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Abstract Background Osteoporosis is a common condition that increases the risk of fracture and mortality. In Taiwan, clinical guidelines recommend pharmaceutical therapy for patients with a T-score of ≤ − 2.5; however, Taiwan’s National Health Insurance (NHI) only covers these medications for those with a history of fragility fractures. This gap in coverage necessitates a discussion of out-of-pocket treatment options. To address this, we provided an integrated care program with patient education and shared decision-making by nurse case managers specializing in osteoporosis. We evaluated whether education by nurse case managers influences patients with a T-score ≤ − 2.5, who are not covered by the NHI, to choose out-of-pocket pharmaceutical therapy. Methods We retrospectively reviewed medical records of patients who underwent bone density scanning at our hospital between January 2014 and December 2021. We identified 4,462 patients with a T-score of ≤ − 2.5 who were ineligible for NHI-covered anti-osteoporotic therapy and analyzed trends in out-of-pocket medication use. Since the integrated care program began in 2018, we evaluated whether education by nurse case managers between 2018 and 2021 influenced patients’ decisions to pay out-of-pocket for therapy. After the implementation of the integrated care program, we identified 2,910 patients with a T-score ≤ -2.5 who were ineligible for NHI-covered anti-osteoporotic therapy. Of these, 640 opted for out-of-pocket treatment, while 2,270 chose conservative care. After a 1:1 propensity score match based on age and sex, logistic regression was used to analyze the impact of nurse case manager education on these decisions. Results Between 2014 and 2021, 888 of the 4,462 patients chose out-of-pocket pharmaceutical therapy. Before the implementation of the integrated care program and patient education by nurse case managers (2014–2017), 16% of the patients opted to pay out-of-pocket for anti-osteoporotic therapy. After the program was implemented (2018–2021), the rate increased significantly to 22% (P

Abstract Background Early identification of frail patients and early interventional treatment can minimize the frailty-related medical burden. This study investigated the use of machine learning (ML) to detect frailty in hospitalized older adults with acute illnesses. Methods We enrolled inpatients of the geriatric medicine ward at Taichung veterans general hospital between 2012 and 2022. We compared four ML models including logistic regression, random forest (RF), extreme gradient boosting, and support vector machine (SVM) for the prediction of frailty. The feature window as well as the prediction window was set as half a year before admission. Furthermore, Shapley additive explanation plots and partial dependence plots were used to identify Fried’s frailty phenotype for interpreting the model across various levels including domain, feature, and individual aspects. Results We enrolled 3367 patients. Of these, 2843 were frail. We used 21 features to train the prediction model. Of the 4 tested algorithms, SVM yielded the highest AUROC, precision and F1-score (78.05%, 94.53% and 82.10%). Of the 21 features, age, gender, multimorbidity frailty index, triage, hemoglobin, neutrophil ratio, estimated glomerular filtration rate, blood urea nitrogen, and potassium were identified as more impactful due to their absolute values. Conclusions Our results demonstrated that some easily accessed parameters from the hospital clinical data system can be used to predict frailty in older hospitalized patients using supervised ML methods.

Background The aim of this study is to evaluate the ability of generative artificial intelligence (AI) models to handle specialized medical knowledge and problem-solving in a formal examination context. Methods This research utilized internal medicine exam questions provided by the Taiwan Internal Medicine Society from 2020 to 2023, testing three AI models: GPT-4o, Claude_3.5 Sonnet, and Gemini Advanced models. Rejected queries for Gemini Advanced were translated into French for resubmission. Performance was assessed using IBM SPSS Statistics 26, with accuracy percentages calculated and statistical analyses such as Pearson correlation and analysis of variance (ANOVA) performed to gauge AI efficacy. Results GPT-4o’s top annual score was 86.25 in 2022, with an average of 81.97. Claude_3.5 Sonnet reached a peak score of 88.13 in 2021 and 2022, averaging 84.85, while Gemini Advanced lagged with an average score of 69.84. In specific specialties, Claude_3.5 Sonnet scored highest in Psychiatry (100%) and Nephrology (97.26%), with GPT-4o performing similarly well in Hematology & oncology (97.10%) and Nephrology (94.52%). Gemini's best scores were in Psychiatry (86.96%) and Hematology & Oncology (82.76%). Gemini Advanced models struggled with Neurology, scoring below 60%. Additionally, all models performed better on text-based questions than on image-based ones, without significant differences. Claude 3 Opus scored highest on COVID-19-related questions at 89.29%, followed by GPT-4o at 75.00% and Gemini Advanced at 67.86%. Conclusions AI models showed varied proficiency across medical specialties and question types. GPT-4o demonstrated higher image-based correction rates. Claude_3.5 Sonnet generally and consistently outperformed others, highlighting significant potential for AI in assisting medical education.

Background Taiwan is well-known for its quality healthcare system. The country's medical licensing exams offer a way to evaluate ChatGPT's medical proficiency. Methods We analyzed exam data from February 2022, July 2022, February 2023, and July 2033. Each exam included four papers with 80 single-choice questions, grouped as descriptive or picture-based. We used ChatGPT-4 for evaluation. Incorrect answers prompted a “chain of thought” approach. Accuracy rates were calculated as percentages. Results ChatGPT-4's accuracy in medical exams ranged from 63.75% to 93.75% (February 2022–July 2023). The highest accuracy (93.75%) was in February 2022's Medicine Exam (3). Subjects with the highest misanswered rates were ophthalmology (28.95%), breast surgery (27.27%), plastic surgery (26.67%), orthopedics (25.00%), and general surgery (24.59%). While using “chain of thought,” the “Accuracy of (CoT) prompting” ranged from 0.00% to 88.89%, and the final overall accuracy rate ranged from 90% to 98%. Conclusion ChatGPT-4 succeeded in Taiwan's medical licensing exams. With the “chain of thought” prompt, it improved accuracy to over 90%.

Abstract Background Osteoporosis and sarcopenia, respectively, have detrimental impact on health, and combination of both conditions, termed osteosarcopenia, is becoming an increasingly important disorder in older adults as populations age. This study aimed to explore the relationship between osteoporosis and possible sarcopenia and their joint effect on physical performance, nutritional status, and cognition in community-dwelling older adults. Methods This study was conducted at a medical center in Taiwan, which included the adjacent community care station. The participants were recruited through regular activities at the community care station between January 01, 2015 and February 28, 2022. During the study period, dual-energy X-ray absorptiometry and comprehensive geriatric assessment consisting of comorbidity burden, functional status, cognition, mood, and nutritional status were performed during the study period. Possible sarcopenia was identified utilizing the criteria set by the Asian Working Group on Sarcopenia in 2019 using the criteria of low muscle strength alone, and osteoporosis was defined by the World Health Organization criteria. Accordingly, the study subjects were divided into four groups: normal, only osteoporosis, only possible sarcopenia, and possible osteosarcopenia. Results There were 337 participants (68.6% female) with a median age of 78.0 years (interquartile range: 71.0–85.0 y/o). According to the clinical definition of osteosarcopenia, 78 participants were normal, 69 participants showed possible sarcopenia, 61 participants had osteoporosis, and 129 had osteoporosis with possible sarcopenia. Among the four groups, the prevalence rates of chronic illness, functional capacity, physical performance, cognitive impairment, and malnutrition revealed statistically significant differences. Using logistic regression analysis after adjusting for the other covariates, osteoporosis with possible sarcopenia was associated with an increased odds ratio of cognitive impairment. Conclusions The findings suggest that compared to osteoporosis or possible sarcopenia alone, osteoporosis with possible sarcopenia was more likely to be associated with cognitive impairment. Early identification and targeted interventions for cognitive impairment in older adults with osteosarcopenia may be valuable in maintaining cognitive well-being and overall quality of life.

Concurrent chemoradiotherapy is an effective treatment option for patients with low-grade colorectal cancer (CRC) in the local disease stage. At present, the principle of the Taiwan Medical Center is to treat CRC patients with combination radiotherapy and chemotherapy (high-dose 5-FU) for a period of about five weeks prior to surgery. Radical resection of the tumor is performed at least six to eight weeks after concurrent chemoradiotherapy (CCRT). However, this approach fails to produce the desired therapeutic effect in approximately 20% to 30% of patients, and such patients are unnecessarily exposed to the risks of radiation and drug toxicity posed by this therapy. Therefore, it is crucial to explore new biomarkers to predict the prognosis of CRC. SUMO-activating enzyme subunit 1 (SAE1) plays an important role in SUMOylation, a post-translational modification involved in cellular functions, such as cell proliferation, cell cycle, and apoptosis. In our study, to explore the clinical–pathological role of SAE1 protein in CRC, we evaluated the clinical data and paraffin sections from CRC patients. The expression of SAE1 was evaluated using immunohistochemical analysis, and clinical parameters were analyzed using chi-square and Kaplan–Meier survival tests. The results of in vitro proliferation and radiosensitive assays were compared between control groups and SAE1 siRNA groups. Western blotting was also used to detect the expressions of the SAE1, PARP, cyclin D1, p-NF-κB, and NF-κB proteins. Flow cytometry and colony formation assays were used to detect the effect of SAE-1 on radiosensitivity. In vivo, we detected the growth curve in a mouse xenograft model. The results showed that SAE-1 was revealed to be an independent prognostic biomarker of CRC. SAE1 knockdown inhibited CRC proliferation in vitro and in vivo, and led to the cleavage of PARP, downregulation of cyclin D1 protein expression, and downregulation of p-NF-κB/NF-κB. Additionally, SAE1 knockdown promoted radiosensitivity in CRC cells. Therefore, it was inferred that SAE1 may be used as a potential therapeutic target in CRC treatment.

IntroductionThe objective of this study was to investigate associations between baseline body constitutions (BCs) in traditional Chinese Medicine (TCM) and all-cause mortality in Chinese individuals with type 2 diabetes.MethodsA total of 887 individuals with type 2 diabetes who were enrolled in managed care in 2010 were included. These individuals were followed up until 2015, and their mortality status was determined through the use of Taiwan National Death Datasets. At baseline, BC status of participants, including Yin deficiency, Yang deficiency, and phlegm stasis, was assessed using a well-developed Body Constitutions Questionnaire. Hazard ratios (HR) were calculated using a multivariate Cox proportional hazards model.ResultsDuring 6807.2 person-years of follow-up of 887 participants, with an average follow-up period of 7.7 years, a total of 190 individuals died, resulting in an incidence density of 0.0279 person-years. Yin deficiency was associated with all-cause mortality (HR, 95% CI: 1.39, 1.02–1.90). This study indicates that individuals diagnosed with Yin deficiency in TCM, characterized by symptoms such as thirst, reduced urine volume, hard stool, and hot flushes, had a 39% higher risk of all-cause mortality.DiscussionThe findings may provide information for TCM practitioners on tailoring treatment plans for persons with type 2 diabetes. No conclusive statements can be made on the basis of the preliminary data presented here. Controlled prospective studies are warranted.

Abstract Background Dying at home accompanied by loved-ones is regarded favorably and brings good luck in Taiwan. This study aimed to examine the relevant factors affecting whether an individual dies at home or not in a group of terminal patients receiving palliative home care service. Methods The patients who were admitted to a palliative home care service at a hospital-affiliated home health care agency were consecutively enrolled between March 1, 2021 and March 31, 2022. During the period of care, the instruments of the palliative care outcomes collaboration was used to assess patients in each home visit twice a week, including symptom assessment scale, palliative care problem severity score, Australia-modified Karnofsky performance status, resource utilization groups-activities of daily living, and palliative care phase. Results There were 56 participants (53.6% female) with a median age of 73.0 years (interquartile range (IQR) 61.3–80.3 y/o), of whom 51 (91.1%) patients were diagnosed with cancer and 49 (96.1%) had metastasis. The number of home visits was 3.5 (IQR 2.0–5.0) and the average number of days under palliative home care service was 31 (IQR 16.3–51.5) before their death. After the end of the study, there was a significant deterioration of sleeping, appetite, and breathing problems in the home-death group, and appetite problems in the non-home death patients. However, physician-reported psychological/spiritual problems improved in the home-death group, and pain improved in the non-home death patients. Physical performance deteriorated in both groups, and more resource utilization of palliative care was needed. The 44 patients who died at home had greater cancer disease severity, fewer admissions, and the proportion of families desiring a home death for the patient was higher. Conclusions Although the differences in palliative outcome indicators were minor between patients who died at home and those who died in the hospital, understanding the determinants and change of indicators after palliative care service at different death places may be helpful for improving the quality of end-of-life care.

Background With higher age, frailty escalates the risk of falls, unexpected physical dysfunction, hospitalization, and mortality. Polypharmacy in the older population is a major challenge that not only increases medical costs, but also may worsen the risk of hospitalization and death. More importantly, the properties of anti-cholinergic drugs contribute various negative effects. This study aimed to investigate the sex difference in the association of polypharmacy, anticholinergic burden, and frailty with mortality. Methods Participants older than 65 years who attended the geriatric outpatient clinic of the study center between January 2015 and July 2020 were invited to participate in this retrospective study. Comprehensive geriatric assessment data were collected and the phenotype of frailty was determined by Fried’s criteria. Cox regression and the Kaplan–Meier curve were used to identify risk factors of 5-year survival along with intergroup differences in the risks. Results Of the 2,077 participants, 47.5% were female. The prevalence of frailty and the rate of polypharmacy were 44.7% and 60.6%, respectively. Higher age, male sex, low body mass index, low Mini-Mental State Examination scores, low activities of daily living, frailty status, polypharmacy, and a high Charlson Comorbidity Index score, and greater anticholinergic burden were significant risk factors that were associated with the 5-year all-cause mortality. Male patients with frailty exhibited the highest risks of mortality compared with male patients without frailty and female patients with or without frailty. Polypharmacy was significantly associated with a higher 5-year mortality rate in the frail male group compared with the non-frail male. In frail female group, individuals with a higher anticholinergic burden (as indicated by the Anticholinergic Cognitive Burden Scale) from drug usage exhibited an elevated 5-year mortality rate. Conclusions Polypharmacy and greater anticholinergic burden, synergistically interacted with frailty and intensified the 5-year mortality risk in a gender-specific manner. To mitigate mortality risks, clinicians should prudently identify polypharmacy and anticholinergic burden in the older population.

Abstract Background Declined renal function is associated with physical function impairment and frailty in a graded fashion. This study aimed to examine the relationship between renal function, frailty and physical performance with mortality in older patients with diabetes, while also determining their combined effects on patient outcome. Methods A retrospective longitudinal study was conducted in elderly patients with diabetes. Kidney disease staging was based on clinical practice guidelines of the International Society of Nephrology, and chronic kiney disease (CKD) was defined as urinary albumin to creatinine ratio (UACR) > 30 mg/g, persistent reduction in estimated glomerular filtration rate (eGFR) below 60 mL/min per 1.73 m2 or both. The modified Rockwood frailty index (RFI) was composed of cumulative health deficits, and physical function was determined by handgrip strength (HGS). Additionally, a timed up and go (TUG) test was assessed at baseline. Kaplan-Meier survival and Cox proportional hazard analyses were used to analyze the association between CKD, frailty, physical function and mortality. Results For the 921 enrolled patients, their mean age was 82.0 ± 6.7 years. After a median 2.92 (interquartile range [IQR] 1.06–4.43) year follow-up, the survival rate was 67.6% and 85.5% in patients with and without CKD, respectively. The mortality hazard ratio (crude HR) with CKD was 5.92 for those with an RFI higher than 0.313 (95% CI 3.44–10.18), 2.50 for a TUG time longer than 21 s (95% CI 1.22–5.13), and 2.67 for an HGS lower than 10.57 kg in females or 20.4 kg in males (95% CI 1.12–6.37). After multivariate adjustment, the mortality hazard ratio for an RFI ≥ 0.313 was 5.34 (95% CI 2.23–12.80) in CKD patients, but not in patients without CKD. In subgroup analysis, patients experiencing CKD and frailty, or physical function impairment, had the lowest survival proportion followed by only frailty/declined physical function, only CKD, without CKD, and non-frailty/non-physical impairment. Conclusion CKD, frailty and physical function impairment were all associated with an increased mortality risk in older patients with diabetes, while the combined effects of these 3 factors were seen on patient outcome.

Abstract Background Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.

BackgroundPredicting physical function upon discharge among hospitalized older adults is important. This study has aimed to develop a prediction model of physical function upon discharge through use of a machine learning algorithm using electronic health records (EHRs) and comprehensive geriatrics assessments (CGAs) among hospitalized older adults in Taiwan.MethodsData was retrieved from the clinical database of a tertiary medical center in central Taiwan. Older adults admitted to the acute geriatric unit during the period from January 2012 to December 2018 were included for analysis, while those with missing data were excluded. From data of the EHRs and CGAs, a total of 52 clinical features were input for model building. We used 3 different machine learning algorithms, XGBoost, random forest and logistic regression.ResultsIn total, 1,755 older adults were included in final analysis, with a mean age of 80.68 years. For linear models on physical function upon discharge, the accuracy of prediction was 87% for XGBoost, 85% for random forest, and 32% for logistic regression. For classification models on physical function upon discharge, the accuracy for random forest, logistic regression and XGBoost were 94, 92 and 92%, respectively. The auROC reached 98% for XGBoost and random forest, while logistic regression had an auROC of 97%. The top 3 features of importance were activity of daily living (ADL) at baseline, ADL during admission, and mini nutritional status (MNA) during admission.ConclusionThe results showed that physical function upon discharge among hospitalized older adults can be predicted accurately during admission through use of a machine learning model with data taken from EHRs and CGAs.

Abstract Background To manage the rapidly growing incidence of, and related medical burden resulting from hip fractures in older adults in an aging society, studies involving orthogeriatric co-management treatment models have reported improved outcomes, including reduced medical costs. The treatment gap for osteoporosis was however seldom emphasized in the published treatment protocols. Aiming to improve the existing orthogeriatric protocol, we have established a patient-centered protocol for elderly patient hip fractures, which simultaneously focuses on fracture care and anti-osteoporosis agent prescription in regarding to healthcare quality and medical expense. Methods This was a retrospective study comparing patients who enrolled in the multidisciplinary co-managed protocol for geriatric hip fractures and those who did not. The inclusion criteria for this study were: (a) single-sided hip fractures treated from 1 to 2018 to 30 June 2020, (b) patients who were 60-years or older (c) trauma treated within 3 days from time of injury, and (d) minimal follow-up period of 12 months after surgery. Results From 1 to 2018 to 30 June 2020, 578 patients were included (267 patients in the protocol group vs. 331 patients in the conventional group). The protocol group was associated with significantly reduced lengths of hospital stay (p = 0.041), medical expenditures (p = 0.006), and mortality (p = 0.029) during their acute in-hospital admission period. Early osteoporosis diagnosis and anti-osteoporosis agent prescription were achieved in the protocol group, with a significantly wider coverage for BMD assessment (p

Abstract Background Dementia indicates a significant disease burden worldwide with increased population aging. This study aimed to investigate the impact of alcohol consumption on the risk of cognitive impairment in older adults. Methods Participants ≥ 60 years were administered the Digit Symbol Substitution Test (DSST) to evaluate cognitive function in National Health and Nutrition Examination Survey (NHANES) cycles from 1999 to 2002 and 2011 to 2014 for enrollment in the present study. Participants were categorized into non-drinker, drinker, and heavy drinker groups. Logistic regression analyses were performed to explore associations between cognitive impairment and alcohol consumption. Results Multivariate analysis showed that older adults, men, people from minority races, persons with lower education or income levels, social difficulties, hypertension, or chronic kidney disease were significantly associated with a higher risk of cognitive impairment (all p

Abstract Diffuse idiopathic skeletal hyperostosis (DISH) is frequently an incidental finding during X-ray examination. Although it has been shown to be associated with several chronic diseases, the hazard of cerebrovascular disease has seldom been explored. Our study aimed at determining the risk of stroke conferred by DISH, which is a retrospective cohort study adopting the largest medical database in Taiwan. Patients with a diagnosis of DISH at least three times from 2005 to 2010 were identified as the study group, and those in the control group were selected by matching age and gender. Patients were followed up until the end of 2015 to trace the incidence of stroke. Cox regression analysis was performed to compute the hazard ratio of stroke. Among the included 5300 patients, 1060 had a diagnosis of DISH. Significantly higher prevalence rates of stroke, hypertension, diabetes, and hyperlipidemia were noted in these patients. Overall, DISH conferred a 1.68 times higher risk of developing stroke. The significantly higher hazard ratio could be identified in both genders whether hypertension existed or not. Even in those without comorbidities, DISH still conferred a significantly higher risk of cerebrovascular disease in the future, which should never be ignored when encountered during clinical practice.

Abstract Aims/Introduction The convergence of tuberculosis (TB) and diabetes mellitus (DM) is a new challenge in Asia as a result of the rising prevalence of diabetes mellitus with higher TB infection rates, and also because diabetes mellitus itself enhances TB disease activity and consequently the spread of TB. We aimed to address the risk presented by diabetes mellitus for TB infection. Materials and Methods Patients with diabetes mellitus were retrospectively recruited. The baseline assessments included age, sex, body mass index, fasting blood glucose, glycated hemoglobin, urine albumin‐to‐creatinine ratio and estimated glomerular filtration rate. TB was determined by meeting the international classification of disease, for TB diagnosis and receiving anti‐TB treatment for at least 2 months. Results In total, 9,750 individuals with diabetes mellitus were recruited. The event rate of TB was 47 (0.48%). Younger age, lower proportion of men, higher fasting blood glucose and glycated hemoglobin values, and better renal function (estimated glomerular filtration rate and urine albumin‐to‐creatinine ratio) were observed in the metformin‐exposed groups. Old age and male sex were associated with higher TB infection risk on multivariate analysis. Metformin users had a significantly lower risk for TB infection, whereas insulin users had a higher risk for TB infection. However, glycemic status had no effect on TB infection risk. Conclusions This study provides clinical evidence from a survey of TB in individuals with diabetes mellitus. Old age, male sex and insulin use were risk factors for TB infection. Metformin remains the first choice of treatment for diabetes mellitus and has a potential protective effect against TB infection.

Abstract Background Day care service (DCS) provides various activities in a professional environment to meet the old people with functional limitations. However, relatively little is known about the effects of DCS on physical and mental functions. Methods This was a retrospective study that we used a comprehensive geriatric assessment to evaluate the changes before and after DCS among participants in a hospital-affiliated geriatric day care center in Taiwan. The burden of the participants’ families was also assessed. Results The 18 participants with a median age of 80.9 (interquartile range (IQR) 75.2–86.6 y/o) were enrolled and followed up for 6 months. Based on the clinical dementia rating (CDR), disease stage was very mild in 3 participants, mild in 10, moderate in 3, and severe in 2. The activities of daily living (ADL) scores of the participants improved significantly from 75 (IQR 60.0–80.0) at baseline to 77.5 (IQR 65.0–90.0) at the 6 month (p

BackgroundsFalls are currently one of the important safety issues of elderly inpatients. Falls can lead to their injury, reduced mobility and comorbidity. In hospitals, it may cause medical disputes and staff guilty feelings and anxiety. We aimed to predict fall risks among hospitalized elderly patients using an approach of artificial intelligence.Materials and methodsOur working hypothesis was that if hospitalized elderly patients have multiple risk factors, their incidence of falls is higher. Artificial intelligence was then used to predict the incidence of falls of these patients. We enrolled those elderly patients aged >65 years old and were admitted to the geriatric ward during 2018 and 2019, at a single medical center in central Taiwan. We collected 21 physiological and clinical data of these patients from their electronic health records (EHR) with their comprehensive geriatric assessment (CGA). Data included demographic information, vital signs, visual ability, hearing ability, previous medication, and activity of daily living. We separated data from a total of 1,101 patients into 3 datasets: (a) training dataset, (b) testing dataset and (c) validation dataset. To predict incidence of falls, we applied 6 models: (a) Deep neural network (DNN), (b) machine learning algorithm extreme Gradient Boosting (XGBoost), (c) Light Gradient Boosting Machine (LightGBM), (d) Random Forest, (e) Stochastic Gradient Descent (SGD) and (f) logistic regression.ResultsFrom modeling data of 1,101 elderly patients, we found that machine learning algorithm XGBoost, LightGBM, Random forest, SGD and logistic regression were successfully trained. Finally, machine learning algorithm XGBoost achieved 73.2% accuracy.ConclusionThis is the first machine-learning based study using both EHR and CGA to predict fall risks of elderly. Multiple risk factors of falls in hospitalized elderly patients can be put into a machine learning model to predict future falls for early planned actions. Future studies should be focused on the model fitting and accuracy of data analysis.

Plumbagin, a natural bicyclic naphthoquinone, has diverse pharmacological properties and biological benefits against a number of disorders, including liver disease. Though plumbagin’s hepatoprotective potential attracts attention, currently no experimental evidence exists on its effectiveness against cholestatic liver injury. The present study investigated its hepatoprotection in the rat model of extrahepatic cholestasis using Bile Duct Ligation (BDL). We found that daily plumbagin supplementation protected the liver from cholestatic damage. Hepatoprotective actions of plumbagin were accompanied by reduction of Transforming Growth Factor β1 (TGF-β1)/Smad, High Mobility Group Box-1 (HMGB1)/Toll-Like Receptor-4 (TLR4), Hypoxia-Inducible Factor-1α (HIF-1α), Aryl Hydrocarbon Receptor (AhR), Heat Shock Protein 90 (HSP90), caveolin-1, NF-κB/AP-1, Dynamin Related Protein-1 (Drp1), malondialdehyde level, Interleukin-1β (IL-1β), p62/SQSTM1, and caspase 3 as well as increase of Farnesoid X Receptor (FXR), bile acid efflux transporters, glutathione, LC3-II, Beclin1, and nuclear NF-E2-Related Factor-2 (Nrf2) and Transcription Factor EB (TFEB). The activation of nuclear Nrf2 caused by plumbagin correlated well with the improvement in bile acid retention, liver histology, serum biochemical, ductular reaction, mitochondrial dysfunction, oxidative stress, inflammation, apoptosis, impaired autophagy, and fibrosis, involving interplay of multiple intracellular signaling pathways. Plumbagin is likely a candidate drug to protect the liver from cholestatic damages. Despite the promising findings from this study, translational implication of plumbagin on cholestatic liver injury warrants further investigation.

To investigate the impact of alcohol use on the risk of cognitive impairment in older adults with chronic illness, we used the Digit Symbol Substitution Test (DSST) to evaluate cognitive function in older adults (≥ 60 years) in the National Health and Nutrition Examination Survey. Participants were categorized as light drinkers, moderate and heavy drinkers. Logistic regression analyses were used to explore associations between cognitive impairment and alcohol drinking in patients with or without diabetes, hypertension, and chronic kidney disease (CKD). Multivariate analysis showed that alcohol heavy drinkers was significantly associated with a higher risk of cognitive impairment in patients with hypertension (aOR 6.089, 95% CI 1.318–28.13) and CKD (aOR 6.324, 95% CI 1.158–34.52) compared with light drinkers. The dose-response analyses revealed that moderate to heavy alcohol use was associated with a higher risk of cognitive decline in patients with diabetes and CKD, heavy drinking increased the risk of cognitive impairment in patients with hypertension. The impacts of alcohol drinking on cognitive impairment are significantly different in patients with different comorbidities.

Background and ObjectiveIn 2014, Taiwan’s National Health Insurance administration launched a post-acute care (PAC) program for patients to improve their functions after acute stroke. The present study was aimed to determine PAC assessment parameters, either alone or in combination, for predicting clinical outcomes.MethodsWe retrospectively enrolled stroke adult patients through one PAC network in central Taiwan between January 2014 and December 2020. We collected data on post-stroke patients’ functional ability at baseline and after PAC stay. The comprehensive assessment included the following: Modified Rankin Scale (MRS), Functional Oral Intake Scale (FOIS), Mini-Nutritional Assessment (MNA), Berg Balance Scale (BBS), Fugl-Meyer Assessment (FMA), Mini-Mental State Examination (MMSE), aphasia test, and quality of life. The above items were assessed first at baseline and again at discharge from PAC. Logistic regression was used to determine factors that were associated with PAC length of stay (LOS), 14-day hospital readmission, and 1-year mortality.ResultsA total of 267 adults (mean age 67.2 ± 14.7 years) with completed data were analyzed. MRS, activities of daily living (ADLs), instrumental activities of daily living (IADLs), BBS, and MMSE all had improved between disease onset and PAC discharge. Higher baseline and greater improvement of physical and cognitive functions between initial and final PAC assessments were significantly associated with less readmission, and lower mortality. Furthermore, the improved ADLs, FOIS, MNA, FMA-motor, and MMSE scores were related to LOS during PAC. Using logistic regression, we found that functional improvements ≥5 items [adjusted odds ratio (aOR) = 0.16; 95% confidence interval (CI) = 0.05–0.45] and improved MMSE (aOR = 0.19; 95% CI = 0.05–0.68) were significantly associated with reduced post-PAC mortality or readmission. Whereas, functional improvements ≥7 items, improved FOIS, and MNA significantly prolonged LOS during PAC.ConclusionPhysical performance parameters of patients with acute stroke improved after PAC. PAC assessment with multiple parameters better predicted clinical outcomes. These parameters could provide information on rehabilitation therapy for acute stroke patients receiving PAC.

Abstract Background Frailty, a syndrome characterized by a decline in function reserve, is common in older patients with heart failure (HF) and is associated with prognosis. This study aimed to evaluate the impact of frailty on outcomes in older patients with preserved and reduced cardiac function. Methods In total, 811 adults aged ≥65 years were consecutively enrolled from 2009 to 2018. HF was diagnosed according to the ICD9 code and a 2D echocardiogram was categorized by reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF). The index date was registered at the time of HF. All patients received a comprehensive geriatric assessment, and clinical outcomes were examined with adjustment of the other prognostic variables. Results Mean age was 80.5 ± 7.1 years. The prevalence of HF, HFpEF, HFrEF, Fried, and Rockwood frailty indicators was 28.5, 10.4, 9.7, 52.5, and 74.9%, respectively. At baseline, scores in the Timed Up and Go test was closely associated with the severity of HF, either with HFpEF or HFrEF. After a mean follow-up of 3.2 ± 2.0 years, we found that HF patients with low handgrip strength (HGS) had the poorest survival, followed by non-HF patients with decreased HGS, and HF with fair HGS in comparison with non-HF with fair HGS (p = 0.008) if participants were arbitrarily divided into two HGS groups. In all patients, a high Rockwood frailty index was independently associated with increased mortality (adjusted hazard ratio [aHR] = 1.05; 95% confidence interval [CI]: 1.0004 to 1.10). In addition, the adjusted mortality HR was 3.42 with decreased HGS (95% CI: 1.03 to 11.40), 7.65 with use of mineralocorticoid receptor antagonist (95% CI: 2.22 to 26.32), and 1.26 with associated multi-comorbidities assessed by Charlson comorbidity index (95% CI: 1.05 to 1.51). Conclusions Our study results indicate that frailty and decreased physical functions were associated with HF. Besides, frailty and HGS predicted prognosis in the patients, and there was a combined effect of HF and low HGS on survival.

Background: Whether diabetes mellitus (DM) patients with chronic kidney disease (CKD) can glean individual renal benefit from dihydropyridine calcium channel blockers (DCCBs) remains to be determined. We conducted a nationwide, population-based, propensity score matching cohort study to examine the effect of DCCBs on CKD progression in DM patients with CKD.Methods: One million individuals were randomly sampled from Taiwan’s National Health Insurance Research Database. The study cohort consisted of DM patients with CKD who used DCCBs. The comparison cohort was propensity-matched for demographic characteristics and comorbidities. The endpoint was advanced CKD or end-stage renal disease (ESRD). The Cox proportional hazards model was used to calculate the risks.Results: In total, 9,761 DCCB users were compared with DCCB nonusers at a ratio of 1:1. DCCB users had lower risk of advanced CKD and ESRD than nonusers—with adjusted hazard ratio [aHR; 95% confidence interval (CI)] of 0.64 (0.53–0.78) and 0.59 (95% CI, 0.50–0.71) for advanced CKD and ESRD, respectively. DCCB users aged ≥65 years had the lowest incidence rates of advanced CKD and ESRD—with aHR (95% CI) of 0.47 (0.34–0.65) and 0.48 (0.35–0.65) for advanced CKD and ESRD, respectively. Finally, cumulative DCCB use for >1,100 days was associated with the lowest advanced CKD and ESRD risks [(aHR, 0.29 (95% CI, 0.19–0.44)].Conclusion: DM patients with CKD who used DCCBs had lower risk of progression to advanced CKD and ESRD than nonusers did.

Abstract Background Chronic kidney disease (CKD), low serum albumin, and anemia are known risk factors for cognitive decline in older people. We investigated the association between kidney function and cognitive impairment severity in oldest-old people with a diagnosis of Alzheimer’s disease (AD). Methods A cross-sectional study of patients aged 80 years and older was conducted at a veterans’ home in Taiwan between 2012 and 2016. Their estimated glomerular filtration rate (eGFR) was determined using the Modification of Diet in Renal Diseases (MDRD) equation. Cognitive function was evaluated with the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating (CDR). Results A total of 84 patients (age mean ± SD, 86.6 ± 3.9 years) had MMSE scores of 10.1 ± 6.7, and CDR scores of 1.6 ± 0.7. The average eGFR was 61.7 ± 21.5 mL/min/1.73m2. The mean hemoglobin concentration was 12.7 ± 1.7 g/dl, and the mean albumin concentration was 4.5 ± 4.8 g/dl. Multivariate regression analyses showed that scores of CDR were significantly correlated with eGFR after adjustment for potential confounders. The scores of MMSE were significantly correlated with serum albumin and hemoglobin after adjustment for potential confounders. Conclusions We found dementia severity was significantly associated with kidney function, serum albumin, and hemoglobin in the oldest-old with AD. We recommend that oldest-old people with a diagnosis of AD be evaluated to determine kidney function, as well as nutritional and hematological status. Further study is needed to establish whether prevention of CKD deterioration, and correction of malnutrition and anemia may help to slow cognitive decline in oldest-old people with dementia.

BackgroundMetabolic syndrome has been shown to be a risk for new onset of cardiovascular disease (CVD) and type 2 diabetes. The subclasses of metabolic syndrome and any associated adverse health outcomes remain obscure. This study aimed to explore potential subtypes of metabolic syndrome, their associations with incidental diabetes, and any Major Adverse Cardiovascular Events (MACE).MethodsData for the retrospective cohort study were extracted from the New Taipei City Elderly Health Examination Database in the years 2014 and 2016. Demographic data, status of metabolic syndrome, its components, and latent class analysis (LCA) were analyzed. All participants were aged 65 years and older, with those having a prior history of CVD, cerebrovascular disease, diabetes mellitus (DM), and currently taking medications for hypertension, diabetes, and dyslipidemia were excluded.ResultsA total of 4,537 senior citizens were enrolled, with 2,207 (48.6%) of them identified as men. The prevalence of both metabolic syndrome and central obesity was increased with age. A 4-latent class model was fitted for participants diagnosed with metabolic syndrome. The central obesity (ABD)+ hyperglycemia (GLU)+ reduced HDL-C (HDL)+ high Blood Pressure (BP) group displayed the highest hazard ratio (HR) for predicting the new onset of diabetes, while the ABD+HDL+BP group showed a high risk for both CVD and MACE when compared after 2 years of follow-up.ConclusionsThis epidemiological analysis demonstrated that the risks of developing new-onset diabetes, CVD, and MACE varied among the different subtypes of metabolic syndrome.

Background: Whether there is a difference in prognosis between elderly patients with ST-elevation myocardial infarction (STEMI) and non-ST-elevation myocardial infarction (NSTEMI) remains mysterious.Methods: We conducted a retrospective cohort study by analyzing the data in the Longitudinal Health Insurance Database (LHID) in Taiwan to explore differences between STEMI and NSTEMI with respect to in-hospital and long-term (3-year) outcomes among older adult patients (aged ≥65 years). Patients were further stratified based on whether they received coronary revascularization.Results: In total, 5,902 patients aged ≥65 years with acute myocardial infarction (AMI) who underwent revascularization (2,254) or medical therapy alone (3,648) were included. In the revascularized group, no difference was observed in cardiovascular (CV) and all-cause mortality during hospitalization or at 3-year follow-up between the two AMIs. Conversely, in the non-revascularized group, patients with NSTEMI had higher crude odds ratio (cOR) for all-cause death during hospitalization [cOR: 1.33, 95% confidence interval (CI) = 1.07–1.65] and at 3-year follow-up (cOR: 1.47, 95% CI = 1.21–1.91) relative to patients with STEMI. However, after multivariable adjustments, only NSTEMI indicated fewer in-hospital CV death [adjusted odds ratio (aOR): 0.75, 95% CI = 0.58–0.98] than STEMI in non-revascularized group. Moreover, major bleeding was not different between patients with STEMI or NSTEMI aged ≥65 years old.Conclusion: Classification of AMI is not associated with the difference of in-hospital or 3-year CV and all-cause death in older adult patients received revascularization. In a 3-year follow-up period, STEMI was an independent predictor of a higher incidence of revascularization after the index event. Non-ST-elevation myocardial infarction had more incidence of MACE than patients with STEMI did in both treatment groups.

BackgroundAlthough carotid sonographic features have been used as predictors of recurrent stroke, few large-scale studies have explored the use of machine learning analysis of carotid sonographic features for the prediction of recurrent stroke.MethodsWe retrospectively collected electronic medical records of enrolled patients from the data warehouse of China Medical University Hospital, a tertiary medical center in central Taiwan, from January 2012 to November 2018. We included patients who underwent a documented carotid ultrasound within 30 days of experiencing an acute first stroke during the study period. We classified these participants into two groups: those with non-recurrent stroke (those who has not been diagnosed with acute stroke again during the study period) and those with recurrent stoke (those who has been diagnosed with acute stroke during the study period). A total of 1,235 carotid sonographic parameters were analyzed. Data on the patients' demographic characteristics and comorbidities were also collected. Python 3.7 was used as the programming language, and the scikit-learn toolkit was used to complete the derivation and verification of the machine learning methods.ResultsIn total, 2,411 patients were enrolled in this study, of whom 1,896 and 515 had non-recurrent and recurrent stroke, respectively. After extraction, 43 features of carotid sonography (36 carotid sonographic parameters and seven transcranial color Doppler sonographic parameter) were analyzed. For predicting recurrent stroke, CatBoost achieved the highest area under the curve (0.844, CIs 95% 0.824–0.868), followed by the Light Gradient Boosting Machine (0.832, CIs 95% 0.813–0.851), random forest (0.819, CIs 95% 0.802–0.846), support-vector machine (0.759, CIs 95% 0.739–0.781), logistic regression (0.781, CIs 95% 0.764–0.800), and decision tree (0.735, CIs 95% 0.717–0.755) models.ConclusionWhen using the CatBoost model, the top three features for predicting recurrent stroke were determined to be the use of anticoagulation medications, the use of NSAID medications, and the resistive index of the left subclavian artery. The CatBoost model demonstrated efficiency and achieved optimal performance in the predictive classification of non-recurrent and recurrent stroke.

The incidence of hypocalcemia is high in patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD) undergoing denosumab treatment. Since 2018, we have carried out a “multidisciplinary integrated care program for osteoporosis among patients with CKD and ESRD” in our hospital. The aim of this study was to compare the incidence of denosumab-associated hypocalcemia among patients with advanced CKD and ESRD before and after the integrated care program. We retrospectively reviewed the records of patients on their first dose of denosumab treatment from January 2012 to December 2021. A total of 3208 patients were included in our study. Among the 3208 patients, there were 101 dialysis patients, 150 patients with advanced CKD (stage 4 and 5), and 2957 patients with an estimated glomerular filtration rate (eGFR) higher than or equal to 30. The incidence of post-treatment severe hypocalcemia (corrected calcium level less than 7.0 mg/dl) within 30 days was significantly higher in the dialysis and advanced CKD group than in patients with an eGFR higher than or equal to 30 (6.9% vs. 2.0% vs. 0.1%, respectively, p < 0.001). Based on the results of the multivariate regression model, poor renal function (p < 0.05) and lower baseline corrected calcium level (p < 0.05) were associated with severe hypocalcemia within 30 days following the first dose of denosumab treatment. The incidence of post-treatment severe hypocalcemia within 30 days in advanced CKD and dialysis patients was significantly lower after the integrated care program (6.8% vs. 0.8%, p < 0.05). Our study shows that multidisciplinary integrated care may reduce the incidence rate of denosumab-associated severe hypocalcemia among patients with advanced CKD and ESRD.

This study evaluated changes of cognitive, physical, and nutritional status before and after the interruption and resumption of daycare services during the COVID-19 pandemic in older dementia people in a daycare center. Comprehensive geriatric assessment data were analyzed before and after the lockdown of daycare center services, including mini-mental state examination, activities of daily living (ADL) scores, mini-nutritional assessment-short forms (MNA-SF), and timed up-and-go (TUG) tests. Among 19 dementia people participating in daycare services, 17 participants were enrolled in the study with, finally, two excluded because of incomplete follow-ups. They had a median age of 81 years; their MNA-SF scores and TUG values deteriorated significantly after a 3-month closure of daycare services (p < 0.05), and after resumption of daycare services the MNA-SF scores and TUG values recovered to near the pre-lockdown levels (p < 0.05). Besides, baseline ADL scores predicted a decline and recovery of TUG and MNA-SF values. Our findings suggest that planning continuous support for older dementia adults is important for daycare facilities during COVID-19 pandemic confinement.

Background: We investigated the association between glucose excursions and the dawn phenomenon, and the effects of oral-glucose lowering drugs on the dawn phenomenon in patients with type 2 diabetes (T2D). Methods: We conducted a post hoc analysis using data from a previous randomized trial. Patients with T2D on metformin monotherapy were randomized to receive add-on acarbose or glibenclamide for 16 weeks. Ambulatory continuous glucose monitoring (CGM) was conducted before randomization and at the end of the study. Using the CGM data, we assessed glucose excursions as indicated by mean amplitude of glycemic excursions (MAGE). The magnitude of the dawn phenomenon was calculated as the difference between the nocturnal nadir (0:00 to 6:00 a.m.) and prebreakfast glucose level. Results: A total of 50 patients with T2D [mean age 53.5 ± 8.2 years, mean glycated hemoglobin (HbA1c) 8.4 ± 1.2%] were analyzed. There was an independent association between MAGE and the dawn phenomenon [β coefficient 0.199, 95% confidence interval (CI) 0.074–0.325, p = 0.003]. HbA1c improved significantly after treatment with acarbose or glibenclamide. However, only treatment with acarbose significantly improved glucose excursions. The dawn phenomenon decreased significantly only in patients treated with acarbose (from 35.9 ± 15.7–28.3 ± 16.5 mg/dl, p = 0.037), but not in those treated with glibenclamide (from 35.9 ± 20.6–34.6 ± 17.0 mg/dl, p = 0.776). Conclusion: Glucose excursions were independently associated with the dawn phenomenon in patients with T2D on metformin monotherapy. Both glucose excursions and the dawn phenomenon improved after treatment with acarbose, but not after treatment with glibenclamide.

Background: In patients with chronic kidney disease (CKD), physical functional limitations and heart failure (HF) are common, and each is associated with adverse outcomes. However, their joint effects on mortality are not clear.Design and Methods: Using administration data from the geriatric department in a tertiary hospital, retrospective longitudinal analyses of patients aged ≥65 years with CKD were consecutively enrolled from February 2010 to November 2015. Baseline CKD stages, HF with reduced and preserved ejection fraction (HFrEF and HFpEF), Rockwood frailty index, handgrip strength (HGS), 6-m walking speed, and timed up-and-go test were used to predict the prevalence of frailty, physical disability, and all-cause mortality.Results: Among 331 old patients with CKD, their mean age was 81.3 ± 6.6 years. CKD stages showed the following distributions: stage 3, 74.9%; stage 4, 15.7%; stage 5, 9.4%. The prevalence of HF was 23.3%, and Rockwood frailty was 74.3%. Rockwood frailty and HF were both significantly associated with CKD stages. After a mean follow-up period of 3.1 ± 2.1 years, 44 patients died, and a crude analysis showed that stage 4, stage 5 CKD, low HGS, and Rockwood frailty index were associated with mortality. Regarding the survival of these patients, the adjusted mortality hazard ratio for CKD stage 5 was 3.84 against stage 3A [95% confidence interval (CI) 1.51–9.75], 1.04 (95% CI 1.01–1.07) for higher Rockwood frailty score, 4.78 (95% CI 1.26–18.11) for HFrEF, and 3.47 (95% CI 1.15–10.42) for low HGS. Survival analysis using Kaplan–Meier survival plots showed that patients with both HF and poor HGS had the poorest survival.Conclusions: Our study shows that both low physical performance and HF were common in old CKD patients and were associated with CKD stages. HF, frailty, and HGS all independently predicted the mortality of these CKD patients. The mortality is especially high amongst individuals with both HF and decreased HGS.

Background: Air pollution is speculated to affect the reproductive health of women. However, a longitudinal association between exposure to air pollution and dysmenorrhea has not been identified, which this study aimed to examine this point.Methods: Two nationwide databases, namely the Taiwan Air Quality Monitoring database and the Taiwan National Health Research Institutes database were linked. Women with a history of dysmenorrhea (International Classification of Disease, Ninth Revision, Clinical Modification code 625.3) before 2000 were excluded. All participants were followed from January 1, 2000 until the diagnosis of dysmenorrhea, withdrawal from National Health Insurance, or December 31, 2013. Furthermore, air pollutants were categorized into quartiles with three cut-off points (25th, 50th, and 75th percentiles). The Cox regression model was used to calculate the hazard ratios of dysmenorrhea.Results: This study enrolled 296,078 women. The mean concentrations of yearly air pollutants were 28.2 (±12.6) ppb for nitric oxides (NOx), 8.91 (±7.93) ppb for nitric oxide (NO), 19.3 (±5.49) ppb for nitrogen dioxide (NO2), 0.54 (±0.18) ppm for carbon monoxide (CO), and 31.8 (±6.80) μg/m3 for PM2.5. In total, 12,514 individuals developed dysmenorrhea during the 12-year follow-up. Relative to women exposed to Q1 concentrations of NOx, women exposed to Q4 concentrations exhibited a significantly higher dysmenorrhea risk [adjusted hazard ratio (aHR)= 27.9, 95% confidence interval (CI) = 21.6–31.3]; similarly higher risk was found for exposure to NO (aHR = 16.7, 95% CI = 15.4–18.4) and NO2 (aHR = 33.1, 95% CI = 30.9–37.4). For CO, the relative dysmenorrhea risk in women with Q4 level exposure was 28.7 (95% CI = 25.4–33.6). For PM2.5, women at the Q4 exposure level were 27.6 times (95% CI = 23.1–29.1) more likely to develop dysmenorrhea than those at the Q1 exposure level.Conclusion: Our results showed that women would have higher dysmenorrhea incidences while exposure to high concentrations of NO, NO2, NOx, CO, and PM2.5.

Background: Fine air pollutant particles have been reported to be associated with risk of preeclampsia. The association between air pollutant exposure and preeclampsia risk in heavily air polluted Taiwan warrants investigation.Methods: We combined data from Taiwan National Health Insurance (NHI) Research Database (NHIRD) and Taiwan Air Quality Monitoring Database. Women aged 16–55 years were followed from January 1, 2000, until appearance of ICD-9 coding of preeclampsia withdrawal from the NHI program, or December 31, 2013. Daily concentration of NOx, NO, NO2, and CO was calculated by Kriging method. The Cox proportional hazard regression model was used for risk assessment.Results: For NOx, Relative to Quartile [Q] 1 concentrations, the Q2 (adjusted hazard ratio adjusted = 2.20, 95% CI = 1.50–3.22), Q3 (aHR = 7.28, 95% CI = 4.78–11.0), and Q4 (aHR = 23.7, 95% CI = 13.7–41.1) concentrations were associated with a significantly higher preeclampsia or eclampsia risk. Similarly, for NO, relative to Q1 concentrations, the Q2 (aHR = 1.82, 95% CI = 1.26–2.63), Q3 (aHR = 7.53, 95% CI = 5.12–11.0), and Q4 (aHR = 11.1, 95% CI = 6.72–18.3) concentrations were correlated with significantly higher preeclampsia or eclampsia risk. Furthermore, for NO2, relative to Q1 concentration, the Q2 (aHR = 1.99, 95% CI = 1.37–2.90), Q3 (aHR = 6.15, 95% CI = 3.95–9.57), and Q4 (aHR = 32.7, 95% CI = 19.7–54.3) concentrations also associated with a significantly higher preeclampsia or eclampsia risk.Conclusion: Women exposed to higher NOX, NO, NO2, and CO concentrations demonstrated higher preeclampsia incidence.

18β-Glycyrrhetinic acid is a nutraceutical agent with promising hepatoprotective effects. Its protective mechanisms against cholestatic liver injury were further investigated in a rodent model of extrahepatic cholestasis caused by Bile Duct Ligation (BDL) in rats. The daily oral administration of 18β-Glycyrrhetinic acid improved liver histology, serum biochemicals, ductular reaction, oxidative stress, inflammation, apoptosis, impaired autophagy, and fibrosis. 18β-Glycyrrhetinic acid alleviated the BDL-induced hepatic and systemic retention of bile acids, matrix-producing cell activation, hepatic collagen deposition, Transforming Growth Factor beta-1/Smad activation, malondialdehyde elevation, glutathione reduction, High Mobility Group Box-1/Toll-Like Receptor-4 activation, NF-κB activation, inflammatory cell infiltration/accumulation, Interleukin-1β expression, Signal Transducer and Activator of Transcription-1 activation, Endoplasmic Reticulum stress, impairment autophagy, and caspase 3 activation. Conversely, the protein expression of Sirt1, Farnesoid X Receptor, nuclear NF-E2-Related Factor-2, Transcription Factor EB, bile acid efflux transporters, and LC3-II, as well as the protein phosphorylation of AMP-Activated Protein Kinase, was promoted in 18β-Glycyrrhetinic acid-treated BDL rats. The hepatoprotective effects of 18β-Glycyrrhetinic acid in the present investigation correlated well with co-activation and possible interactions among Sirt, FXR, and Nrf2. The concurrent or concomitant activation of Sirt1, FXR, and Nrf2 not only restored the homeostatic regulation of bile acid metabolism, but also alleviated oxidative stress, inflammation, apoptosis, impaired autophagy, and fibrosis.

Background & aimsWhether living liver donors have a higher risk of biliary tract disease compared with non-donors remains unknown.MethodsData were collected from the Taiwan Longitudinal Health Insurance Database for the 2003-2011 period. The study cohort comprised 1,446 patients aged ≥ 18 years who had served as living liver donors. The primary outcome was the incidence of biliary tract disease. Cox proportional hazards modeling was used to determine the hazard ratios.ResultsThe incidence density rate of biliary tract disease was 13.9-fold higher in the liver donor (LD) cohort than in the non-LD cohort (10.2 vs. 0.71 per 1,000 person-years), with an adjusted hazard ratio (HR) of 14.2 (95% confidence interval [CI] = 7.73-26.1). Stratified by comorbidity, the relative risk of biliary tract disease was higher in the LD cohort than in the non-LD cohort for both patients with or without comorbidity. The incidence density rate of biliary tract disease was significantly higher in the first 3 years (13.5 per 1,000 person-years in the LD cohort). The highest adjusted HR of biliary tract disease for LD patients compared with the non-LD cohort was 22.4 (95% CI = 10.8-46.1) in the follow-up ≤ 3 years.ConclusionLiving liver donors had a higher risk of biliary tract disease compared with non-donors.

Poststroke hyperglycemia and inflammation have been implicated in the pathogenesis of stroke. Janus Kinase 2 (Jak2), a catalytic signaling component for cytokine receptors such as Interleukin-6 (IL-6), has inflammatory and metabolic properties. This study aimed to investigate the roles of Jak2 in poststroke inflammation and metabolic abnormality in a rat model of permanent cerebral ischemia. Pretreatment with Jak2 inhibitor AG490 ameliorated neurological deficit, brain infarction, edema, oxidative stress, inflammation, caspase-3 activation, and Zonula Occludens-1 (ZO-1) reduction. Moreover, in injured cortical tissues, Tumor Necrosis Factor-α, IL-1β, and IL-6 levels were reduced with concurrent decreased NF-κB p65 phosphorylation, Signal Transducers and Activators of Transcription 3 phosphorylation, Ubiquitin Protein Ligase E3 Component N-Recognin 1 expression, and Matrix Metalloproteinase activity. In the in vitro study on bEnd.3 endothelial cells, AG490 diminished IL-6-induced endothelial barrier disruption by decreasing ZO-1 decline. Metabolically, administration of AG490 lowered fasting glucose, with improvements in glucose intolerance, plasma-free fatty acids, and plasma C Reactive Proteins. In conclusion, AG490 improved the inflammation and oxidative stress of neuronal, hepatic, and muscle tissues of stroke rats as well as impairing insulin signaling in the liver and skeletal muscles. Therefore, Jak2 blockades may have benefits for combating poststroke central and peripheral inflammation, and metabolic abnormalities.

Abstract Background There is a high hospitalization rate for diabetic patients. Since retinopathy and albuminuria are both important manifestations of microvascular disease in diabetes, our aim was to investigate the effect of retinopathy and albuminuria on long-term mortality in type 2 diabetic inpatients through this observational cohort study. Methods Type 2 diabetic inpatients given a primary diagnosis of poor glucose control were consecutively enrolled during their hospitalization periods. Clinical information was collected through review of each patient’s medical records, and mortality data were obtained from the national registry in Taiwan. Results A total of 761 type 2 diabetic inpatients were enrolled in the study with a median follow-up period of 6.6 years (interquartile range, 4.0–9.6 years). Patients in the Albuminuria(−)/Retinopathy(+), Albuminuria(+)/Retinopathy(−) and Albuminuria(+)/Retinopathy(+) groups had significantly higher risks of all-cause mortality and cardiovascular mortality than those in the Albuminuria(−)/Retinopathy(−) group. However, among patients with albuminuria, there was no significant difference in cumulative mortality between those with and without retinopathy (P = 0.821). A decrease in the estimated glomerular filtration rate (eGFR), but not retinopathy, was an independent predictor of all-cause mortality (95% CI 0.647‒0.893; P

Background/Purpose: Comprehensive and continuous care is crucial for patients with diabetes. The diabetes pay-for-performance (P4P) program launched by the National Health Insurance (NHI) administration in Taiwan provides a financial incentive to facilitate this goal. In this study, we explored the characteristics of patients in the P4P program between 2005 and 2014. Methods: Data of patients with diabetes enrolled in the NHI program between 2005 and 2014 were extracted from the NHI research database. Patients were classed as having diabetes if they had three or more outpatient visits within 365 calendar days with an International Classification of Diseases, 9th Revision, Clinical Modification diagnostic code of 250 or hospitalization one or more times with such a diagnosis. The trends of participating in the P4P program were analyzed. Results: Participation rate of the P4P program increased from 12.1% to 19% between 2005 and 2014. Participants were younger and more likely to be female than those not participating in the program. Lower risks of cancer-related mortality, annual mortality and heart failure were seen in patients participating in the P4P program than in those not participating. Conclusion: Older, male patients with a high disease severity may be less likely to enroll in the P4P program. Although participation rate is increasing, a broad enrollment is expected. Keywords: Diabetes, National health insurance, Pay-for-performance

Background/Purpose: Several new antidiabetic drugs have been introduced in Taiwan. However, the trends in antidiabetic treatment remain unexamined. Methods: We studied data from the Taiwan National Health Insurance Database to identify outpatient prescriptions for antidiabetic drugs from 2005 to 2014. The patterns in antidiabetic treatment and the number of different classes of antidiabetic drugs were analyzed. The proportions of prescriptions of antidiabetic monotherapy, combination therapy, or insulin therapy were further analyzed. Results: The total and mean prescriptions gradually increased during the study period. Prescription of oral antidiabetic drugs (OADs) only or insulin-only therapy decreased slightly. Prescriptions of monotherapy and dual therapy decreased, whereas those of triple or higher order combinations increased. Prescriptions of sulfonylureas (SUs) decreased, whereas those of metformin and dipeptidyl peptidease-4 (DPP4) inhibitors increased. Insulin prescriptions increased but accounted for only 13.07% of prescriptions in 2014. Among monotherapy prescriptions, SU prescriptions decreased, but metformin and DPP4 inhibitor prescriptions increased. Among dual OAD prescriptions, those including SUs decreased, and those of metformin and DPP4 inhibitors increased. Although prescriptions of the metformin–SU combination decreased, they remained the most common among all dual OAD prescriptions, followed by the metformin–DPP4 inhibitor combination. Prescriptions of human insulin decreased and those of insulin analogs increased considerably; those of basal insulin increased, and those of mixed insulin decreased. However, mixed insulin was prescribed more than basal–bolus insulin. Conclusion: Antidiabetic treatment has become complex in Taiwan. Although combination therapy would become the major treatment strategy gradually, the underuse of insulin therapy must improve. Keywords: Antidiabetic drugs, Diabetes, Insulin, Oral antidiabetic drugs

Purpose: The association between neurodegenerative diseases and transfusion remains to be investigated.Methods: The study population comprised 63,813 patients who underwent a blood transfusion and 63,813 propensity score-matched controls between 2000 and 2010. Data were obtained from the Taiwan National Health Insurance Research Database, which is maintained by the National Health Research Institutes. A Cox regression analysis was conducted to elucidate the relationship between blood transfusions and the risk of dementia.Results: A multivariate Cox regression analysis of factors, such as age, sex, cardiovascular ischemia disease, and depression, revealed that patients who underwent a blood transfusion showed a 1.73-fold higher risk of dementia [95% confidence interval (CI) = 1.62-1.84] and a 1.37-fold higher risk of Alzheimer’s disease (AD) [95% CI = 1.13-1.66] than those who did not. Patients who received a transfusion of washed red blood cells showed a 2.37-fold higher risk of dementia (95% CI = 1.63-3.44) than those who did not.Conclusion: Blood transfusion, especially transfusion of any type of red blood cells is associated with an increased risk of dementia.

AimsThe aim of the present study was to investigate the major determinants of diabetic peripheral neuropathy (DPN) in patients with type 2 diabetes (T2D), considering the traditional and newly discovered risk factors, including hypoglycaemia and glycemic variability.MethodsThis retrospective case-control study was conducted in a tertiary care hospital in Taiwan. A total of 2,837 patients with T2D were recruited, medical history and biochemical data were obtained, and patients were screened for DPN using the Michigan Neuropathy Screening Instrument (MNSI). DPN was defined as an MNSI exam score > 2. A stepwise selection of variables was used based on the Akaike Information Criterion (AIC) and the Schwarz Criterion (SC). Multivariate analysis was performed using the identified variables obtained from the stepwise selection.ResultsAmong the recruited patients, 604 (21.3%) were found to have DPN. 275 patients with DPN were selected because of longer follow up period before enrollment and complete data of glycemic parameters, and paired with 351 patients with T2D without DPN and matched for age, gender, and diabetes duration. The results of the stepwise selection showed that the presence of moderately and severely increased albuminuria yielded the lowest values of AIC and SC, which indicate the best predictive performance. Multivariate analysis demonstrated that moderately and severely increased albuminuria and greater long-term glycemic variability significantly increased the risk of DPN, with a corresponding odds ratio of 1.85 and 1.61 (95%confidence intervals of 1.25-2.73and1.02-2.55, respectively), after adjusted for hypoglycaemia and types of diabetes treatment.ConclusionsAlbuminuria is a potent predictor of DPN, and greater long-term glycemic variabilityis clearly associated with DPN in adults with T2D. These findings indicate that, in addition to achieve average blood glucose control, screening for albuminuria and reducing blood glucose fluctuations might be useful for improving diabetic microvascular complications.

Hyperglycemia and inflammation, with their augmented interplay, are involved in cases of stroke with poor outcomes. Interrupting this vicious cycle thus has the potential to prevent stroke disease progression. Tumor necrosis factor-α (TNF-α) is an emerging molecule, which has inflammatory and metabolic roles. Studies have shown that TNF-α receptor inhibitor R-7050 possesses neuroprotective, antihyperglycemic, and anti-inflammatory effects. Using a rat model of permanent cerebral ischemia, pretreatment with R-7050 offered protection against poststroke neurological deficits, brain infarction, edema, oxidative stress, and caspase 3 activation. In the injured cortical tissues, R-7050 reversed the activation of TNF receptor-I (TNFRI), NF-κB, and interleukin-6 (IL-6), as well as the reduction of zonula occludens-1 (ZO-1). In the in vitro study on bEnd.3 endothelial cells, R-7050 reduced the decline of ZO-1 levels after TNF-α-exposure. R-7050 also reduced the metabolic alterations occurring after ischemic stroke, such as hyperglycemia and increased plasma corticosterone, free fatty acids, C reactive protein, and fibroblast growth factor-15 concentrations. In the gastrocnemius muscles of rats with stroke, R-7050 improved activated TNFRI/NF-κB, oxidative stress, and IL-6 pathways, as well as impaired insulin signaling. Overall, our findings highlight a feasible way to combat stroke disease based on an anti-TNF therapy that involves anti-inflammatory and metabolic mechanisms.

Background: The evidence indicates that the optimal observation period following renal biopsy ranges between 6 and 8 h. This systematic review and meta-analysis explored whether differences exist in the complication rates of renal biopsies performed in outpatient and inpatient settings. Methods: We searched the MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews from 1985 to February 2020. Two reviewers independently selected studies evaluating the bleeding risk from renal biopsies performed in outpatient and inpatient settings and reviewed their full texts. The primary and secondary outcomes were risks of bleeding and major events (including mortality) following the procedure, respectively. Subgroup analysis was conducted according to the original study design (i.e., prospective or retrospective). Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a random effect meta-analysis. Heterogeneity was assessed using the I2 test. Results: Data from all 10 eligible studies, which included a total of 1801 patients and 203 bleeding events, were included for analysis. Renal biopsies in outpatient settings were not associated with a higher bleeding risk than those in inpatient settings (OR = 0.81; 95% CI, 0.59–1.11; I2 = 0%). The risk of major events was also comparable across both groups (OR = 0.45; 95% CI, 0.16–1.29; I2 = 4%). Conclusions: Similar rates of bleeding and major events following renal biopsy in outpatient and inpatient settings were observed.

Protein-bound uremic toxins, such as p-cresol sulfate (PCS), can be accumulated with declined renal function and aging and is closely linked with central nervous system (CNS) diseases. In the periphery, PCS has effects on oxidative stress and inflammation. Since oxidative stress and inflammation have substantial roles in the pathogenesis of neurological disorders, the CNS effects of PCS were investigated in unilateral nephrectomized C57/BL/6 mice. Unlike intact mice, unilateral nephrectomized mice showed increased circulating levels of PCS after exogenous administration. Upon PCS exposure, the unilateral nephrectomized mice developed depression-like, anxiety-like, and cognitive impairment behaviors with brain PCS accumulation in comparison with the nephrectomy-only group. In the prefrontal cortical tissues, neuronal cell survival and neurogenesis were impaired along with increased apoptosis, oxidative stress, and neuroinflammation. Circulating brain-derived neurotrophic factors (BDNF) and serotonin were decreased in association with increased corticosterone and repressor element-1 silencing transcription factor (REST), regulators involved in neurological disorders. On the contrary, these PCS-induced changes were alleviated by uremic toxin absorbent AST-120. Taken together, PCS administration in mice with nephrectomy contributed to neurological disorders with increased oxidative stress and neuroinflammation, which were alleviated by PCS chelation. It is suggested that PCS may be a therapeutic target for chronic kidney disease-associated CNS diseases.

Anesthetics, particularly volatile anesthetics, have been shown to impair glucose metabolism and cause hyperglycemia, closely linking them with mortality and morbidity as related to surgery. Beyond being an anesthetic used for general anesthesia and sedation, intravenous hypnotic propofol displays an effect on glucose metabolism. To extend the scope of propofol studies, its effects on glucose metabolism were evaluated in male Sprague-Dawley rats of various ages. Unlike chloral hydrate and isoflurane, propofol had little effect on basal glucose levels in rats at 2 months of age, although it did reduce chloral hydrate- and isoflurane-induced hyperglycemia. Propofol reduced postload glucose levels after either intraperitoneal or oral administration of glucose in both 7- and 12-month-old rats, but not those at 2 months of age. These improved effects regarding propofol on glucose metabolism were accompanied by an increase in insulin, fibroblast growth factor-21 (FGF-21), and glucagon-like peptide-1 (GLP-1) secretion. Additionally, an increase in hepatic FGF-21 expression, GLP-1 signaling, and FGF-21 signaling, along with a decrease in endoplasmic reticulum (ER) stress, were noted in propofol-treated rats at 7 months of age. Current findings imply that propofol may turn into insulin-sensitizing molecules during situations of existing insulin resistance, which involve FGF-21, GLP-1, and ER stress.