SNPs) from a genome-wide association study (GWAS) on a substantial cohort of Taiwanese individuals, to evaluate the predictive efficacy of the model., Methods: There were 75,121 subjects, that included 5694 AF patients and 69,427 normal control subjects with GWAS data, and we merged polygenic risk scores from AF-associated SNPs with phenome-wide association study-derived risk factors. Advanced statistical and machine learning techniques were used to develop and evaluate AF predictive models for discrimination and calibration., Results: The study identified the top 30 significant SNPs associated with AF, predominantly on chromosomes 10 and 16, implicating genes like NEURL1, SH3PXD2A, INA, NT5C2, STN1, and ZFHX3. Notably, INA, NT5C2, and STN1 were newly linked to AF. The GWAS predictive power using polygenic risk score-continuous shrinkage analysis for AF exhibited an area under the curve of 0.600 (P < 0.001), which improved to 0.855 (P < 0.001) after adjusting for age and sex. Phenome-wide association study analysis showed the top 10 diseases associated with these genes were circulatory system diseases., Conclusions: Integrating genetic and phenotypic data enhanced the accuracy and clinical relevance of AF predictive models. The findings suggest promise for refining AF risk assessment, enabling personalized interventions, and reducing AF-related morbidity and mortality burdens., Competing Interests: Disclosures The authors have no conflicts of interest to disclose., (Copyright © 2024 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Background: Type 2 diabetes mellitus (T2DM) and its related complications are associated with schizophrenia. However, the relationship between antipsychotic medications (APs) and T2DM risk remains unclear. In this population-based, retrospective cohort study across the country, we investigated schizophrenia and the effect of APs on the risk of T2DM, and glucose homeostasis-related gene expression., Methods: We used information from the Longitudinal Health Insurance Database of Taiwan for individuals newly diagnosed with schizophrenia (N = 4,606) and a disease-free control cohort (N = 4,606). The differences in rates of development of T2DM between the two cohorts were assessed using a Cox proportional hazards regression model. The effects of APs on the expression of glucose homeostasis-related genes in liver and muscle cell lines were assessed using quantitative real-time PCR., Results: After controlling potential associated confounding factors, the risk of T2DM was higher in the case group than that in the control group [adjusted hazard ratio (aHR), 1.80, p < 0.001]. Moreover, the likelihood of T2DM incidence in patients with schizophrenia without AP treatment (aHR, 2.83) was significantly higher than that in non-schizophrenia controls and those treated with APs (aHR ≤ 0.60). In an in vitro model, most APs did not affect the expression of hepatic gluconeogenesis genes but upregulated those beneficial for glucose homeostasis in muscle cells., Conclusion: This study demonstrates the impact of schizophrenia and APs and the risk of developing T2DM in Asian populations. Unmeasured confounding risk factors for T2DM may not have been included in the study. These findings may help psychiatric practitioners identify patients at risk of developing T2DM., (© 2024. The Author(s).)

Current genome-wide association studies (GWAS) for kidney function lack ancestral diversity, limiting the applicability to broader populations. The East-Asian population is especially under-represented, despite having the highest global burden of end-stage kidney disease. We conducted a meta-analysis of multiple GWASs (n = 244,952) on estimated glomerular filtration rate and a replication dataset (n = 27,058) from Taiwan and Japan. This study identified 111 lead SNPs in 97 genomic risk loci. Functional enrichment analyses revealed that variants associated with F12 gene and a missense mutation in ABCG2 may contribute to chronic kidney disease (CKD) through influencing inflammation, coagulation, and urate metabolism pathways. In independent cohorts from Taiwan (n = 25,345) and the United Kingdom (n = 260,245), polygenic risk scores (PRSs) for CKD significantly stratified the risk of CKD (p < 0.0001). Further research is required to evaluate the clinical effectiveness of PRS CKD in the early prevention of kidney disease., (© 2024. The Author(s).)

One person suffers from dementia every 3 seconds globally. Thirteen older adults aged 65 and older will have dementia, and 1 in 5 older adults over the age of 80 years will have dementia in Taiwan. Older adults should be equipped with demonstrated health beliefs regarding dementia prevention and health promotion about Ascertain Dementia 8-item Questionnaire (AD8), cues to action, health beliefs, self-efficacy, and behavioral intention in daily life. The purpose of this study was to survey older adults' demographic background, AD8, cues to action, health beliefs, self-efficacy, and behavioral intention for dementia prevention and health promotion. A cross-sectional survey design was used. Convenience sampling was performed. A total of 330 older adults participated in the study. The questionnaire used in this study included questions on older adults' demographic background, AD8, cues to action, health beliefs, self-efficacy, and behavioral intention. The researcher collected complete data by receiving the sampling on paper or by interview from October 8, 2021, to February 12, 2022. The SPSS 23.0 statistical package was employed for quantitative analysis. Data analysis included frequency, percentage, mean, standard deviation (SD), Spearman's rho correlation, and simple regression analysis. The findings showed that older adults had the following mean scores on health beliefs (perceived susceptibility 13.45 ± SD 2.34, perceived severity 13.54 ± SD 2.69, perceived benefits 16.57 ± SD 2.84, perceived barriers 8.20 ± SD 3.69), self-efficacy 16.96 ± SD3.52, and behavioral intention 19.56 ± SD 3.51. Older adults' demographic background, perceived susceptibility, perceived severity, perceived benefits, perceived barriers, and self-efficacy explained 56.1% of the variance in behavioral intention. The conclusions of the study indicated that older adults' demographic background, AD8, cues to action, health beliefs, self-efficacy, and behavioral intention constituted the main factors for effective dementia prevention and health promotion. In the future, the research team will continue to explore older adults' dementia prevention and develop many strategies on health promotion, as well as slowing the aging brain process., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Clinical studies have shown that glucagon-like peptide-1 receptor agonists (GLP-1 RA) can have beneficial effects on cardiopulmonary function. We conducted this longitudinal cohort study to compare the risk of cardiopulmonary outcomes and mortality between GLP-1 RA use and no use in patients with type 2 diabetes (T2D) and chronic obstructive pulmonary disease (COPD)., Methods: The study identified 8060 matched GLP-1 RA users and non-users from Taiwan's National Health Insurance Research Database from 1 January 2008 to 31 December 2019. Cox proportional hazards models were used to determine the risk of cardiopulmonary outcomes between GLP-1 RA users and non-users., Results: The mean follow-up time was 2.51 and 2.46 years for GLP-1 RA users and non-users, respectively. In the matched cohorts, GLP-1 RA users had a significantly lower risk of mortality (adjusted HR (aHR) 0.46, 95% CI 0.38 to 0.56), cardiovascular events (aHR 0.73, 95% CI 0.65 to 0.82), non-invasive positive pressure ventilation (aHR 0.66, 95% CI 0.47 to 0.93), invasive mechanical ventilation (aHR 0.64, 95% CI 0.51 to 0.8) and bacterial pneumonia (aHR 0.76, 95% CI 0.65 to 0.88) than GLP-1 RA non-users. The subsequent analyses for various subgroup and medication duration also showed that GLP-1 RA was associated with a significantly lower risk of mortality, cardiovascular events, ventilation support and bacterial pneumonia than non-GLP-1 RA., Conclusion: This nationwide cohort study showed that GLP-1 RA had a lower risk of cardiopulmonary outcomes and all-cause mortality than non-GLP-1 RA in patients with T2D and COPD. GLP-1 RA may help manage diabetes in people with COPD., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Scabies is typically treated with scabicides like lindane, which poses a risk for acute neural toxicity. Lindane's prolonged use, particularly in agriculture, is linked to neurodegenerative diseases, including Parkinson's disease (PD), the second most common neurodegenerative disorder. This study aimed to evaluate whether scabies patients, particularly those treated with topical lindane, are at increased risk of developing PD., Methods: A nationwide population-based cohort study was conducted using data from Taiwan's National Health Research Institutes claims database from 2000 to 2018. The study included 27,173 patients with scabies, matched to a control group, with both groups followed for up to 18 years. The primary outcome was the incidence of newly diagnosed PD, and the hazard ratio (HR) for PD was calculated, focusing on those treated with topical lindane., Results: Among the 54,346 patients, 1639 (3.0%) were newly diagnosed with PD, with 993 (60.6%) from the scabies group and 646 (39.4%) from the control group. Scabies patients had an adjusted hazard ratio (aHR) of 1.46 (95% CI 1.32-1.63) for developing PD compared to controls. However, patients treated with topical lindane had a significantly lower aHR for PD at 0.15 (95% CI 0.12-0.19; p < 0.001), with a lower cumulative incidence of PD also observed in this group ( p < 0.001)., Conclusions: Scabies patients are at a 1.46-fold increased risk of developing PD, but those treated with lindane exhibit a significantly lower risk, suggesting potential protective effects of lindane against PD.

Background: Several risk factors for peptic ulcer disease (PUD) have been identified; however, the recurrence rate of PUD remains high even with standard ulcer treatments. High cholesterol levels have been proposed as a risk factor for PUD, but clinical evidence remains limited. Therefore, this database study investigated whether hyperlipidemia increases PUD risk and whether antihyperlipidemic drugs reduce this risk., Methods: A long-term cohort design was adopted, and Taiwan's National Health Insurance Research Database was used to enroll patients diagnosed with hyperlipidemia between 2000 and 2016. Patients without hyperlipidemia were randomly matched based on variables such as age and gender to establish a comparison cohort at a 1:1 ratio. Another cohort study was conducted to determine whether antihyperlipidemic drugs or red yeast rice prescriptions can reduce the incidence of PUD in patients with hyperlipidemia., Results: The overall incidence of PUD was 1.48 times higher in the hyperlipidemia cohort (203,235 patients) than in the nonhyperlipidemia cohort (adjusted hazard ratio, 1.48; 95% CI, 1.46-1.50; p < 0.001). Among the patients with hyperlipidemia, those who used antihyperlipidemic drugs with or without red yeast rice prescriptions exhibited a lower risk of developing PUD relative to those who did not use them; the adjusted hazard ratios were 0.33 (95% CI, 0.21-0.52) and 0.81 (95% CI, 0.78-0.84), respectively. When the cumulative exposure to antihyperlipidemic drugs and red yeast rice prescriptions increased, the risk of developing PUD showed a decreasing trend, which was statistically significant for antihyperlipidemic drugs but not for red yeast rice., Conclusion: Hyperlipidemia is associated with a higher risk of PUD, which can be reduced through the administration of antihyperlipidemic drugs with or without red yeast rice prescriptions., Competing Interests: Conflicts of interest: The authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2024, the Chinese Medical Association.)

Background: In Taiwan, nonionic iodinated contrast media (ICMs) are commonly used but can occasionally cause severe side effects. The infrequency of these adverse events, coupled with the complexities in establishing direct causality, poses significant challenges for genetic research., Objective: : To investigate the genetic factors associated with skin reactions mediated by nonionic ICMs on a genome-wide scale., Methods: A hospital-based cohort from the China Medical University Hospital biobank was utilized to conduct a comprehensive genome-wide association study (GWAS) using PLINK v1.9. The study incorporated two distinct cohorts: one based on adverse drug reaction (ADR) reports, capturing immediate reactions, and the other based on self-reports, which primarily reflected delayed reactions. Known loci were determined by the GWAS catalog. Fine mapping was conducted by FINEMAP to predict causal variants. Pathway enrichment analysis was performed by clusterProfiler to reveal the biological function of the identified genetic signatures., Results: The ADR-based cohort included 120 cases and 3640 controls. GWAS identified 6 candidate risk loci, namely rs150515068, rs6847491, rs192044153, rs191908641, rs376660317, and rs368821335. The self-report-based cohort, consisting of 275 cases and 8338 controls, revealed 36 additional candidate risk loci. Fine mapping further identified 4 causal variants within each cohort. Pathway analysis showed that immediate HSR-related genes are linked to growth hormone response and signaling, while non-immediate HSR genes are involved in neurotransmission., Conclusion: This study offers new perspectives on the genetic foundation of nonionic ICM-induced skin reactions within the Taiwanese population, suggesting that the genes contributing to immediate and non-immediate HSRs might have different functional roles.