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Abstract Carotid intima-media thickness (cIMT), a marker of subclinical atherosclerosis, has been found to be associated with incident stroke. High-sensitivity C-reactive protein (CRP) and fibrinogen have been demonstrated to be associated with atherosclerosis. Previous studies on heritability estimates of IMT, CRP, and fibrinogen among Chinese populations are limited. This study aims to estimate the heritability of these risk factors in residents who participated in the Taichung Community Health Study (TCHS) and their family members. A total of 2671 study subjects from 805 families were enrolled in the study, selected from a random sample of TCHS participants and their family members. CRP, and fibrinogen were obtained from each participant, and a questionnaire interview was conducted. cIMT was measured by high-resolution B-mode ultrasound and expressed as the mean of the maximum. Heritability estimates and the familial correlation of cIMT, CRP, and fibrinogen among family pairs were determined with SAGE software. With multivariate adjustments, significant heritability was found for cIMT (h2 = 0.26, P

Abstract Background Sleeping problems and cognitive impairment are common in elders. Baseline sleep duration and cognitive status are predictors of mortality. But few studies have explored whether longitudinal changes in sleep duration and cognitive function are related to mortality in older adults. The present study investigated the time-varying relationships of sleep duration and cognitive function with subsequent mortality among community-dwelling elders by using 12 years of repeated-measure data. Methods Taichung Community Health Study for Elders (TCHS-E) is a retrospective, population-based cohort that started in 2009 (wave 1) with a total of 912 elders aged 65 years or above. Follow up was conducted in 2010 (wave 2), 2018 (wave 3), and 2020 (wave 4). Sleep duration and Mini-Mental State Examination (MMSE) forms were executed at baseline and three visits during follow-up. Time-varying Cox proportional hazards regression estimated adjusted hazard ratios (HRs) of mortality with 95% confidence intervals (CIs). Results During about 12 years (9,396 person-years) follow-up, 329 deaths from all causes were documented, including 102 deaths due to expanded cardiovascular disease (CVD). In the multivariable-adjusted, time-varying Cox proportional hazard model, the adjusted HR values of all-cause mortality were 1.47 (1.02–2.12) for sleep duration > 9 h/day (vs. 7 h/day) and 1.81 (1.26–2.59) for MMSE

Abstract Background This study aimed to explore trends, in 3 periods, in the intake of energy and macronutrients among Taiwanese older adults. Methods Study subjects were those aged ≥65 years in the Nutrition and Health Survey in Taiwan 1999–2000 as well as the surveys in 2005–2008 and 2013–2016. Twenty-four-hour dietary recall data were obtained. This study used the 3 nutrition survey datasets for 1999–2000, 2005–2008, and 2013–2016, including data on the questionnaire, physical examination, and dietary intakes. Each nutrition survey involved the face-to-face household interview, and individual’s dietary intake of carbohydrate, fat, and protein (% of energy) was estimated. Subsequently, intake statuses of the three macronutrients were classified into below, meeting, and above intake categories. Results In the 2013–2016 survey, approximately 40% of the older adults had a low intake of energy. The prevalence of older adults with a meeting intake of carbohydrate, fat, and protein have increased from the 1999–2000 to 2013–2016 periods. The prevalence of people having a low intake of carbohydrate declined from the 1999–2000 period to the 2013–2016 period. The prevalence of high fat intake in 2013–2016 was approximately 5% higher than that in 1999–2000. In the 2013–2016 period, the prevalence of low intake of carbohydrate, fat, and protein were 25.9, 24.5, and 4.9%, respectively; moreover, the prevalence of high intake of the aforementioned macronutrients were 38.7, 36.2, and 17.6%, respectively. Conclusions Our study provides important evidence on the dietary patterns, as well as their changes over time among Taiwanese older adults. Such information would be useful for health policy makers about the burden of unbalanced diet and for nutrition educators on planning nutrition promotion interventions about well-balanced dietary for the older persons.

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.

Introduction A body shape index (ABSI) is independently associated with mortality in general population, but studies on the predictability of ABSI in the risk of mortality in patients with type 2 diabetes (T2D) are limited. We aimed to examine the independent and joint association of ABSI, body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR), and body roundness index (BRI) with mortality in patients with T2D.Research design and methods The study included 11 872 patients (46.5% women) aged 30 years and older and who took part in diabetes care management program of a medical center in Taiwan. Body indices were evaluated by anthropometric measurements at baseline between 2001 and 2016, and their death status was followed up through 2021. Multivariate Cox regression models were used to assess the effect of body indices on mortality.Results During a mean follow-up of 10.2 years, 560 cardiovascular disease (CVD) deaths and 3043 deaths were recorded. For ABSI, WC, WHR, WHtR and BRI, all-cause mortality rates were statistically significantly greater in Q4 versus Q2. For BMI and WHtR, all-cause mortality rates were also statistically significantly greater in Q1 versus Q2. The combination of BMI and ABSI exhibited a superiority in identifying risks of all-cause mortality and CVD mortality (HRs: 1.45 and 1.37, both p

Abstract Background Obesity and cognitive impairment prevalence increases as age increases. Recent growing evidence finds links between obesity and cognitive impairment in older adults. However, the association between the two is controversial. This study aims to identify obesity marker trajectory patterns, and to assess whether these patterns are associated with cognitive impairment and cognitive decline during a 10-year follow-up period among community-dwelling older adults. Methods A total of 626 older adults aged 65 and older were involved in the study, with at least two repeated measurements at baseline, one-year or 10-year follow-up. Cognitive function was measured through the Mini Mental State Examination. Obesity markers included body mass index, waist circumference, waist-to-hip (WHR), fat mass (FM), and abdominal fat (AF) measured by dual-energy X-ray absorptiometry. Multivariate logistic regression analyses were performed to estimate the adjusted odds ratios (ORs) and 95% confidence intervals (CIs) of cognitive impairment and cognitive decline for obesity marker trajectory patterns. Results After a 10-year follow-up, 168 older adults with incident cognitive impairment and 156 with rapid cognitive decline were defined as the top 25th percentile of cognitive decline. Four distinct trajectory groups of obesity markers were identified. In multivariate logistic regression analyses, a low likelihood of cognitive impairment was observed in the consistently high-level group from FM trajectory (ORs = 0.41, 95% CI = 0.20–0.85); the high-level U-shaped group from WHR trajectory (0.43, 0.22–0.84); and the median-level flat inverse U-shaped, consistently high-level, and low-level flat U-shaped groups from AF trajectory (0.44, 0.26–0.77; 0.33, 0.18–0.61; 0.39, 0.18–0.82). In addition, a low likelihood of rapid decline was found in the low-level, slightly increasing trend group from WHR trajectory (0.43, 0.22–0.85). Conclusion FM and AF trajectories with consistent high levels and WHR trajectory with high level with U-shaped group are associated with low risks of incident cognitive impairment in older adults. Similarly, WHR trajectory with a low but slowly increasing trend is associated with a decreased risk of cognitive decline.

Background: The incidence of carbapenem-resistant Klebsiella pneumoniae (CRKP) has rapidly increased. This study aimed to assess the effect of Coptis chinensis and its compounds on the minimal inhibitory concentrations (MICs) of eight antibiotics against CRKP. Methods: Cell cultures were used to investigate the effects of C. chinensis and its compounds on the MICs of eight antibiotics against CRKP. The MICs for antibiotics alone and antibiotics with C. chinensis or compounds were measured and compared. Furthermore, the effects of C. chinensis on cell membrane injury and intracellular adenosine triphosphate (ATP) CRKP concentration were also measured. The Mann–Whitney rank-sum test was used to analyze the differences between means. Results: C. chinensis exhibits a notable MIC bacteriostatic effect at 5 mg/mL on CRKP. A significant MIC reduction against CRKP exists when C. chinensis was added to colistin and colistin-containing two-antibiotic combinations. Moreover, C. chinensis could damage cell membrane integrity and decrease intracellular ATP concentration in CRKP. Thus, C. chinensis exhibits antimicrobial activity superiority with colistin against CRKP. Furthermore, the effects of identified compounds in C. chinensis on the MICs of colistin, four-to eight-, two-to four-, and one-to two-fold reductions were found in ferulic acid, magnoflorine, and jatrorrhizine hydrochloride, respectively. Among these compounds, ferulic acid destroys membrane integrity and decreases intracellular ATP concentration. Conclusion: C. chinensis and ferulic acid can potentiate the antimicrobial activity of colistin and may represent a promising component of combination therapy against CRKP infections in a clinical setting.

Hepatic events can occur after discontinuing antiviral therapy. We investigated factors associated with hepatitis flares and hepatic decompensation after discontinuing tenofovir disoproxil fumarate (TDF) and entecavir (ETV). Hepatitis flares within 6 months and hepatic decompensation were compared between non-cirrhotic hepatitis B e antigen-negative patients after discontinuing TDF or ETV by using the Cox proportional hazard model. The cumulative rates of hepatitis flare at 6 months after discontinuing ETV and TDF were 2% and 19%, respectively (p < 0.001). The respective rates of hepatic decompensation at 6 months were 0% and 7% (p = 0.009). Higher alanine aminotransferase (ALT) (AASLD criteria) at the end of treatment (EOT) (HR = 4.93; p = 0.001), an off-therapy dynamic change in HBV DNA (rapid rebound of HBV DNA from the nadir, ≥1 log10 IU/mL per month) (HR = 10.7; p < 0.001), and the discontinuation of TDF (HR = 6.44; p = 0.006) were independently associated with hepatitis flares within 6 months. Older age (HR = 1.06; p < 0.001) and an off-therapy dynamic change in HBV DNA (HR = 3.26; p = 0.028) were independently associated with hepatic decompensation after the discontinuation of antiviral therapy. In summary, we demonstrated several factors associated with hepatitis flares and hepatic decompensation after discontinuing antiviral therapy in non-cirrhotic hepatitis B e antigen-negative patients.

Abstract Background Decreased skeletal muscle mass and low physical performance are independently associated with increased mortality in elderly individuals. However, little is known about the effects of skeletal muscle mass combined with physical performance on the prediction of mortality risk among community-dwelling older adults. This study aimed to determine the combined effects of skeletal muscle mass and physical performance on total mortality. Methods A community-based prospective cohort study was conducted among 641 participants aged 65 and older in 2009. The height-adjusted skeletal muscle index (hSMI) and the weight-adjusted SMI (wSMI) were determined by dual-energy X-ray absorptiometry examination. Physical performance tests measured at baseline included gait speed (GS), timed up-and-go (TUG) test, timed chair stand (TCS), weight-adjusted leg press (WaLP), and handgrip strength (HS). Cox proportional hazards regression models were applied to determine the adjusted hazard ratios (HRs) of mortality with 95% confidence intervals (95% CIs) for baseline skeletal muscle mass, physical performance, and traditional risk factors. Results During the follow-up of 12 years, 198 (30.89%) participants died. Low hSMI, low GS, high TUG, high TCS, low WaLP, and low HS were associated with high risks of mortality after the adjustment for confounders. The results of receiver operating characteristic (ROC) curve analyses revealed the values of ROC for models with additional consideration for TUG or all indicators significantly improved the discriminatory ability of mortality compared with the model with traditional factors (all P

Abstract Ankle-brachial index (ABI) and brachial-ankle pulse wave velocity (baPWV) are used as non-invasive indicators for detecting atherosclerosis and arterial stiffness, two well-known predictors of mortality in patients with type 2 diabetes mellitus (T2DM). ABI and baPWV have independent associations with mortality; however, their joint and interactive effects on mortality have not been assessed in patients with T2DM. This work aims to evaluate the independent, joint, and interactive associations of ABI and baPWV with all-cause and expanded cardiovascular disease (CVD) mortality in patients with T2DM. This observational study included 2160 patients with T2DM enlisted in the Diabetes Care Management Program database of China Medical University Hospital from 2001 to 2016 and then followed their death status until August 2021. Cox proportional hazard models were used to evaluate the independent, joint, and interactive effects of ABI and baPWV on the risk of all-cause and expanded CVD mortality. A total of 474 patient deaths occurred after a mean follow-up of 8.4 years, and 268 of which were attributed to cardiovascular events. Abnormal ABI (≤ 0.9) and highest baPWV quartile were independently associated with increased risks of all-cause [ABI: hazard ratio (HR) 1.67, 95% confidence interval (CI) 1.30–2.11; baPWV: 1.63, 1.16–2.27] and expanded CVD mortality (ABI: 2.21, 1.62–3.02; baPWV: 1.75, 1.09–2.83). The combination of abnormal ABI (≤ 0.9) and highest baPWV quartile was associated with a significantly higher risk of all-cause (4.51, 2.50–8.11) and expanded CVD mortality (9.74, 4.21–22.51) compared with that of the combination of normal ABI and lowest baPWV quartile. Significant interactions were observed between ABI and baPWV in relation to all-cause and expand CVD mortality (both p for interaction

Introduction Observational studies support the relationship between C-reactive protein (CRP) level and diabetic nephropathy (DN) in patients with diabetes. The research question regarding whether the relationship between serum high-sensitivity C-reactive protein (hsCRP) level and DN is causal lacks experimental evidence. Therefore, this study aimed to evaluate the causality between hsCRP and DN based on Mendelian randomization (MR) analysis.Research design and methods A total of 2332 participants with type 2 diabetes from the Taiwan Biobank database was analyzed. Genetic risk scores (GRSs), which comprise four validated CRP loci as two instrumental variables, were calculated as unweighted and weighted scores to evaluate the causal relationship of hsCRP with DN risk. The two-stage regression model was used to estimate OR and 95% CI.Results The analyses of the observational study showed that the hsCRP level was significantly associated with DN after multivariate adjustment (adjusted OR 1.15; 95% CI 1.01 to 1.32). Unweighted/weighted GRSs for log-transformed hsCRP satisfied MR assumptions 1 and 3, respectively; that is, a significant association with hsCRP was observed but that with DN was absent (adjusted OR 1.00, 95% CI 0.92 to 1.09; 1.00, 0.72 to 1.39, respectively). The MR analyses demonstrated that a 1-unit increase in the log-transformed genetically predicted hsCRP by unweighted and weighted GRSs was associated with DN, demonstrating ORs of 1.80 (95% CI 1.51 to 2.14) and 1.67 (95% CI 1.40 to 1.98), respectively.Conclusions The current study provided experimental evidence that hsCRP level was causally related to DN. These findings suggest that the elevated hsCRP may be a causal risk factor for DN in patients with type 2 diabetes.

Abstract Background Sleep duration is associated with mortality. However, prior studies exploring whether sleep duration predicts subsequent long-term mortality in patients with diabetes are limited. This study aims to examine whether metabolic factors affect the associations between baseline sleep duration and subsequent risks of all-cause, expanded, and non-expanded cardiovascular disease (CVD) mortalities among patients with type 2 diabetes (T2D). Methods A total of 12,526 T2D patients aged 30 years and older, with a follow-up period ≥ 3 years, were identified from the Diabetes Case Management Program of a medical center in Taiwan. Sleep duration was measured using computerized questionnaires by case managers, and the time frame for this question was 1 month prior to the interview date. Sleep duration in relation to subsequent mortality from all causes, expanded CVD, and non-expanded CVD was examined using Cox proportional hazard models. Results Within 10 years of follow-up, 2918 deaths (1328 CVD deaths and 1590 non-CVD deaths) were recorded. A J-shaped association was observed for all-cause, expanded CVD, and non-expanded CVD mortalities, and the lowest risks were observed for patients with 5–7 h of sleep. The significant joint effects included sleep duration of more or less than 7 h with age ≥ 65 years [adjusted HRs: 4.00 (3.49–4.60)], diabetes duration ≥ 5 years [1.60 (1.40–1.84)], age at diabetes diagnosis ≤ 45 years [1.69 (1.38–2.07)], insulin use [1.76 (1.54–2.03)], systolic blood pressure/diastolic blood pressure > 130/85 mmHg [1.24 (1.07–1.43)], triglyceride ≥ 150 mg/dL [1.38 (1.22–1.56)], HbA1c ≥ 7% [1.31 (1.13–1.52)], and body mass index

Abstract Many studies had established the chronic kidney disease (CKD) prediction models, but most of them were conducted on the general population and not on patients with type 2 diabetes, especially in Asian populations. This study aimed to develop a risk prediction model for CKD in patients with type 2 diabetes from the Diabetes Care Management Program (DCMP) in Taiwan. This research was a retrospective cohort study. We used the DCMP database to set up a cohort of 4,601 patients with type 2 diabetes without CKD aged 40–92 years enrolled in the DCMP program of a Taichung medical center in 2002–2016. All patients were followed up until incidences of CKD, death, and loss to follow-up or 2016. The dataset for participants of national DCMP in 2002–2004 was used as external validation. The incident CKD cases were defined as having one of the following three conditions: ACR data greater than or equal to 300 (mg/g); both eGFR data less than 60 (ml/min/1.73 m2) and ACR data greater than or equal to 30 (mg/g); and eGFR data less than 45 (ml/min/1.73 m2). The study subjects were randomly allocated to derivation and validation sets at a 2:1 ratio. Cox proportional hazards regression model was used to identify the risk factors of CKD in the derivation set. Time-varying area under receiver operating characteristics curve (AUC) was used to evaluate the performance of the risk model. After an average of 3.8 years of follow-up period, 3,067 study subjects were included in the derivation set, and 786 (25.63%) were newly diagnosed CKD cases. A total of 1,534 participants were designated to the validation set, and 378 (24.64%) were newly diagnosed CKD cases. The final CKD risk factors consisted of age, duration of diabetes, insulin use, estimated glomerular filtration rate, albumin-to-creatinine ratio, high-density lipoprotein cholesterol, triglyceride, diabetes retinopathy, variation in HbA1c, variation in FPG, and hypertension drug use. The AUC values of 1-, 3-, and 5-year CKD risks were 0.74, 0.76, and 0.77 in the validation set, respectively, and were 0.76, 0.77, and 0.76 in the sample for external validation, respectively. The value of Harrell’s c-statistics was 0.76 (0.74, 0.78). The proposed model is the first CKD risk prediction model for type 2 diabetes patients in Taiwan. The 1-, 3-, and 5-year CKD risk prediction models showed good prediction accuracy. The model can be used as a guide for clinicians to develop medical plans for future CKD preventive intervention in Chinese patients with type 2 diabetes.

Abstract Background Dyslipidemia is a major cardiovascular risk factor and common in diabetes patients. Most guidelines focus on optimal lipid levels, while variation of lipid profiles is far less discussed. This study aims to investigate the association of visit-to-visit variability in blood lipids with all-cause, cardiovascular, and non-cardiovascular mortality in patients with type 2 diabetes. Methods We identified 10,583 type 2 diabetes patients aged ≥ 30 years with follow-up ≥ 3 years and who participated in the Diabetes Care Management Program at a medical center in Taiwan. Variability in lipid profiles within 3 years after entry was calculated using coefficient of variation. Cox proportional hazard models were used to evaluate lipid variability in relation to subsequent mortality. Results Over a mean follow-up of 6.4 years, 1838 all-cause deaths (809 cardiovascular deaths) were observed. For each 10% increase in variability in high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and total cholesterol, the hazard ratios (95% confidence intervals) of all-cause mortality were 1.30 (1.22–1.37), 1.05 (1.01–1.09), and 1.10 (1.03–1.16), respectively; those of cardiovascular mortality were 1.27 (1.16–1.39), 1.08 (1.02–1.15), and 1.16 (1.07–1.27), respectively. Each 10% increase in high-density lipoprotein cholesterol variability conveyed 31% greater risk of non-cardiovascular mortality. High variability in total cholesterol and low-density lipoprotein cholesterol increased all-cause mortality in subgroups of nonsmoking, regular exercising, non-dyslipidemia, and more severe status of diabetes at baseline. Conclusions Blood lipid variability except for triglyceride variability was associated with all-cause and cardiovascular mortality in patients with type 2 diabetes.

Abstract Hypertension (HTN), which frequently co‐exists with diabetes mellitus, is the leading major cause of cardiovascular disease and death globally. This study aimed to develop and validate a risk scoring system considering the effects of glycemic and blood pressure (BP) variabilities to predict HTN incidence in patients with type 2 diabetes. This research is a retrospective cohort study that included 3416 patients with type 2 diabetes without HTN and who were enrolled in a managed care program in 2001–2015. The patients were followed up until April 2016, new‐onset HTN event, or death. HTN was defined as diastolic BP (DBP) ≥ 90 mm Hg, systolic BP (SBP) ≥ 140 mm Hg, or the initiation of antihypertensive medication. Cox proportional hazard regression model was used to develop the risk scoring system for HTN. Of the patients, 1738 experienced new‐onset HTN during an average follow‐up period of 3.40 years. Age, sex, physical activity, body mass index, type of DM treatment, family history of HTN, baseline SBP and DBP, variabilities of fasting plasma glucose, SBP, and DBP and macroalbuminuria were significant variables for the prediction of new‐onset HTN. Using these predictors, the prediction models for 1‐, 3‐, and 5‐year periods demonstrated good discrimination, with AUC values of 0.70–0.76. Our HTN scoring system for patients with type 2 DM, which involves innovative predictors of glycemic and BP variabilities, has good classification accuracy and identifies risk factors available in clinical settings for prevention of the progression to new‐onset HTN.

Abstract This study aimed to explore the associations between renal-related and arterial stiffness biomarkers with all-cause and expanded cardiovascular disease (CVD) mortality in a general Taiwanese population. This prospective community-based cohort study included 4883 subjects aged ≥ 20 years who were followed up until December 31, 2016. Renal-related biomarkers consisted of blood urea nitrogen (BUN), estimated glomerular filtration rate (eGFR), and urine albumin-to-creatinine ratio (UACR). Arterial stiffness biomarker consisted of brachial-ankle pulse wave velocity (baPWV). The death status of the subjects was ascertained by matching information from death records with the identification number and date of birth of the subjects. Cox proportional hazard models with restricted cubic splines estimated the hazard ratios and 95% confidence intervals for all-cause mortality and expanded CVD mortality. During a mean 8.3 years of follow up, 456 deaths were recorded, 146 of which were due to expanded CVD mortality. The multivariable-adjusted hazard ratios of all-cause mortality was 1.53 (95% CI 1.21–1.94) for BUN (≥ 20 mg/dL vs.

Abstract Background This study determined (1) whether a change in frailty status after a 1 year follow up is associated with healthcare utilization and evaluated (2) whether a change in frailty status after a 1 year follow up and health care utilization are associated with all-cause mortality in a sample of Taiwan population. Methods This work is a population-based prospective cohort study involving residents aged ≥65 years in 2009. A total of 548 elderly patients who received follow-ups in the subsequent year were included in the current data analysis. Fried frailty phenotype was measured at baseline and 1 year. Information on the outpatient visits of each specialty doctor, emergency care utilization, and hospital admission during the 2 month period before the second interview was collected through standardized questionnaires administered by an interviewer. Deaths were verified by indexing to the national database of deaths. Results At the subsequent 1 year follow-up, 73 (13.3%), 356 (64.9%), and 119 (21.7%) elderly participants exhibited deterioration, no change in status, and improvement in frailty states, respectively. Multivariate logistic analysis showed the high risk of any type of outpatient use (odds ratios [OR] 1.94, 95% confidence interval [CI] 1.02–3.71) among older adults with worse frailty status compared with those who were robust at baseline and had unchanged frailty status after 1 year. After multivariate adjustment, participants with high outpatient clinic utilization had significantly higher mortality than those with low outpatient clinic visits among unchanged pre-frail or frail (hazard ratios [HR] 2.79, 95% CI: 1.46–5.33) and frail to pre-frail/robust group (HR 9.32, 95% CI: 3.82–22.73) if the unchanged robustness and low outpatient clinic visits group was used as the reference group. Conclusions The conditions associated with frailty status, either after 1 year or at baseline, significantly affected the outpatient visits and may have increased medical expenditures. Combined change in frailty status and number of outpatient visits is related to increased mortality.

Hepatocellular carcinoma (HCC) is one of the most frequent and life-threatening human cancers worldwide. Despite curative resection surgery, the high recurrence rate of HCC leads to poor patient survival. Chronic hepatitis B virus (HBV) infection is a major etiological factor for HCC. HBV pre-S2 gene deletion mutation leads to the expression of an important oncoprotein called a pre-S2 mutant. It represents an independent prognostic biomarker for HCC recurrence. This study aimed to identify other independent prognostic biomarkers from clinicopathological characteristics of 75 HBV-related HCC patients receiving resection surgery and to validate their potential to be combined with pre-S2 gene deletion mutation as a combination biomarker for HCC recurrence. Patients with both the presence of pre-S2 gene deletion mutation and tumor-node-metastasis (TNM) stage IIIA–IIIC had a higher HCC recurrence risk than patients with either one or none of these two factors. Moreover, the combination of pre-S2 gene deletion mutation and TNM stage exhibited better performance than either of these two factors alone in discriminating patients from patients without HCC recurrence. Collectively, this study proposed that the TNM stage held significance as a combination biomarker with pre-S2 gene deletion mutation with a greater performance in predicting HCC recurrence after curative surgical resection.

Abstract Hepatocellular carcinoma (HCC) is a frequent and deadly human cancer worldwide that is intimately associated with chronic hepatitis B virus (HBV) infection. Pre-S2 mutant is a HBV oncoprotein that plays important roles in HCC development and is linked to poor prognosis in HCC patients. However, the profiles of tumor-infiltrating lymphocytes in HCC tissues of pre-S2 mutant-positive patients remain unknown. In this study, we performed fluorescent immunohistochemistry staining to detect the infiltration of ‘anti-tumor’ cytotoxic T lymphocytes (CTLs) and ‘pro-tumor’ regulatory T cells (Tregs) in pre-S2 mutant-positive and -negative HCC patients. We showed that pre-S2 mutant-positive patients had a significantly higher infiltration of CD4+CD25+ cells and forkhead box P3 (Foxp3)-expressing cells but similar CTLs and lower granzyme B-expressing cells in HCC tissues compared with pre-S2 mutant-negative patients. Moreover, the percentage of pre-S2 plus pre-S1 + pre-S2 deletion (pre-S2 mutant) was positively correlated with the density of CD4+CD25+ cells and Foxp3-expressing cells but negatively with granzyme B-expressing cells in HCC tissues. Considering that increased intratumoral Tregs have been shown to promote tumor immune evasion, our data may provide new insights into the pathogenesis of HBV pre-S2 mutant-induced HCC and suggest that therapeutics targeting Tregs may be a promising strategy for treating pre-S2 mutant-positive high-risk patient population.

Abstract Background Renal function is a key factor of cardiovascular disease. Carotid intima-media thickness (IMT) has been widely used as a marker of early subclinical atherosclerosis. The determinants of cystatin C, a novel marker of renal function, have not been extensively studied in the Asian population. This study aimed to assess the determinants of cystatin C and explore whether carotid thickening was associated with urinary albumin-creatinine ratio and cystatin C in community-living Taiwanese adults. Methods A cross-sectional study was conducted on participants from Taichung City, Taiwan. All the participants underwent carotid ultrasonography. Carotid IMT-mean and IMT-maximum were derived. Kidney biomarkers were measured on the basis of urinary albumin-to-creatinine ratio (ACR) and cystatin C. Multiple linear regression analysis was used. Results A total of 1032 individuals were recruited, and 469 (45.44%) of them were men. An increased cystatin C level was significantly associated with older age, male gender, lack of physical activity, low HDL cholesterol, abdominal obesity, high hs-CRP, and high ACR. The multivariate-adjusted mean carotid IMT-mean and IMT-maximum values significantly increased by 80.49 and 195.23 μm for every one unit of increase in cystatin C level and by 0.07 and 0.14 μm for every one unit of increase in ACR, respectively (all p

Abstract Background Cognitive impairment is accompanied with high rates of comorbid conditions, leading ultimately to death. Few studies examine the relation between cognitive transition and mortality, especially in Asian population. This study evaluated baseline cognition and cognitive transition in relation to all-cause mortality among community-dwelling older adults. Methods We conducted a community-based prospective cohort study among 921 participants of Taichung Community Health Study for Elders in 2009. Cognitive function was evaluated by the Mini-Mental State Examination. Cognitive impairment was considered if the total score is less than 27, 24, and 21 for a participant’s educational level of more than 6 years, equal or less than 6 years, and illiteracy, respectively. One-year transition in cognitive function was obtained among 517 individuals who were assessed in both 2009 and 2010. Mortality was followed up until 2016. Cox proportional hazards models were applied to estimate the adjusted hazard ratios of mortality for baseline cognitive impairment and one-year transition in cognitive status. Results After a follow-up of 6.62 years, 160 deaths were recorded. The multivariate adjusted hazard ratio (95% confidence interval) for baseline cognitive impairment was 2.08 (1.43, 3.01). Significantly increased mortality risk was observed for cognitively impaired–normal and impaired–impaired subgroups over 1 year as compared with those who remained normal [2.87 (1.25, 6.56) and 3.79 (1.64, 8.73), respectively]. The area under the receiver operating characteristic curves demonstrated that baseline cognition and one-year cognitive transition had no differential predictive ability for mortality. Besides, there was an interaction of cognitive impairment and frailty, with an additive mortality risk [5.41 (3.14, 9.35)] for the elders who presented with both. Conclusion Baseline cognitive impairment rather than one-year progression is associated with mortality in a six-year follow-up on older adults.

Abstract Background This study investigated whether visit-to-visit fasting plasma glucose (FPG) variability, as measured by the coefficient of variation (CV), increased peripheral artery disease (PAD) risk. Methods Individuals with type 2 diabetes from the National Diabetes Care Management Program during the period 2002–2004, ≥ 30 years of age, and free of PAD (n = 30,932) were included and monitored until 2011. Cox proportional hazards regression models were implemented to analyze related determinants of PAD. Results A total of 894 incident cases of PAD were identified during an average 8.2 years of follow-up, resulting in a crude incidence rate of 3.53 per 1000 person-years. Both FPG-CV and HbA1c were significantly associated with PAD after multivariate adjustment, with corresponding hazard ratios of 1.24 [95% confidence interval (CI) 1.04–1.47] for FPG-CV in the third tertile and 1.50 (95% CI 1.10–2.04) for HbA1c ≥ 10%. The findings of the sensitivity analysis remained consistent after excluding potential confounders, demonstrating the consistency of the results. Conclusions The associations between HbA1c, variability in FPG-CV, and PAD suggest a linked pathophysiological mechanism, suggesting the crucial role of glycemic variability in clinical management and therapeutic goals in preventing PAD in type 2 diabetes.

Objective: The aim of this study was to explore mothers’ perceived level of stress one month after hospital discharge following the birth of singleton and multiple preterm infants. Design: A cross-sectional design was used to compare mother’s perceived stress in two groups of postpartum mothers and the relationship of the theoretical antecedents and these variables. Setting: A neonatal intensive care unit in a medical center in Taiwan. Participants: Mothers of 52 singletons and 38 multiple premature infants were recruited. One month after the infant was discharged, the participants completed a self-reported questionnaire that included demographic data about the mother and infant, the 21-item Social Support Scale, and the 15-item Perceived Stress Scale. This was returned by email or completed at the outpatient unit. Analysis: Descriptive and inferential analysis. Results: The mean social support scores were 76.6 and 76.5 (out of 105) for mothers with singleton and multiple birth infants, respectively. The most important supporter was the husband. The mean perceived stress scores of 25.8 and 31.0 for mothers with singleton and multiple birth infants, respectively, were significantly different (p = 0.02). Sleep deprivation and social support were predictive indicators of perceived stress in mothers with preterm infants. Conclusions: We suggest that the differences in stress and needs of mothers with singleton and multiple births should be recognized and addressed in clinics. The findings of this study serve as a reference for promoting better preterm infant care.

Abstract Background Previous studies have reported the associations of frailty phenotype or its components with mortality. However, studies that explored the effects of transition in frailty status on mortality were far less in Asian or Chinese. The aim of this study was to evaluate baseline frailty status and one-year change of frailty status in relation to all-cause mortality in Taiwanese community-dwelling older adults who participated in the Taichung Community Health Study for Elders. Methods We conducted a community-based prospective cohort study. A total of 921 community-dwelling elderly men and women aged 65–99 years in Taichung City were enrolled in 2009–2010 and were followed up through 2016. We adopted the definition of frailty proposed by Fried et al., including five components: shrinking, weakness, poor endurance and energy, slowness, and low physical activity. Cox proportional hazards models were used to determine adjusted hazard ratios (HRs) of mortality with 95% confidence intervals (CIs) for frailty at baseline and one-year change in frailty status. Results There were 160 deaths during the follow-up period. The mortality rates in groups of robust and frail were 20.26 and 84.66 per 1000 person-years respectively. After multivariate adjustment, the HR (CIs) for baseline frailty was 2.67 (1.73–4.12). Poor endurance and energy [1.88 (1.03–3.42)], slowness [2.60 (1.76–3.83)] and weakness [1.65 (1.16–2.33)] were found to be predictors of mortality. Increased risks in mortality for subgroups of robust-to-frail [2.76 (1.22–6.27)], frail-to-robust [3.87 (1.63, 9.19)], and frail-to-frail [4.08 (1.92–8.66)] over one-year period were observed compared with those remaining robust. Conclusion Baseline frailty status and one-year change in frailty status are associated with 6-year all-cause mortality among Taiwanese elderly adults. Frailty may be useful for identifying older adults at high risks for mortality prevention.

Although surgical resection is available as a potentially curative therapy for hepatocellular carcinoma (HCC), high recurrence of HCC after surgery remains a serious obstacle for long-term patient survival. Therefore, the discovery of valuable prognostic biomarkers for HCC recurrence is urgently needed. Pre-S2 mutant is a mutant form of hepatitis B virus (HBV) large surface protein which is expressed from the HBV surface gene harboring deletion mutations spanning the pre-S2 gene segment. Pre-S2 mutant-positive HCC patients have been regarded as a high-risk population of HCC recurrence after resection surgery and display increased immune checkpoint programmed death ligand 1 (PD-L1) expression and pro-tumor regulatory T cells (Tregs) infiltration in tumor tissues. In this study, the association of higher levels of PD-L1 expression and Tregs infiltration in tumor tissues with post-operative HCC recurrence in pre-S2 mutant-positive HCC patients was evaluated. We found that patients with pre-S2 mutant in combination with higher levels of PD-L1 expression and Tregs infiltration in tumor tissues were independently associated with a higher risk of HCC recurrence (hazard ratio, 4.109; p value = 0.0011) and poorer recurrence-free survival (median, 8.2 versus 18.0 months; p value = 0.0004) than those of patients with either one or two of these three biomarkers. Furthermore, a combination of pre-S2 mutant, intra-tumoral PD-L1 expression, and tumor-infiltrating Tregs exhibited superior performance in identifying patients at a higher risk of HCC recurrence (area under the receiver operating characteristic curve, 0.8400). Collectively, this study suggests that higher levels of PD-L1 expression and Tregs infiltration in tumor tissues predicted a higher risk of HCC recurrence in pre-S2 mutant-positive HCC patients after curative surgical resection.

Our study used data collected in Chung-Hsing Village in Taiwan in May 1998 to evaluate the distribution of triglycerides and the association between hypertriglyceridemia and its correlates in elderly people. All individuals aged 65 and over were recruited as study subjects. A total of 1093 persons, out of 1774 registered residents, were contacted in face-to-face interviews. The response rate was 61.6%. However, only 586 respondents had blood tests and completed questionnaires. Analysis in this study was based on these 586 subjects. To study the significant correlates of hypertriglyceridemia, t-tests, ANOVAs, chi-square analysis and multivariate logistic regression were used. Among the study population, 66.0% were men and 34.0% were women. The mean age was 73.1 ± 5.3 years. The mean triglyceride values were 1.65 ± 0.93 mmol/L in men and 2.02 ± 1.44 mmol/L in women (p < 0.01). The proportions of hypertriglyceridemia were 18.7% in men and 27.6% in women (p < 0.05). After controlling the other covariates, analysis by multivariate logistic regression showed that the factors significantly related to hypertriglyceridemia were high systolic pressure, abnormal glutamic pyruvic transaminase, hypercholesterolemia and hyperglycemia. Thus, these results support the hypothesis that it is important to examine the other cardiovascular risk factors if one cardiovascular risk factor is observed. The data also suggest one should determine the triglyceride level when abnormal glutamic pyruvic transaminase is identified in an elderly subject.

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death globally. Previous studies have addressed the impact of comorbidity on short-term mortality in patients with COPD. However, the prevalence of cardiovascular disease (CVD) and the association of statins prescription with mortality for aged COPD patients remains unclear. We enrolled 296 aged, hospitalized patients who were monitored in the pay-for-performance (P-4-P) program of COPD. Factors associated with long-term mortality were identified by Cox regression analysis. The median age of the study cohort was 80 years old, and the prevalence of coronary artery disease (CAD) and statins prescriptions were 16.6% and 31.4%, respectively. The mortality rate of the median 3-year follow-up was 51.4%. Through multivariate analysis, body mass index (BMI), statin prescription, and events of respiratory failure were associated with long-term mortality. A Cox analysis showed that statins prescription was associated with lower mortality (hazard ratio (HR): 0.5, 95% Confident interval, 95% CI: 0.34–0.73, p = 0.0004) and subgroup analysis showed that rosuvastatin prescription had protective effect on long-term mortality (HR: 0.44; 95% CI: 0.20–0.97; p < 0.05). Statin prescriptions might be associated with better long-term survival in aged COPD patients, especially those who experienced an acute exacerbation of COPD (AECOPD) who require hospitalization.

BackgroundThere is emerging interest in multimorbidity in type 2 diabetes (T2D), which can be either concordant (T2D related) or discordant (unrelated), as a way of understanding the burden of disease in T2D. Current diabetes guidelines acknowledge the complex nature of multimorbidity, the management of which should be based on the patient's individual clinical needs and comorbidities. However, although associations between multimorbidity, glycated haemoglobin (HbA1c), and mortality in people with T2D have been studied to some extent, significant gaps remain, particularly regarding different patterns of multimorbidity, including concordant and discordant conditions. This study explores associations between multimorbidity (total condition counts/concordant/discordant/different combinations of conditions), baseline HbA1c, and all-cause mortality in T2D.Methods and findingsWe studied two longitudinal cohorts of people with T2D using the UK Biobank (n = 20,569) and the Taiwan National Diabetes Care Management Program (NDCMP) (n = 59,657). The number of conditions in addition to T2D was used to quantify total multimorbidity, concordant, and discordant counts, and the effects of different combinations of conditions were also studied. Outcomes of interest were baseline HbA1c and all-cause mortality. For the UK Biobank and Taiwan NDCMP, mean (SD) ages were 60.2 (6.8) years and 60.8 (11.3) years; 7,579 (36.8%) and 31,339 (52.5%) were female; body mass index (BMI) medians (IQR) were 30.8 (27.7, 34.8) kg/m2 and 25.6 (23.5, 28.7) kg/m2; and 2,197 (10.8%) and 9,423 (15.8) were current smokers, respectively. Increasing total and discordant multimorbidity counts were associated with lower HbA1c and increased mortality in both datasets. In Taiwan NDCMP, for those with four or more additional conditions compared with T2D only, the mean difference (95% CI) in HbA1c was -0.82% (-0.88, -0.76) p < 0.001. In UK Biobank, hazard ratios (HRs) (95% CI) for all-cause mortality in people with T2D and one, two, three, and four or more additional conditions compared with those without comorbidity were 1.20 (0.91-1.56) p < 0.001, 1.75 (1.35-2.27) p < 0.001, 2.17 (1.67-2.81) p < 0.001, and 3.14 (2.43-4.03) p < 0.001, respectively. Both concordant/discordant conditions were significantly associated with mortality; however, HRs were largest for concordant conditions. Those with four or more concordant conditions had >5 times the mortality (5.83 [4.28-7.93] p ConclusionsMultimorbidity patterns associated with the highest mortality differed between UK Biobank (a population predominantly comprising people of European descent) and the Taiwan NDCMP, a predominantly ethnic Chinese population. Future research should explore the mechanisms underpinning the observed relationship between increasing multimorbidity count and reduced HbA1c alongside increased mortality in people with T2D and further examine the implications of different patterns of multimorbidity across different ethnic groups. Better understanding of these issues, especially effects of condition type, will enable more effective personalisation of care.

Objective: This study is aimed to investigate the association between interferon-alpha (IFN-α) plus ribavirin (RBV) treatment and emergence of somatic pain symptoms in patients with hepatitis C virus (HCV) over a 24-week treatment. Method: In this prospective cohort study, 297 patients with HCV were evaluated at baseline and 2nd, 4th, 8th, 12th, 16th, 20th, and 24th week with structured Mini-International Neuropsychiatric Interview for Major Depressive Disorder (MDD) diagnosis and the Neurotoxicity Rating Scale (NRS) for somatic symptoms. Results: Eighty-seven out of the 297 patients (29%) developed IFN-α induced depression and had significantly higher somatic pain symptoms as early as the 2nd week and at all the assessment time points (p ​

Evidence suggests the existence of association between a large panel of modifiable biomarkers representing inflammation, coagulation, paraoxonase, and endothelial activation pathways and carotid atherosclerosis. Thus, this study investigated whether CRP, FGA, FGB, FGG, PON1, and EDNRA gene variants affected plasma hs-CRP, fibrinogen levels, and thickness of carotid intima media thickness (IMT). Nineteen single-nucleotide polymorphisms of CRP, FGA, FGB, FGG, PON1, and EDNRA genes were examined in 480 participants from 160 families. Carotid IMT was measured by ultrasound. Generalized linear models with generalized estimating equation were utilized to consider the dependence of subjects within families. In the recessive model, homozygotes for the minor alleles of rs1800789, rs1800790 and rs4220 SNPs in FGB gene indicated a reduced risk of IMT (Exp. β = 0.89, 0.89, 0.88), which remained significant after adjustment for confounding factors. Significant interaction effects between CRP SNP rs1130864 and rs3093059 and gender for IMT were observed with a significant association in men only. Men carrying minor-minor genotype of CRP SNP rs1130864 and rs3093059 had 0.70- and 0.78-fold lower IMT than men carrying minor-major/major-major genotype. We also observed that the interaction of CRP SNP rs1130864 and rs3093059 with obesity on IMT, hs-CRP and fibrinogen levels. These results support the hypothesis that inflammatory genes are involved in atherosclerosis, most likely via complex gene-gender and gene-obesity interactions.

Hepatocellular carcinoma (HCC) is among the leading causes of cancer-related death worldwide. Patients with hepatitis B virus (HBV) pre-S mutants in liver tissues or blood have been regarded as a high-risk population for HCC development and recurrence. Detection of pre-S mutants in clinical specimens is thus important for early diagnosis and prognosis of HCC to improve patient survival. Recently, we have developed a next-generation sequencing (NGS)-based platform that can quantitatively detect pre-S mutants in patient plasma with superior sensitivity and accuracy. In this study, we compared the pre-S genotyping results from plasma by the NGS-based analysis with those from liver tissues by the immunohistochemistry (IHC)-based analysis in 30 HBV-related HCC patients. We demonstrated that the detection rate of pre-S mutants was significantly higher by NGS- than by IHC-based analysis. There was a moderate to good agreement between both analyses in detection of pre-S mutants. Compared with the IHC, the NGS-based detection of pre-S mutants in patient plasma could determine the patterns of pre-S mutants in liver tissues more efficiently in a noninvasive manner. Our data suggest that the NGS-based platform may represent a promising approach for detection of pre-S mutants as biomarkers of HBV-related HCC in clinical practice.

Prediction model mainly focused on specific diseases, such as diabetes, hypertension, cardiovascular disease, or patients with cancer, or populations of Europe and America, thereby limiting its generalization. This study aimed to develop and validate a 10-year mortality risk score by using data from a population-representative sample of adults. Data were collected from 2,221 Taichung Community Health study participants aged ≥40 years. The baseline period of the study was 2004, and all participants were followed up until death or in 2016. Cox's proportional hazards regression analyses were used to develop the prediction model. A total of 262 deaths were ascertained during the 10-year follow-up. The all-cause mortality prediction model calculated the significant risk factors, namely, age, sex, marital status, physical activity, tobacco use, estimated glomerular filtration rate, and albumin-to-creatinine ratio, among the baseline risk factors. The expanded cardiovascular disease (CVD) mortality prediction model consisted of six variables: age, sex, body mass index, heart disease plus heart disease medication use, stroke plus medication use, and ankle-brachial index. The areas under receiver operating curves of the 3-, 5- and 10-year predictive models varied between 0.97, 0.96, and 0.88 for all-cause mortality, and between 0.97, 0.98, and 0.84 for expanded CVD mortality. These mortality prediction models are valid and can be used as tools to identify the increased risk for mortality.

This study assessed the interactions among IGF-1, AKT2, FOXO1, and FOXO3 variations and the interactions of gene and physical activity on handgrip strength, arm muscle mass-adjusted handgrip (armGrip), gait speed (GS), timed up and go (TUG), and leg press strength (LPS). Nine single nucleotide polymorphisms (SNPs) containing three IGF-1 SNPs (rs6214, rs5742692, and rs35767), two AKT2 SNPs (rs892119 and rs35817154), two FOXO1 SNPs (rs17446593 and rs10507486), and two FOXO3 SNPs (rs9480865 and rs2153960) were genotyped in 472 unrelated elders with a mean age of 73.8 years. We observed significant interactions of IGF-1 SNP rs6214 and rs35767 with regular physical activity on TUG and GS; and AKT2 SNP rs892119 and FOXO3 SNP rs9480865 with regular physical activity on armGrip. Genotype GG of IGF-1 rs6214 and rs35767 in individuals without regular physical activity had poor performance in TUG and GS, as well as GG of AKT2 rs892119 decreased armGrip in individuals without regular physical activity. After FDR adjustment, no significant gene-gene interactions were found. A sedentary lifestyle may increase the risk of impairing physical performance and regular physical activity is a remedy for sarcopenia, even a little regular physical activity can overcome carrying some risk alleles in this pathway.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. Despite curative surgical resection, high recurrence of HCC after surgery results in poor patient survival. To develop prognostic markers is therefore important for better prevention and therapy of recurrent HCC to improve patient outcomes. Deletion mutations over the pre-S1 and pre-S2 gene segments of hepatitis B virus (HBV) have been closely associated with recurrence of HCC after curative surgical resection. In this study, we applied a next-generation sequencing-based approach to further evaluate the association of pre-S deletion regions with HCC recurrence. We demonstrated that the pre-S2 deletion (nucleotide 1 to 54) was the most predominant deletion regions of pre-S gene in plasma of HBV-related HCC patients. Moreover, patients with the pre-S2 deletion (nucleotide 1 to 54) exhibited a significantly higher risk of HCC recurrence after curative surgical resection than those without. The pre-S2 deletion (nucleotide 1 to 54) in plasma represented a prognostic factor that independently predicted HCC recurrence with greater performance than other clinicopathological and viral factors. Our data suggest that detection of the pre-S2 deletion (nucleotide 1 to 54) in plasma may be a promising noninvasive strategy for identifying patients at high risk for HCC recurrence after curative surgical resection.

Abstract Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. Early diagnosis and treatment of HCC remain a key goal for improving patient survival. Chronic hepatitis B virus (HBV) infection is a major risk factor for HCC development. Pre-S mutants harboring deletions in HBV large surface antigen have been well demonstrated as HBV oncoproteins that dysregulate multiple signaling pathways in hepatocytes, leading to HCC formation. The presence of pre-S mutants in plasma represents important predictive and prognostic markers for HCC in patients with chronic HBV infection. However, the method to detect pre-S mutants remains to be optimized. In this study, we developed a platform, based on the next-generation sequencing (NGS) technology, for detection of pre-S mutants in plasma of HBV-related HCC patients. Compared to the current TA cloning-based analysis, the NGS-based analysis could detect pre-S deletion quantitatively, and the detection rate was significantly more sensitive in 49 plasma analyzed (McNemar’s paired proportion test, P value

With an increasing geriatric population, the need for effective management of chronic conditions and medication use in the elderly is growing. Medication use in the elderly presents significant challenges due to changes in pharmacodynamic and pharmacokinetic profiles. We aimed to examine the impact of a collaborative physician-pharmacist medication therapy management (MTM) program for polypharmacy elderly patients. Methods: Elderly patients with multiple chronic conditions on polypharmacy were enrolled in this prospective, randomized, and controlled study over 16 months of implementation. The intervention group consisted of patients randomized to a collaborative pharmacist-physician MTM program. They were monitored continuously by a clinical pharmacist, while patients in the control group received only usual care with follow-up assessment. Primary outcome was economic differences, measured in total medical expenditure. Secondary outcomes of clinical and humanistic effects were compared between the two groups. Results: The total number of enrolled patients was 87 and 91 in the MTM and usual groups, respectively. The difference-in-difference estimate on medical expenditure during the 16-month implementation period was $3,758,373 New Taiwan Dollars ($127,015 US Dollars) less than the usually care group. Impact was also seen in humanistic outcomes while lipid profiles and mortality trended toward improvement. Conclusion: The pharmacist-physician collaborative MTM program for polypharmacy elderly had significant cost savings and improvement in humanistic measures, demonstrating the importance of clinical pharmacists and MTM programs for elderly patients in Taiwan. The results suggest the possibility of clinical benefits, but the study was not substantially powered to find a statistical difference.

Hepatocellular carcinoma (HCC) is, globally, one of the most prevalent and deadly human cancers; despite curative surgical resection, its high recurrence rate after surgery remains a large threat, resulting in poor patient survival. The hepatitis B virus (HBV) pre-S2 mutant that harbors deletions spanning the pre-S2 gene segment has emerged as an important oncoprotein for HCC development and a valuable prognostic biomarker for HCC recurrence; however, its relationship with clinicopathological factors is largely unexplored. In this study, the correlation of the deletion spanning the pre-S2 gene segment with clinicopathological factors and the association of such correlation with HCC recurrence after curative surgical resection were examined in HBV-related HCC patients. Inverse correlation between serum albumin level and the deletion spanning the pre-S2 gene segment was identified. HCC patients with the presence of the deletion spanning the pre-S2 gene segment and a low serum albumin level were associated with higher HCC recurrence than patients with either factor alone or neither factor were. Moreover, a combination of the serum albumin level and the deletion spanning the pre-S2 gene segment exhibited better performance than that of either factor alone in predicting HCC recurrence. Collectively, this study shows an association of low serum albumin level with pre-S2 mutant-positive HCC patients, and validates the prognostic value of this association in identifying patients with higher HCC recurrence after curative surgical resection.

Abstract Background Indigo naturalis is a Traditional Chinese Medicine (TCM) ingredient long-recognized as a therapy for several inflammatory conditions, including psoriasis. However, its mechanism is unknown due to lack of knowledge about the responsible chemical entity. We took a different approach to this challenge by investigating the molecular profile of Indigo naturalis treatment and impacted pathways. Methods A randomized, double-blind, placebo-controlled clinical study was conducted using Indigo naturalis as topical monotherapy to treat moderate plaque psoriasis in a Chinese cohort (n = 24). Patients were treated with Indigo naturalis ointment (n = 16) or matched placebo (n = 8) twice daily for 8 weeks, with 1 week of follow-up. Results At week 8, significant improvements in Psoriasis Area and Severity Index (PASI) scores from baseline were observed in Indigo naturalis-treated patients (56.3% had 75% improvement [PASI 75] response) compared with placebo (0.0%). A gene expression signature of moderate psoriasis was established from baseline skin biopsies, which included the up-regulation of the interleukin (IL)-17 pathway as a key component; Indigo naturalis treatment resulted in most of these signature genes returning toward normal, including down-regulation of the IL-17 pathway. Using an in vitro keratinocyte assay, an IL-17-inhibitory effect was observed for tryptanthrin, a component of Indigo naturalis. Conclusions This study demonstrated the clinical efficacy of Indigo naturalis in moderate psoriasis, and exemplified a novel experimental medicine approach to understand TCM targeting mechanisms. Trial registration NCT01901705 .

Abstract We assessed gene–gene and gene-physical activity interactions of polymorphisms in C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), and lymphotoxin α (LTA) genes on lower extremity performance in community-dwelling elders in Taiwan. Five SNPs (rs1205, rs1130864, rs1800947, rs2794520, and rs3093059) of CRP gene, three SNPs (rs909253, rs1041981, and rs2239704) of LTA gene, and three SNPs (rs3093662, rs1800629, and rs1799964) of TNF-α gene of 472 unrelated elders were genotyped. Lower extremity performance included timed up-and-go test (TUG), walking speed, weight-adjusted leg press (waLP), and timed chair stand (TCS). We detected significant interactions between physical activity with CRP rs2794520, rs1205, and rs3093059; LTA rs909253 and rs1041981; and TNF-α rs1799964 for TCS in women after covariate adjustment (all P

Exposure to air pollutants is known to have adverse effects on human health; however, little is known about the association between hydrocarbons in air and an ischemic stroke (IS) event. We investigated whether long-term exposure to airborne hydrocarbons, including volatile organic compounds, increased IS risk. This retrospective cohort study included 283,666 people aged 40 years or older in Taiwan. Cox proportional hazards regression analysis was used to fit single- and multiple-pollutant models for two targeted pollutants, total hydrocarbons (THC) and nonmethane hydrocarbons (NMHC), and estimated the risk of IS. Before controlling for multiple pollutants, hazard ratios (HRs) of IS with 95% confidence intervals for the overall population were 2.69 (2.64-2.74) at 0.16-ppm increase in THC and 1.62 (1.59-1.66) at 0.11-ppm increase in NMHC. For the multiple-pollutant models controlling for PM2.5, the adjusted HR was 3.64 (3.56-3.72) for THC and 2.21 (2.16-2.26) for NMHC. Our findings suggest that long-term exposure to THC and NMHC may be a risk factor for IS development.

This study aimed to investigate whether long-term exposure to airborne hydrocarbons, including volatile organic compounds, increases the risk of developing retinal vein occlusion (RVO) among the population of Taiwan. A retrospective cohort study involving 855,297 people was conducted. Cox proportional hazards regression analysis fitted the multiple pollutant models for two targeted pollutants, including total hydrocarbons (THC), nonmethane hydrocarbons (NMHC) were used, and the risk of RVO was estimated. The chi-squared test and one-way analysis of variance were used to test differences in demographics and comorbidity distribution among tertiles of the targeted pollutants. Before controlling for multiple pollutants, hazard ratios for the overall population were 19.88 (95% CI: 17.56-22.50) at 0.51-ppm increases in THC and 4.33 (95% CI: 3.97-4.73) at 0.27-ppm increases in NMHC. The highest adjusted hazard ratios for different multiple pollutant models of each targeted pollutant were statistically significant (all p values were ≤0.05) for all patients at 29.67 (95% CI: 25.57-34.42) for THC and 16.24 (95% CI: 14.14-18.65) for NMHC. Our findings suggest that long-term exposure to THC and NMHC contribute to RVO development.

Gene effects on osteoporosis have been studied separately and may have been masked by gene-gene and gene-environment interactions. We evaluated gene-gene and gene-physical activity interactions of the variants of tumor necrosis factor-α (TNF-α) and vitamin D receptor (VDR) genes on osteoporosis. A total of 472 elders were included. Seven variants (TNF-α: rs1799964, rs1800629, rs3093662; VDR: rs7975232, rs1544410, rs2239185, rs3782905) were genotyped. Bone mineral densities of the lumbar spine, femoral neck, and total hip were measured by dual-energy X-ray absorptiometry. Predictive models' ability to discriminate osteoporosis status was evaluated by areas under the receiver operating characteristics (AUROC) curve. After multivariable adjustment, significant interactions of TNF-α rs1800629 and VDR rs3782905 were observed on overall and lumbar spine osteoporosis. In elderly women, we found that those carrying the CG/CC genotype of VDR rs3782905 were significantly associated with increased odds of overall osteoporosis compared with those carrying the GG genotype of VDR rs3782905 among those carrying TNF-α rs1800629 GG genotype. The adjusted odds ratios (ORs) for VDR rs3782905 CG/CC genotype in elderly women carrying TNF-α rs1800629 AG/AA and GG genotypes were 0.1 (0.01, 0.98) and 3.54 (1.51, 8.30), respectively. We observed significant differences in AUROCs between the model with traditional covariates plus variants and their interaction term and the model with traditional covariates only (AUROCs: 0.77 and 0.81; p = 0.028). Although the sample size of this study may have been relatively small, our results suggest that the interaction of the CG/CC genotype of VDR rs3782905 with TNF-α rs1800629 GG genotype was associated with increased odds of overall and lumbar spine osteoporosis in elderly women.

Hepatocellular carcinoma (HCC) is among the most common and lethal human cancers worldwide. Despite curative resection, high recurrence of HCC remains a big threat, leading to poor patient outcomes. Hepatitis B virus (HBV) pre-S mutants, which harbor deletions over pre-S1 and pre-S2 gene segments of large surface proteins, have been implicated in HCC recurrence. Therefore, a reliable approach for detection of pre-S mutants is urgently needed for predicting HCC recurrence to improve patient survival. In this study, we used a next-generation sequencing (NGS)-based platform for quantitative detection of pre-S mutants in the plasma of HBV-related HCC patients and evaluated their prognostic values in HCC recurrence. We demonstrated that the presence of deletions spanning the pre-S2 gene segment and the high percentage of pre-S2 plus pre-S1 + pre-S2 deletions, either alone or in combination, was significantly and independently associated with poor recurrence-free survival and had greater prognostic performance than other clinicopathological and viral factors in predicting HCC recurrence. Our data suggest that the NGS-based quantitative detection of pre-S mutants in plasma represents a promising approach for identifying patients at high risk for HBV-related HCC recurrence after surgical resection in a noninvasive manner.

The best macronutrient percentages of dietary intake supporting longevity remains unclear. The strength of association between dietary intake and mortality in patients with type 2 diabetes (T2DM) should be quantified as a basis for dietary recommendations. Our study cohort consisted of 15,289 type 2 diabetic patients aged 30 years and older in Taiwan during 2001–2014 and was followed up through 2016. Percentages of macronutrient intakes were calculated as dietary energy intake contributed by carbohydrate, protein, and fat, divided by the total energy intake using a 24 h food diary recall approach. Cox proportional hazard models were applied to examine the temporal relation of macronutrient intakes with all-cause and cause-specific mortality. The average follow-up time was 7.4 years, during which 2784 adults with T2DM died. After multivariable adjustment, people with fourth and fifth quintiles of total energy, second and third quintiles of carbohydrate, and fourth quintiles of protein intakes were likely to have lower risks of all-cause and expanded cardiovascular disease (CVD) mortality. People with fifth quintiles of total energy intake were likely to have decreased non-expanded CVD mortality. We found a significant interaction between gender and fat intake on all-cause and expanded CVD mortality. Fat intake was associated with all-cause, expanded and non-expanded CVD mortality among males with T2DM. Total energy, carbohydrate, and protein intakes were associated with lower risks of all-cause and expanded CVD mortality, with minimal risks observed at ≥1673 Kcal total energy, 43–52% carbohydrate intake, and 15–16% protein intake among people with T2DM.

PURPOSE:The changes of the risk of peripheral arterial disease (PAD) in patients with end-stage renal disease after parathyroidectomy are scant. METHODS:We used a nationwide health insurance claims database to select all dialysis-dependent patients with end-stage renal disease aged 18 years and older for the study population in 2000 to 2006. Of the patients with end-stage renal disease, we selected 947 patients who had undergone parathyroidectomy as the parathyroidectomy group and frequency matched 3746 patients with end-stage renal disease by sex, age, years since the disease diagnosis, and the year of index date as the non-parathyroidectomy group. We used a multivariate Cox proportional hazards regression analysis with the use of a robust sandwich covariance matrix estimate, accounting for the intra-cluster dependence of hospitals or clinics, to measure the risk of peripheral arterial disease for the parathyroidectomy group compared with the non-parathyroidectomy group after adjusting for sex, age, premium-based income, urbanization, and comorbidity. RESULTS:The mean post-op follow-up periods were 5.08 and 4.52 years for the parathyroidectomy and non-parathyroidectomy groups, respectively; the incidence density rate of PAD in the PTX group was 12.26 per 1000 person-years, significantly lower than the data in the non-PTX group (24.09 per 1000 person-years, adjusted HR = 0.66, 95% CI = 0.46-0.94). CONCLUSION:Parathyroidectomy is associated with reduced risk of peripheral arterial disease in patients with end-stage renal disease complicated with severe secondary hyperparathyroidism.

[This corrects the article DOI: 10.1371/journal.pone.0156863.].

A stroke often results in post-stroke dementia, a rapid decline in memory and intelligence causing dysfunctions in daily life. The Chinese medicine doctor uses 4 examinations of inspection, listening, smelling, and feeling to determine the Chinese medicine pattern (CMP). Therefore, the purpose of the present study was to investigate the CMP in patients with post-stroke dementia. A total of 101 stroke patients were examined, consistent with the DSM IV diagnostic criteria of the American Psychiatric Association, as well as the National Institute of Neurological Disorders and Stroke-Association International pour Ia Recherche et I’Enseignement en Neurosciences vascular dementia diagnostic criteria of post-stroke dementia. Results: 100 patients (99.0%) were KEDP (kidney essence deficiency pattern, shèn jīng kuī xū zhèng, 腎精虧虛證), 83 patients were AHLYP (ascendant hyperactivity of liver yang pattern, gān yáng shàng kàng zhèng, 肝陽上亢證), 83 patients were QBDP (qi-blood deficiency pattern, qì xuè kuī xū zhèng, 氣血虧虛證), 81 patients were SBOCP (static blood obstructing the collaterals pattern, yū xuè zǔ luò zhèng, 瘀血阻絡證), 72 patients were BSTRP (bowels stagnation turbidity retention pattern, fǔ zhì zhuó liú zhèng, 腑滯濁留證), 50 patients were FHIEP (fire heat interior excess pattern, huǒ rè nèi sheng zhèng, 火熱內盛證), and 39 participants (38.6%) were PTOOP (phlegm turbidity obstructing the orifices pattern, tán zhuó zǔ qiào zhèng, 痰濁阻竅證); one to 31 patients have at least 2 CMPs simultaneously. In conclusion, the most CMP is KEDP CMP in the post-stroke dementia patients, and one patient may have one or at least 2 CMPs simultaneously.

The purpose of the present study was to investigate effect of electro-acupuncture (EA) at different frequencies on autonomic function. Twenty healthy adult volunteers were studied, and underwent 4 sessions of EA (sham, 2 Hz, 15 Hz, and 50 Hz). Sham, 2 Hz, 15 Hz, and 50 Hz EA was applied to the bilateral Leg Three Li (足三里 zú sān lǐ, ST-36) and Upper Great Hollow (上巨虛 shàng jù xū, ST-37) acupoints. The intensity of electrical stimulation was adjusted to obtain visible twitching of the anterior tibial muscle about 2.0-2.5 mA except sham without electrical stimulation. The components of heart rate variability (HRV) and blood pressure were measured before EA (BLP), EA (EAP), and post-EA periods (PEP). The results indicated that the natural logarithmic high frequency power (lnHF) of HRV was greater during PEP than during the BLP in the 2 Hz EA sessions. The natural logarithmic low frequency power (lnLF) of HRV was greater during the PEP than during the BLP in 15 Hz EA sessions, suggesting that 2 Hz EA apply to Leg Three Li (足三里 zú sān lǐ, ST-36) and Upper Great Hollow (上巨虛 shàng jù xū, ST-37) acupoints increased vagal activity, whereas 15 Hz EA increased sympathetic activity.

Right lower quadrant (RLQ) pain is a common complaint in children presenting at emergency departments. This study analyzed the etiologies of RLQ pain, and compared the clinical presentations, laboratory test results and imaging findings in patients with appendicitis with those in other groups of patients. We also investigated if active observation resulted in delayed diagnosis, to the detriment of patients. Medical records for the period January 2006 to July 2006 were reviewed for children (age < 18 years) who presented to the emergency department of one medical center, complaining of RLQ pain. Out of a total of 100 patients (age range: 2–17 years; mean: 11 years), 46 patients presented with only one symptom of RLQ pain, while 32 patients had ≥ 2 associated signs or symptoms, including fever, nausea/vomiting, diarrhea, or rebound tenderness. Imaging studies, including abdominal sonography and/or computed tomography, were performed in 73 patients; 44 underwent surgery for presumed appendicitis and one received surgery for a right paraduodenal hernia. Eleven patients underwent surgery because of peritoneal signs, and eight because of persistent or aggravated RLQ pain. Postoperative pathologic examinations revealed 53 cases of appendicitis, six normal appendices, and other morbidities (1 perforated peptic ulcer, 1 pelvic inflammatory disease, 1 ovarian cyst, 1 diverticulitis, and 1 right paraduodenal hernia). Thirty-three patients were discharged after several hours of observation (range: 0.5–18 hours; mean: 4 hours), and three patients were admitted for further observations. All were discharged without operation. There were significant differences in the incidences of fever (p = 0.004) and rebound tenderness (p = 0.019), and in white cell counts (p < 0.001), neutrophil percentages (p < 0.001), and C-reactive protein levels (p < 0.001) between patients with appendicitis and patients with other causes of RLQ pain. Clinical signs and symptoms, laboratory tests, and imaging studies can be used to differentiate between the causes of RLQ pain. Patients without the classical features of appendicitis or peritonitis can be safely managed by active observation and repeated physical examinations.

Combinations of Chinese herbal products (CHPs) are widely used for ischemic heart disease (IHD) in Taiwan. We analyzed the usage and frequency of CHPs prescribed for patients with IHD.A nationwide population-based cross-sectional study was conducted, 53531 patients from a random sample of one million in the National Health Insurance Research Database (NHIRD) from 2000 to 2010 were enrolled. Descriptive statistics, the multiple logistic regression method and Poisson regression analysis were employed to estimate the adjusted odds ratios (aORs) and adjusted risk ratios (aRRs) for utilization of CHPs.The mean age of traditional Chinese medicine (TCM) nonusers was significantly higher than that of TCM users. Zhi-Gan-Cao-Tang (24.85%) was the most commonly prescribed formula CHPs, followed by Xue-Fu-Zhu-Yu-Tang (16.53%) and Sheng-Mai-San (16.00%). The most commonly prescribed single CHPs were Dan Shen (29.30%), Yu Jin (7.44%), and Ge Gen (6.03%). After multivariate adjustment, patients with IHD younger than 29 years had 2.62 times higher odds to use TCM than those 60 years or older. Residents living in Central Taiwan, having hyperlipidemia or cardiac dysrhythmias also have higher odds to use TCM. On the contrary, those who were males, who had diabetes mellitus (DM), hypertension, stroke, myocardial infarction (MI) were less likely to use TCM.Zhi-Gan-Cao-Tang and Dan Shen are the most commonly prescribed CHPs for IHD in Taiwan. Our results should be taken into account by physicians when devising individualized therapy for IHD. Further large-scale, randomized clinical trials are warranted in order to determine the effectiveness and safety of these herbal medicines.