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Background Whether a sex difference exists in long-term cardiovascular (CV) outcomes after acute myocardial infarction (AMI) is worth exploration. This study is sought to investigate the relationships among sex, age and the long-term prognosis after AMI. Methods This population-based retrospective cohort study used Taiwan's National Health Insurance Research Database (NHIRD) to investigate the sex differences in in-hospital and long-term CV outcomes in patients with AMI. We enrolled patients who were first diagnosed with AMI from January 1, 2000 to December 31, 2013. The outcomes of interest included all-cause mortality, CV death, nonfatal stroke, nonfatal heart failure, and AMI recurrence during hospitalization and 5-year follow up. The CV outcomes were also analyzed by age stratification. Results Overall, 201,921 patients with AMI were analyzed; 68.72% were men and 31.28% were women, with mean ages of 65.34 ± 14.12 and 73.05 ± 12.22 years, respectively. Major adverse cardiac events (MACE) during hospitalization and up to 5 years were consistently greater in women than in men. Multivariable regression analysis revealed no sex difference existed in long-term all-cause and CV mortality. Men of all age groups consistently showed higher risk of both short- and long-term recurrence of AMI. Nonetheless, the female sex still independently predicted increased risk of nonfatal stroke and heart failure from hospitalization until 3-year follow up. Conclusion Women with AMI had poorer short-term and long-term outcomes. The sex differences in long-term all-cause and CV death disappear after multivariate analysis. Nonetheless, female AMI patients independently predicted higher risk of stroke and heart failure from hospitalization until a 3-year follow-up. To better understand the pathophysiology of female patients with AMI and develop more effective management, more studies in this field are necessary in the future.

Idiopathic pulmonary fibrosis (IPF) is a rare lung disease with high mortality. Finding an effective predictor of survival is therefore important for both clinicians and patients. In this prospective observational study, we evaluated the prognostic value of the parameters of cardiopulmonary exercise test (CPET), pulmonary function test (PFT), 6-min walk test (6MWT), and certain questionnaires on mortality in Asian patients with IPF. A total of 34 patients diagnosed with IPF were enrolled and followed up for 12 months, during which 6 patients died. The non-survivors had significantly higher minute ventilation to carbon dioxide output (VE/VCO2) slope, more oxygen desaturation during CPET and 6MWT, less heart rate recovery one minute after CPET, higher dead space, higher Gender-Age-Physiology (GAP) index and Modified Medical Research Council (mMRC) score. GAP index, mMRC score, VE/VCO2 slope, and end-tidal partial pressure of carbon dioxide (PETCO2) at maximal exercise demonstrated an area under curve (AUC) of >0.7, and the corresponding cutoff values were 4, 2, 35.1 and 3.6 kPa. Therefore, GAP index, mMRC scores, VE/VCO2 slope, and PETCO2 at maximal exercise could be important predictors for mortality in Asian patients with IPF.

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.

We investigated the association between postchallenge glucose increment and hemoglobin glycation index (HGI), the difference between observed and predicted glycated hemoglobin (HbA1c), in subjects with no history of diabetes. We enrolled 1381 subjects who attended our outpatient clinic for an oral glucose tolerance test (OGTT) to screen for diabetes. HGI was defined as observed HbA1c minus predicted HbA1c. The predicted HbA1c was calculated by entering fasting plasma glucose (FPG) level into an equation [HbA1c(%)=FPG(mg/dL)*0.029+2.9686] determined from an HbA1c versus FPG regression analysis using data from an independent cohort of 2734 subjects with no history of diabetes. The association between 2-hour glucose increment and HGI was analyzed using linear regression analyses with adjustment of relevant parameters. Overall, the proportions of subjects with normal glucose tolerance, pre-diabetes, and newly diagnosed diabetes were 42.3%, 41.3%, and 16.4%, respectively. Compared with subjects who had an HGI≤0, subjects with an HGI>0 had a lower FPG (95.0±13.3 vs 98.5±15.3 mg/dL, p

Additional file 1 Supplementary information accompanies this paper at BMC Geriatrics online.

Objectives We aimed to investigate whether the risk of diabetes mellitus (DM) is heightened in patients with prostate cancer receiving injection therapy. Methods Men diagnosed with prostate cancer between 2000 and 2012 were included in the case cohort, and men without prostate cancer were included as controls. Each patient with prostate cancer was matched with a control patient with the same index year, demographic variables and comorbidities, and comparisons were made using propensity score matching. The hazard ratio of DM was estimated using the Cox proportional hazards model. Results This cohort study consisted of 1213 patients with prostate cancer and 1213 control patients. The risk of DM in patients with prostate cancer was 1.60 times (95% CI = 1.12, 2.27) that of patients without prostate cancer. Compared with the controls, the hazard ratios of DM for patients with prostate cancer not receiving oral hormone therapy, patients with prostate cancer receiving oral hormone therapy, and patients with prostate cancer not receiving injection hormone therapy were 1.65 (95% CI = 1.01, 2.70), 1.57 (95% CI = 1.07, 2.70), and 1.94 (95% CI = 1.34, 2.81), respectively. The risk of DM in patients who received injection hormone therapy was 0.45 times (95% CI = 0.25, 0.82) that of patients who did not receive injection hormone therapy. Conclusion Patients with prostate cancer had an increased risk of DM compared with patients without prostate cancer. Patients with prostate cancer who received injection therapy had a lower risk of DM compared with those who did not.

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.

Background: This retrospective cohort study compared patient survival and technique survival between patients on continuous ambulatory peritoneal dialysis (CAPD) and automated peritoneal dialysis (APD) using recent data at a single tertiary medical center in Taiwan. Methods: From medical records, we identified incident 459 CAPD patients and 266 APD patients on dialysis for at least 90 days and aged more than 18 years to estimate mortality and technique failure rates, and related hazard ratio (HR) and 95% confidence interval (CI) from 2007 to 2018. Results: There were more women (52.3%) in the CAPD group, whereas patients in the APD group were younger. Compared to CAPD patients, APD patients had a lower mortality rate (2.83 vs. 5.79 per 100 person-years) with an adjusted HR of 0.69 (95% CI = 0.47–1.02), and a lower technique failure rate (9.70 vs. 17.52 per 100 person-years) with an adjusted HR of 0.65 (95% CI = 0.51–0.83). Further subgroup analyses revealed that, compared to CAPD, APD was associated with a significant lower risk of technique failure in male patients, patients aged 50–65 years, diabetic patients, patients without cardiovascular disease (CVD), patients with higher peritoneal permeability, or patients initiating PD in an earlier era. Conclusions: The mortality risk was not significant between CAPD and APD patients. APD is associated with a lower risk of technique failure than CAPD, particularly for male patients, and patients aged 50–65 years, with diabetes, without CVD, with high or high average peritoneal permeability, or initiating PD in an earlier era.

Glycaemic traits are used to diagnose and monitor type 2 diabetes, and cardiometabolic health. To date, most genetic studies of glycaemic traits have focused on individuals of European ancestry. Here, we aggregated genome-wide association studies in up to 281,416 individuals without diabetes (30% non-European ancestry) with fasting glucose, 2h-glucose post-challenge, glycated haemoglobin, and fasting insulin data. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P-8), 80% with no significant evidence of between-ancestry heterogeneity. Analyses restricted to European ancestry individuals with equivalent sample size would have led to 24 fewer new loci. Compared to single-ancestry, equivalent sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase understanding of diabetes pathophysiology by use of trans-ancestry studies for improved power and resolution.

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.

Background and Objective: Idiopathic pulmonary fibrosis (IPF) is a lung disease with a high mortality rate. Finding an effective predictor of survival is therefore important for clinicians and patients. Several parameters have been established to predict mortality, but none of these have been validated in the Asian population. In this study, we evaluated the prognostic value of the parameters of cardiopulmonary exercise test (CPET), pulmonary function test (PFT), 6-min walk test (6MWT), and certain questionnaires on mortality in Asian patients with IPF. Methods: This prospective observational study analysed patient data, including age, gender, height, and body weight; scores of Saint George’s Respiratory Questionnaire (SGRQ), Modified Medical Research Council (mMRC) for dyspnoea, and Short Form-36 (SF-36); and parameters of PFT, 6MWT, and CPET. Results: In total, 24 patients diagnosed as having IPF were followed up for 14 months, during which 3 patients died. The nonsurvivors had significantly lower body weight; lower forced vital capacity (FVC); higher ratio of forced expiratory volume in 1 s to forced vital capacity (FEV1/FVC); higher gender, age, and pulmonary physiology (GAP) index; shorter walk distance in 6MWT; lower end-tidal pressure of carbon dioxide (DLCO); higher functional aerobic impairment (FAI) during exercise; and higher mMRC score. FEV1/FVC, FAI, GAP index, and mMRC dyspnoea score demonstrated an area under curve (AUC) of >0.7, and the corresponding cut-off values were 89%, 54%, 7, and 3. Conclusions: The predictive abilities of PFT, CPET, and mMRC scores were validated successfully in the study cohort of Asian patients with IPF.

Background Day care service (DCS) provides various activities in a professionally 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 We used a comprehensive geriatric assessment to evaluate the changes before and after DCS among participants in a hospital-affiliated geriatric day care center. 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 six 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 sixth month (p

Background Whether patients with end-stage renal disease (ESRD) have a higher risk of idiopathic polyneuropathy (IPN) than those without ESRD remains unclear. We hypothesised that carpal tunnel syndrome (CTS) is a prodrome of IPN in patients with ESRD. Methods Data were collected from the Taiwan National Health Insurance research database (NHIRD) for the 2000-2011 period. Two matching strategies, age- and sex-matching and propensity matching, were used, which yielded 2596 age- and sex-matched patients with ESRD and 2210 propensity-matched patients with ESRD. The comparison cohort was chosen in a 1:4 ratio for the age- and sex-matched method and in a 1:1 ratio for the propensity-matching method. The primary outcome was the incidence of IPN. Cox proportional hazards modelling was used. Results In the age- and sex-matched cohort, the IPN incidence was 7.64 and 2.88 per 1000 person-years for the ESRD and controls cohorts, respectively. After we adjusted for age, sex, comorbidities and medications relative to controls, having ESRD was significantly associated with increased risk of IPN (hazard ratio [HR] = 2.45, 95% confidence interval [CI] = 1.76-3.41). Competing risk of death as sensitivity analysis revealed that having ESRD with CTS was still associated with higher risk of IPN than having CTS without ESRD (HR = 2.85, 95% CI = 1.87-4.34). Conclusion Patients with ESRD with CTS had higher incidences of idiopathic peripheral neuropathy than those without ESRD with CTS.

Ischemic stroke provokes an inflammatory response concurrent with both sympathetic nervous system activation and hyperglycemia. Currently, their crosstalk and consequences in stroke outcomes are of clinical attraction. We have provided experimental evidence showing the suppressive effects of the nonselective &beta, adrenoreceptor antagonist propranolol on hyperglycemia, inflammation, and brain injury in a rat model experiencing cerebral ischemia. Pretreatment with propranolol protected against postischemic brain infarction, edema, and apoptosis. The neuroprotection caused by propranolol was accompanied by a reduction in fasting glucose, fasting insulin, glucose tolerance impairment, plasma C-reactive protein, plasma free fatty acids, plasma corticosterone, brain oxidative stress, and brain inflammation. Pretreatment with insulin alleviated&mdash, while glucose augmented&mdash, postischemic brain injury and inflammation. Additionally, the impairment of insulin signaling in the gastrocnemius muscles was noted in rats with cerebral ischemia, with propranolol improving the impairment by reducing oxidative stress and tumor necrosis factor-&alpha, signaling. The anti-inflammatory effects of propranolol were further demonstrated in isoproterenol-stimulated BV2 and RAW264.7 cells through its ability to decrease cytokine production. Despite their potential benefits, stroke-associated hyperglycemia and inflammation are commonly linked with harmful consequences. Our findings provide new insight into the anti-inflammatory, neuroprotective, and hypoglycemic mechanisms of propranolol in combating neurodegenerative diseases, such as stroke.

Chronic treatment involving opioids exacerbates both the risk and severity of ischemic stroke. We have provided experimental evidence showing the anti-inflammatory and neuroprotective effects of the &mu, opioid receptor antagonist &beta, funaltrexamine for neurodegenerative diseases in rat neuron/glia cultures and a rat model of cerebral Ischemia/Reperfusion (I/R) injury. Independent of in vitro Lipopolysaccharide (LPS)/interferon (IFN-&gamma, )-stimulated neuron/glia cultures and in vivo cerebral I/R injury in Sprague&ndash, Dawley rats, &beta, funaltrexamine downregulated neuroinflammation and ameliorated neuronal degeneration. Alterations in microglia polarization favoring the classical activation state occurred in LPS/IFN-&gamma, stimulated neuron/glia cultures and cerebral I/R-injured cortical brains. &beta, funaltrexamine shifted the polarization of microglia towards the anti-inflammatory phenotype, as evidenced by decreased nitric oxide, tumor necrosis factor-&alpha, interleukin-1&beta, and prostaglandin E2, along with increased CD163 and arginase 1. Mechanistic studies showed that the suppression of microglia pro-inflammatory polarization by &beta, funaltrexamine was accompanied by the reduction of NF-&kappa, B, AP-1, cyclic AMP response element-binding protein, along with signal transducers and activators of transcription transcriptional activities and associated upstream activators. The effects of &beta, funaltrexamine are closely linked with its action on neuroinflammation by switching microglia polarization from pro-inflammatory towards anti-inflammatory phenotypes. These findings provide new insights into the anti-inflammatory and neuroprotective mechanisms of &beta, funaltrexamine in combating neurodegenerative diseases, such as stroke.

Background: Direct evidence of lung cancer risk in Asian users of angiotensin-converting enzyme inhibitors (ACEIs) is lacking. Methods: The ACEI cohort comprised 22,384 patients aged &ge, 18 years with a first prescription of ACEI. The comparison angiotensin receptor blocker (ARB) cohort consisted of age-, sex- and comorbidity-matched patients at a ratio of 1:1. The primary outcome was the incidence of lung cancer, which was evaluated using a proportional hazard model. Results: The overall incidence rates of lung cancer in the ACEI and ARB cohorts were 16.6 and 12.2 per 10,000 person-years, respectively. The ACEI cohort had a significantly higher risk of lung cancer than the ARB cohort (adjusted hazard ratio [aHR]. = 1.36, 95% confidence interval [CI]. = 1.11&ndash, 1.67). Duration&ndash, response and dose&ndash, response analyses revealed that compared with patients who did not receive ACEIs, patients who received ACEIs for more than 45 days per year (aHR = 1.87, 95% CI = 1.48&ndash, 2.36) and patients who received more than 540 defined daily doses of ACEIs per year (aHR =1.80, 95% CI = 1.43&ndash, 2.27) had a significantly higher risk of lung cancer. The cumulative incidence of lung cancer was also significantly higher in the ACEI cohort than in the ARB cohort (log-rank test, p = 0.002). Conclusions: ACEI use is associated with an increased risk of lung cancer compared with ARB use. Patients using ARBs have a significantly lower risk of lung cancer than non-ARB users.

Obesity is associated with a wide range of chronic diseases, including cancer. It has been noted that the integration of metabolic mechanisms in obese patients may predispose them to suffer from cancer incidence and its progression. Thus, a better understanding of metabolic alterations in obesity, along with the development of feasible therapeutic approaches for intervention, are theoretically relevant to the prevention and treatment of cancer malignancy. Using a syngeneic tumor model involving Lewis Lung Carcinoma (LLC) cells and C57BL/6 mice fed with a high fat diet, obesity was found to be associated with dysregulated glucose and glutamine metabolism, inflammation, along with platelet activation and the promotion of tumor growth. Tumor-bearing lowered glucose levels while moderately increasing inflammation, platelet activation, and glutamine levels. The antiplatelet drug aspirin, mitigated tumor growth in obese mice, paralleled by a decrease in systemic glucose, insulin, inflammation, platelet activation, glutamine and tumor expression of cell proliferation, aerobic glycolysis, glutaminolysis, platelets, and leukocyte molecules. The anti- and pro-cell proliferation, aerobic glycolysis, and glutaminolysis effects of aspirin and glutamine were further demonstrated in a LLC cell study. Although there remains limitations to our experiments, glucose and glutamine metabolism are proposed targets for the anticancer effects of aspirin.

Background: The objective of this study was aimed to investigate whether sleep apnea patients had a higher risk of traumatic brain injury. Methods: Data were collected from the Taiwan Longitudinal Health Insurance Database during the period of 2000–2012. The study cohort comprised 6,456 patients aged ≥20 years with a first diagnosis of sleep apnea. The primary outcome was the incidence of traumatic brain injury. Kaplan-Meier survival analysis and Cox proportional-hazards modeling were used. Results: After adjustments for associated comorbidities and hypnotic medications, sleep apnea patients were associated with a 1.19-fold higher risk of traumatic brain injury (95% CI, 1.07–1.33) compared with patients without sleep apnea. Sleep apnea patients who took benzodiazepine (BZD) had a 1.30-fold increased risk of traumatic brain injury compared with patients without sleep apnea (95% CI, 1.14–1.49). However, this risk was not statistically significant, with a 1.03-fold risk of traumatic brain injury in sleep apnea patients without BZD use (95% CI, 0.84–1.25) compared with patients without sleep apnea. Compared with patients without sleep apnea, the risk of traumatic brain injury in sleep apnea patients aged 65–79 years old was higher (adjusted hazard ratio, 1.36; 95% CI, 1.06–1.74). Conclusion: Sleep apnea patients, regardless of hypnotic use, had a higher risk of traumatic brain injury compared with patients without sleep apnea.

Supplemental Material, Table_S1_109.5.8 for Comparison of patient survival and technique survival between continuous ambulatory peritoneal dialysis and automated peritoneal dialysis by I-Kuan Wang, Tung-Min Yu, Tzung-Hai Yen, Shih-Yi Lin, Chia-Ling Chang, Ping-Chin Lai, Chi-Yuan Li and Fung-Chang Sung in Peritoneal Dialysis International

Background: Association between hydroxychloroquine (HCQ) and bacterial infections required to be determined. Whether hydroxychloroquinehad use could reduce lesser risk of bacterial infections are unknown. We aimed to conduct a retrospective cohort propensity-matching study to investigate the association between HCQ use and the incidence of bacterial pneumonia in rheumatic patients. Methods: The Longitudinal Health Insurance Database (LHID), a one million extract from Taiwan National Health Insurance Research Database (NHIRD) of 23 million Taiwanese populations was used. We included patients who newly diagnosed rheumatic and immune disease (ICD-9-CM codes 696.0, 710, 714) within 2000-2012.HCQ users and nonusers were then matched according to age, sex, urbanization level, monthly income, comorbidities and medications in the ratio of 1:1 by the propensity score matching. Cox proportional hazard model was used to evaluate the risk of bacterial pneumonia in rheumatic patients who used HCQ and who did not use HCQ. Results: There were total 3285 patients with rheumatic and immune disease enrolled. The cumulative incidence curve of patients with the use of HCQ sulfate had no difference to that of patient without the use of HCQ sulfate in propensity score matched cohort, (Log-rank test: p-value=0.5). However, patients used HCQ sulfate for more than 1400 average use days had a lesser risk of bacterial pneumonia (adjusted HR=0.55, 95% CI=0.35, 0.89) in the cohort matched, with regarding HCQ nonusers as a reference. Conclusion: Rheumatic patients taking HCQ had no overall significant differences of bacterial pneumonia incidences compared with rheumatic patients not taking HCQ. HCQ used more than >1400 days was associated with lower risk of bacteria pneumonia. Funding Statement: This study is supported in part by Taiwan Ministry of Health and Welfare Clinical Trial Center (MOHW109-TDU-B-212-114004), China Medical University Hospital (CMU107-ASIA-19, DMR-109-231); MOST Clinical Trial Consortium for Stroke (MOST 108-2321-B-039-003-), Tseng-Lien Lin Foundation, Taichung, Taiwan. No additional external funding was received for this study. Declaration of Interests: The authors declare no conflict of interest. Ethics Approval Statement: This study was approved by the Institutional Review Board of the China Medical University Hospital (CMUH104-REC2-115(AR-4)).

Renal ischemia/reperfusion (I/R) is an alternation of renal hemodynamics, which results in diverse postischemic responses and eventually acute kidney injury. Although renal ischemic preconditioning (IPC) is known to protect the kidney from I/R injury, the precise renoprotective mechanisms are not completely understood. The multiple renoprotective effects of IPC underscore the importance in understanding molecular mechanisms and the targets of action involved. This study aimed to identify the biochemical changes in renal I/R injury and investigate the renoprotective mechanisms of IPC. Herein, renal I/R was produced in adult male Sprague-Dawley rats through the bilateral ligation of renal pedicles for 45 min, followed by reperfusion for 24 h. For the IPC group, rats were subjected to three cycles of 2-min ischemia, followed by a 5-min reperfusion, 15 min prior to renal I/R. Our data confirmed the beneficial effects that IPC has on renal I/R injury. IPC-mediated renoprotection was associated with the resolution of oxidative stress, inflammation, apoptosis, and hyperglycemia. Among the numerous signaling molecules involved in the renoprotective mechanisms of IPC, an elevated protein expression of Nrf2, HO-1, LC3 II conversion, along with Atg12 and protein phosphorylation of AMPK, as well as a decreased protein phosphorylation of ERK, p38 MAPK, and Akt and NF-κB DNA binding activity were identified. Importantly, the post renal I/R overproduction of counter-regulatory hormones, impaired hepatic insulin action, and augmented hepatic gluconeogenesis were improved through IPC. As counter-regulatory hormones have been implicated in the induction of oxidative stress, inflammation, apoptosis, impaired insulin action, hyperglycemia, and tissue destruction, our findings suggest that counter-regulatory hormones may well be valuable targets of IPC for combatting renal I/R injury. © 2018 IUBMB Life, 71(3):321-329, 2019.

Background The aim of the present study was to investigate the association between serum aryl hydrocarbon receptor (AhR) levels and insulin resistance and β-cell function in patients undergoing coronary angiography with no history of diabetes. Methods Patients with no history of diabetes who had undergone coronary angiography underwent an oral glucose tolerance test (OGTT) 2-4 weeks after discharge from hospital; blood samples were collected for measurements of glucose, insulin, and AhR. Patients' glucose regulation status was determined on the basis of the OGTT. Insulin resistance was assessed using the homeostasis model assessment of insulin resistance (HOMA-IR). β-Cell function was assessed using the insulinogenic index (IGI). Results The study included 473 patients (mean (±SD) age 61 ±12 years, 81.8% male, mean body mass index 26.1 ±3.6 kg/m2 ). Overall, mean serum AhR concentrations were 25.1 ±12.2 pg/mL. Patients with normal glucose tolerance had a lower serum AhR concentrations than patients with prediabetes or newly diagnosed diabetes (23.4 ±10.8 vs 26.2 ±13.2 and 26.9 ±12.3 pg/mL, respectively; P = 0.029). Linear regression analysis revealed that serum AhR concentrations were not associated with HOMA-IR, but were negatively associated with IGI after adjustment for several confounders, including HOMA-IR (β = -0.162; 95% confidence interval - 0.302, -0.022; P = 0.023). Conclusions In patients with no history of diabetes, serum AhR concentrations were negatively associated with β-cell function, independent of several confounders, including insulin resistance.

Aim To investigate the effect of changes in fasting plasma glucose (FPG) variability, as assessed by 2-year trajectories of FPG variability, on mortality risk in patients with type 2 diabetes (T2D). Methods From 2009 to 2012, outpatients with T2D, aged>18 years, were enrolled from a medical centre. FPG was measured every 3 months for 2 years in 3569 people. For each of the eight 3-month intervals, FPG variability and means were calculated, with variability defined as the coefficient of variation of FPG. Also, trajectories of FPG variability and means were determined separately, using group-based trajectory analysis with latent class growth models. These models were fitted using the SAS Proc Traj procedure. The primary outcome was all-cause mortality, which was followed-up to the end of 2014. Results Five distinct trajectories of FPG variability (low, increasing, fluctuating, decreasing and high) and means (well controlled, stable control, worsening control, improving control and poor control) were established. The five trajectories of mean FPG were all associated with the same mortality risk. In contrast, in comparison to the low FPG variability trajectory, the fluctuating, decreasing and high variability trajectories all had significantly higher risks of mortality, with respective hazards ratios of 2.63 (95% CI: 1.40–4.93; P = 0.003), 2.78 (95% CI: 1.33–5.80; P = 0.007) and 4.44 (95% CI: 1.78–11.06; P = 0.001) after multivariable adjustment. Conclusion Changes in FPG variability were independently associated with increased mortality risk in patients with T2D.

AIM We used insurance claims data of Taiwan to compare the risk of non-traumatic lower extremity amputation between haemodialysis (HD) and peritoneal dialysis (PD) patients. METHODS We identified 77 669 HD patients and 10 035 PD patients without prior amputation from 2000 to 2010. Incidence rates and hazard ratios (HRs) of lower extremity amputation, and subsequent 30-day mortality after amputation were evaluated up to 31 December 2011. RESULTS There were 2427 and 216 patients undergoing lower extremity amputation during follow-up in the HD and PD groups with incidence rates of 8.35 and 5.79 per 1000 person-years, respectively. Compared with the HD group, the overall adjusted HR of lower extremity amputation for the PD group was 1.27 (95% CI = 1.10-1.46). The impact of diabetes status on the risk of lower extremity amputation interacted with dialysis modality significantly (P

Mounting evidence suggests that physical exercise shows health benefits in a range of diseases, including psychiatric disorders. Perinatal opioid exposure produces neurobehavioral abnormality, which includes depression symptoms, in patients and their offspring following chronic use of buprenorphine, a mixed agonist/antagonist with a high affinity to opioid receptors, for pain control. Previously, we demonstrated that prenatal buprenorphine exposure in pregnant Sprague-Dawley rats starting from gestation day 7 and lasting for 14 days caused the development of depression-like phenotypes in pups at postnatal day 21. Using the same prenatal buprenorphine exposure model, we further demonstrated that a 4-week course of moderate treadmill exercise conducted on pups starting from postnatal day 22 improved depression-like neurobehaviors. Prenatal buprenorphine exposure-induced neurobehavioral changes were accompanied by reductions of neuronal survival, neural stem cell-associated genes, plasma level of brain-derived neurotrophic factor (BDNF) and serotonin, phosphorylated tropomyosin-related kinase receptor type B (TrkB), phosphorylated extracellular signal-regulated kinase (ERK), PKA activity, phosphorylated cAMP response element-binding protein (CREB), and CREB DNA binding activity, as well as elevation of repressor element-1 silencing transcription factor (REST), oxidative stress, and inflammatory responses. Those changes in parameters of plasma and brain were improved by treadmill exercise. In conclusion, the findings of the current study suggest that a non-pharmacological option, i.e., moderate treadmill exercise, alleviated the development of depression-like neurobehaviors by resolving the oxidative and inflammatory burden as well as by enhancing neurochemical and neuroendocrine signaling.

Background Prostate cancer (PC) can be related to increased systemic oxidative stress and dihydrotestosterone level, which are also reported to be involved in the pathogenesis of age-related macular degeneration (AMD). We conducted a cohort study to determine whether patients with PC have an increased risk of AMD. Patients and methods Data were collected from the Taiwan Longitudinal Health Insurance Database for the 1999–2010 period. The study PC cohort comprised 22 084 patients aged ≥18 years with a first diagnosis of PC. The comparison cohort consisted of age-, occupation-, and urbanization level-matched patients at a ratio of 1 : 1. The primary outcome was the incidence of AMD, which was evaluated using Kaplan–Meier survival analysis and proportional hazards modeling. Results The mean follow-up periods (standard deviation) for the patients with AMD in the age-, occupation-, and urbanization level-matched PC cohort and non-PC cohorts were 4.69 (2.90) and 5.51 (2.82) years. The mean age of the PC cohort was 73.9 years and that of the non-PC cohort was 73.2 years, with approximately 85.9% of the patients aged >65 years. The PC cohort had a higher risk of AMD than did the propensity score-matched non-PC cohort with an adjusted hazard ratio of 1.25 (95% confidence interval, 1.12–1.39). Compared with PC cohort receiving no injection hormone therapy, the PC cohort receiving injection hormone therapy had a lower risk of AMD (adjusted hazard ratio, 0.56; 95% confidence interval, 0.41–0.76). Conclusion PC is associated with an increased risk of AMD. Patients with PC receiving injected form of androgen deprivation therapy had a lower risk of AMD than patients with PC not receiving injected form of androgen-deprivation therapy.

We investigated the associations of fibroblast growth factor 21 (FGF-21) with cardiovascular risk and β-cell function in patients who had no history of diabetes.We enrolled 269 outpatients who had been referred for an oral glucose tolerance test (OGTT). Plasma glucose, insulin, and FGF-21 were measured before and at 2h after the OGTT. β-cell function was assessed using the insulinogenic index, corrected for insulin resistance. Patients' 10-year coronary heart disease (CHD) risk was assessed using the Chinese Multi-provincial Cohort Study functions.Overall, there was a 10% decrease in FGF-21 after OGTT (p0.001). The decrease of FGF-21 after OGTT in patients with normal glucose tolerance, prediabetes, and diabetes was 8%, 10%, and 21%, respectively (all p0.05). Patients with a history of admission for coronary angiography had a higher 10-year CHD risk and fasting FGF-21 (both p0.001). In multivariate regression analysis, fasting FGF-21 was positively associated with 10-year CHD risk, while FGF-21 relative change 2h after OGTT was positively associated with β-cell function.In patients who had no history of diabetes, fasting FGF-21 was positively associated with 10-year CHD risk, while FGF-21 relative change 2h after OGTT was positively associated with β-cell function.

Chibby has been identified as a putative tumor suppressor and antagonist to β-catenin, thereby controlling the Wnt signaling pathway. Chibby is typically downregulated in numerous types of cancer and may be associated with tumorigenesis. The present study aimed at clarifying the following: i) Whether Chibby antagonizes β-catenin in cervical cancer; ii) whether Chibby and β-catenin mRNA expression is associated with cancer progression; and iii) whether Chibby and β-catenin expression may be used as a biomarker. A total of 87 paraffin-embedded cervical sections with distinct cervical intraepithelial neoplasia (CIN) stages (chronic cervicitis, CIN 1, CIN 2, CIN 3 and invasive squamous cell carcinoma) were collected between June 2004 and October 2012 The mRNA expression level of Chibby and β-catenin was determined using the polymerase chain reaction. Protein expression and cellular localization of Chibby and β-catenin were determined using immunohistochemistry. Chibby and β-catenin were analyzed for possible association with the progression of cervical cancer. Chibby mRNA expression and the Chibby/β-catenin ratio were identified to be downregulated in invasive tumors. Positive cytoplasmic and nuclear staining for Chibby was associated with CIN staging and decreased as the CIN stage increased. In addition, the cytoplasmic and membrane intensity of β-catenin was associated with invasive tumors, in which a significantly increased level of protein expression was detected. Chibby may be a tumor suppressor in cervical cancer, since the dysregulation of Chibby expression is associated with tumorigenesis in cervical cancer. Chibby and β-catenin expression together may potentially to a biomarker for disease progression in cervical cancer.

Background This study compared the risk of developing new-onset diabetes between hemodialysis (HD) and peritoneal dialysis (PD) patients. We further investigated the effectiveness of icodextrin in reducing the risk of new-onset diabetes in PD patients. Methods From the Taiwan health insurance database, 36 879 incident HD patients and 6382 incident PD patients from 2000 to 2010 were identified as study cohorts. We further selected an additional HD cohort matched by propensity scores (PSs) of PD patients. Incidence rates and hazard ratios (HRs) of new-onset diabetes were assessed among cohorts and between icodextrin users and nonusers by the end of 2011. Results For the unmatched cohorts, the incidence of new-onset diabetes was higher in PD patients than in HD patients (9.16 versus 8.18 per 1000 person-years), with an adjusted HR of 1.51 (95% CI 1.30-1.75) for PD patients. For the PS-matched cohorts, the corresponding incidence rates were 9.43 and 5.90 per 1000 person-years, respectively, with an adjusted HR of 1.61 (95% CI 1.32-1.97). Among PD patients, the incidence was lower in icodextrin users than in nonusers (6.22 versus 12.1 per 1000 person-years), with an adjusted HR of 0.66 (95% CI 0.50-0.88) for users. Conclusions Our study suggests that PD patients are at a higher risk of developing new-onset diabetes than HD patients. Icodextrin is recommended for PD patients to reduce the risk of new-onset diabetes.

// Shih-Yi Lin 1, 2, 3 , Cheng-Li Lin 4, 5 , Chao-Hsiang Chang 6 , His-Chin Wu 6 , I-Kuan Wang 1, 2, 3 , Che-Yi Chou 1, 2, 3 and Ji-An Liang 1, 7 1 Graduate Institute of Clinical Medical Science, College of Medicine, China Medical University, Taichung, Taiwan 2 Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan 3 Division of Nephrology and Kidney Institute, China Medical University Hospital, Taichung, Taiwan 4 Managment Office for Health Data, China Medical University Hospital, Taichung, Taiwan 5 College of Medicine, China Medical University, Taichung, Taiwan 6 Department of Urology, China Medical University Hospital, Taichung, Taiwan 7 Department of Radiation Oncology, China Medical University Hospital, Taichung, Taiwan Correspondence to: Ji-An Liang, email: d4615@mail.cmuh.org.tw Keywords: upper tract urothelial carcinoma, acute myocardial infarction, mortality, radical nephroureterectomy, multivariable Cox proportional hazard regression analysis Received: April 07, 2017 Accepted: May 29, 2017 Published: June 15, 2017 ABSTRACT Background: The outcomes of upper tract urothelial carcinoma (UTUC) receiving radical nephroureterectomy were usually limited to small sample size, case-control studies, and often focused on cancer progression. Risk of acute myocardial infarction (AMI) in these patients was never investigated. Results: The overall incidences of AMI were 3.39, 1.44, and 1.70 per 10,000 person-years in the radical nephroureterectomy, nonnephroureterectomy, and non-UTUC cohorts, respectively. Multivariable Cox proportional hazard regression analysis revealed a significantly higher AMI risk in the radical nephroureterectomy cohort [adjusted HR (aHR) = 1.83, 95% confidence interval (CI) = 1.08–3.11], compared with non-UTUC cohorts. The risk of mortality were the highest in patients with UTUC who had undergone radical nephroureterectomy [adjusted HR (aHR) = 5.37, 95% confidence interval (CI) = 4.80–6.02]. Materials and Methods: From the Taiwan National Health Insurance claims data, 1,359 patients with UTUC who had undergone radical nephroureterectomy and 3,154 patients with UTUC who had undergone nephron sparing surgery and were newly diagnosed between 2000 and 2010 were identified. For each patient, 4 individuals without UTUC were randomly selected and frequency matched by age, sex, and diagnosis year. Conclusions: Patients with UTUC who have undergone radical nephroureterectomy are at a higher risk of developing AMI, compared with those receiving nephron sparing surgery.

Aim It has been reported that many people with dementia require hospitalizations. The objective of the present study was to determine predictive factors for hospitalizations in people with dementia. Methods A total of 70 individuals with dementia living in a veterans’ home in southern Taiwan were consecutively enrolled. During prospective follow up, all hospitalization events were recorded. Results The mean age of residents with dementia was 86.1 ± 4.0 years, and the mean follow-up time for this population was 2.2 ± 1.1 years. Among individuals, 62.9% suffered from malnutrition or were at risk of malnutrition (minimal nutritional assessment-short form score ≤11), and 8.6% of individuals had a body mass index of

Aim To develop experimental multi-domain interventions for older people with mild-to-moderate dementia, and to evaluate the effect of delaying cognitive and physical decline, and improvement or prevention of geriatric syndromes during 1-year follow up. Methods Participants aged 65 years and older with mild-to-moderate dementia (clinical dementia rating [CDR] 1 or 2) were grouped as intervention in Jia-Li Veterans Home and usual care model in the community (Memory clinic). All residents in Jia-Li Veterans Home received comprehensive intervention, including Multi-disciplinary team consultation and intervention, Multi-component non-pharmacological management, geriatric syndromes survey and intervention by CGA, and a dementia friendly medical Green channel Approach (2MCGA). The decline of cognitive and physical function are determined by the change of Mini-Mental State Examination score, CDR and the sum of CDR box, as well as activities of daily living based on the Barthel Index. We also screened geriatric syndromes at baseline and 1 year later. Results Participants in the intervention group were older and had a lower educational level, lower body mass index, poor baseline activities of daily living function, lower visual impairment, and higher rates of hearing impairment, polypharmacy and risk of malnutrition. The residents receiving 2MCGA had lower baseline Mini-Mental State Examination scores, and higher CDR. For residents in Jia-Li Veterans Home, all cognitive measurements except Mini-Mental State Examination were significantly associated with delaying the decline of cognition after analyzing by multiple linear regression, and multivariate logistic regression also showed that patients living in the community was independently associated with a higher odds ratio for activities of daily living decline (3.180, 95% CI 1.384–7.308, P = 0.006). There are also more improvement in their baseline geriatric syndromes and suffered less from new geriatric syndromes, including falls, urinary incontinence, and risk of malnutrition. Conclusions The 2MCGA intervention shows strong delays in the decline of cognition and physical function for older residents with mild-to-moderate dementia. Furthermore, this strategy can also improve or prevent the onset of new geriatric syndromes, especially fall episodes, urinary incontinence and risk of malnutrition. Geriatr Gerontol Int 2017; 17 (Suppl. 1): 36–43.

Japanese encephalitis is a mosquito-borne disease caused by Japanese encephalitis virus (JEV) infection. Although JEV infects and replicates in cells with multiple tissue origins, neurons are the preferential cells for JEV infection. Currently, the identities of JEV cell tropism are largely unclear. To gain better insight into the underlying identities of JEV cell tropism, this study was designed to compare the JEV cell tropism with naive or differentiated PC12 cells. Through nerve growth factor-differentiated PC12 cells, we discovered that JEV efficiently replicated in differentiated PC12 cells rather than naive cells. Mechanistic studies revealed that viral adsorption/attachment seemed not to be a crucial factor. Supporting data showed that antagonizing postreceptor intracellular signaling of interferons, along with the activation of suppressor of cytokine signaling-3 (SOCS3) expression and protein tyrosine phosphatase activity, were apparent in differentiated PC12 cells after JEV infection. Independent of differentiating inducing agents, the upregulation of SOCS3 expression and protein tyrosine phosphatase activity, as well as preferential JEV tropism, were common in JEV-infected differentiated PC12 cells. Using cultured primary neurons, JEV efficiently replicated in embryonic neurons rather than adult neurons, and the preference was accompanied by higher SOCS3 expression and protein tyrosine phosphatase activity. Given that both SOCS3 and protein tyrosine phosphatases have been implicated in the process of neuronal differentiation, JEV infection seems to not only create an antagonizing strategy to escape host's interferon antiviral response but also takes advantage of cellular machinery to favor its replication. Taken together, current findings imply that dynamic changes within cellular regulators of antiviral machinery could be accompanied by events of neuronal differentiation, thus concurrently playing roles in the control of JEV cell tropism and replication. © 2017 IUBMB Life, 69(2):79-87, 2017.

Backgrounds Worldwide, the incidence of acute kidney injury (AKI) has been increasing. However, information on the long-term incidence of Parkinson disease (PD) in patients with AKI has not been reported. Methods A total of 9380 patients with AKI and 37,484 age- and sex-matched patients who did not have AKI were identified during 2003–2011. All patients were tracked until a diagnosis of PD, death, or the end of 2011. Cumulative incidences and hazard ratios (HRs) were calculated. Results The mean follow-up time for PD was 6.89 (SD = 3.30) years in the AKI cohort and 6.78 (SD = 3.29) years in the non-AKI cohort. The overall incidence densities of PD were significantly higher in the AKI cohort than in the non-AKI cohort (6.04 vs. 3.99/1000 person-years), with an adjusted HR of 1.47 (95% confidence interval [CI] = 1.18–1.83). Compared with the patients in the non-AKI cohort aged ≤ 64 years, the relative risk (95% CI) of PD was 2.17 (1.12–4.18), 14.1 (9.16–21.8), and 14.1 (8.43–23.6) for the patients in the AKI cohort aged ≤ 64, 65–79, and ≥ 80 years, respectively. Conclusion Patients with AKI were associated with a higher long-term risk of PD.

Background: Air pollutants cause endocrine disorders and hormone disruption. The relationship between air pollutants and polycystic ovary syndrome (PCOS) must be carefully investigated using a nationwide cohort. Methods: Data were extracted from two nationwide databases, namely Longitudinal Health Insurance Database and Taiwan Air Quality Monitoring Database, and analyzed. The study considered a range of data that began on 1 January 2000 and ended on 31 December 2013. Women diagnosed with PCOS were excluded. From the residential data, the study assessed the daily concentrations of sulfur dioxide (SO2), nitrogen oxides (NOx), nitrogen monoxide (NO), nitrogen dioxide (NO2), and PM2.5 the women were exposed to. A Cox proportional hazard regression model was applied to assess PCOS risk. Results: In total, 91,803 women were enrolled in this study, of those women, 2072 developed PCOS after 12 years of follow-up. The mean daily concentrations of SO2, NOx, NO, NO2, and PM2.5 women were exposed to were 4.25 (&plusmn, 1.44) ppb, 20.41 (&plusmn, 6.65) ppb, 9.25 (&plusmn, 4.36) ppb, 20.99 (&plusmn, 3.33) ppb, and 30.85 (&plusmn, 6.16) &mu, g/m3, respectively. Compared with the first-quartile levels of exposure, the fourth-quartile levels of exposure to SO2, NOx, NO, NO2, and PM2.5 increased PCOS risk by 10.31 times (95% CI = 8.35&ndash, 12.7), 3.37 times (95% CI = 2.86&ndash, 3.96), 4.18 times (95% CI = 3.57&ndash, 4.89), 7.46 times (95% CI = 6.38&ndash, 8.71), and 3.56 times (95% CI = 3.05&ndash, 4.15), respectively. Conclusion: Women exposed to a high concentrations of air pollutants, namely SO2, NO, NO2, NOx, and PM2.5, had a high PCOS risk.

Air pollutants have been reported to be a possible risk factor of chronic kidney disease (CKD). However, epidemiologic results regarding acidic gases and CKD have yet to be elucidated. We linked the Taiwan Air Quality Monitoring Database (TAQMD) to the Longitudinal Health Insurance Database. An observational cohort of 161,970 Taiwan citizens who had not been diagnosed with CKD was formed. The concentrations of air pollutant were classified into four levels based on quartile. Multivariable and univariable Cox proportional hazard regression models were used to assess the risk of developing CKD and end-stage renal disease (ESRD). Compared with Q1-level SO2, exposure to the Q4 level was at a 1.46-fold risk of developing CKD (95% confidence interval [CI] = 1.28-1.65) and 1.32-fold risk of ESRD (95% CI = 1.03-1.70). Compared with Q1-level NOx, exposure to the Q4 level was at a 1.39-fold higher risk of developing CKD (95% CI = 1.22-1.58) and 1.70-fold risk of ESRD (95% CI = 1.33-2.18). Compared with Q1-level NO, exposure to the Q4 level was at a 1.48-fold risk of CKD (95% CI = 1.30-1.68) and 1.54-fold risk of ESRD (95% CI = 1.20-1.98). Compared with Q1-level particles2.5 μm (PM2.5), exposure to the Q4 level were at a 1.74-fold risk of CKD (95% CI = 1.53-1.98) and 1.69-fold risk of ESRD (95% CI = 1.32-2.16). Exposure to particulate and acidic gas air pollution was observed to be associated with an increased risk of CKD and ESRD.

Objective To investigate whether strength or aerobic training can offer significantly more benefits with regarding the activities of daily living of elderly patients with dementia as well as to determine the effects of exercise on cognition, depression, and biochemical markers. Design Single-blind randomized controlled trial. Setting A nursing home for veterans. Participants A volunteer sample of participants (N=80) whose scores on the Mini-Mental State Examination were between 15 and 26 were included. Because of cardiopulmonary or orthopedic conditions that prohibit exercise training, along with any cognitive problems that may impede answering the contents of our questionnaires, 11 participants were excluded. During the exercise training period, 8 participants voluntarily dropped out of the study. Interventions The participants were randomly assigned to perform either strength or aerobic training for a total of 4 weeks. Main Outcome Measures The main outcome measure was the Barthel Index. Other outcome measures included the Mini-Mental State Examination, Montreal Cognitive Assessment, Geriatric Depression Scale, plasma monocyte chemotactic protein-1 levels, insulin-like growth factor-1 levels, and serum brain-derived neurotrophic factor levels. Results After completion of the program, we discovered a significant improvement in the patients’ Barthel Index, Mini-Mental State Examination, Montreal Cognitive Assessment, and plasma monocyte chemotactic protein-1 levels in the strength-training group. For the patients who had received aerobic training, their serum brain-derived neurotrophic factor also improved significantly. However, the degree of improvement regarding these outcome measures did not achieve significant statistical difference between the 2 groups. Conclusions Through our study, an intensive 4-week exercise program, whether it be strength or aerobic training, is evidenced to bring significant benefits to elderly patients with dementia, while the serum brain-derived neurotrophic factor was additionally improved through aerobic training.

Background: In Taiwan, the causes of death and related factors in the oldest old people with Alzheimer disease (AD) are not well characterized. We investigated the factors associated with mortality in the oldest old patients with newly diagnosed AD admitted to a long-stay residential facility. Methods: We performed a prospective study of newly diagnosed AD patients at a veterans’ home between 2012 and 2016. At admission, all eligible participants received a comprehensive geriatric assessment, including demographic variables, lifestyle habits, cognitive evaluations, medical conditions (comorbidities, Age-Adjusted Charlson Comorbidity Index score, and polypharmacy), nutritional status evaluated by the Mini Nutritional Assessment-Short Form and body mass index (BMI), and global functional status. A Cox proportional hazards model was used to evaluate the predictive values of clinical parameters for all-cause mortality. Results: The cohort comprised 84 newly diagnosed AD patients (mean age 86.6 ± 3.9 years) with a mean follow-up period of 2.1 ± 1.2 years. The overall median survival was 3.5 years from the time of AD diagnosis (95% confidence interval, 3.1–3.9 years). BMI was significantly lower in the deceased group than in the alive group (20.7 ± 2.9 vs. 22.6 ± 3.4, p = 0.023). Logistic regression demonstrated that the clinical parameters significantly associated with mortality were high global comorbidity, low nutritional status (malnutrition and underweight), and impaired physical function at the time of AD diagnosis. Conclusion: Comorbidity burden, nutritional status, and physical functional status at the time of dementia diagnosis are important contributors to poor outcome in the oldest old. Efforts to control concurrent chronic disorders, nutritional interventions, and physical independency as a long-term care strategy for dementia may provide survival benefit.

Background: Prognosis of the aged population requiring maintenance dialysis has been reportedly poor. We aimed to develop prediction models for one-year cost and one-year mortality in aged individuals requiring dialysis to assist decision-making for deciding whether aged people should receive dialysis or not. Methods: We used data from the National Health Insurance Research Database (NHIRD). We identified patients first enrolled in the NHIRD from 2000&ndash, 2011 for end-stage renal disease (ESRD) who underwent regular dialysis. A total of 48,153 Patients with ESRD aged &ge, 65 years with complete age and sex information were included in the ESRD cohort. The total medical cost per patient (measured in US dollars) within one year after ESRD diagnosis was our study&rsquo, s main outcome variable. We were also concerned with mortality as another outcome. In this study, we compared the performance of the random forest prediction model and of the artificial neural network prediction model for predicting patient cost and mortality. Results: In the cost regression model, the random forest model outperforms the artificial neural network according to the mean squared error and mean absolute error. In the mortality classification model, the receiver operating characteristic (ROC) curves of both models were significantly better than the null hypothesis area of 0.5, and random forest model outperformed the artificial neural network. Random forest model outperforms the artificial neural network models achieved similar performance in the test set across all data. Conclusions: Applying artificial intelligence modeling could help to provide reliable information about one-year outcomes following dialysis in the aged and super-aged populations, those with cancer, alcohol-related disease, stroke, chronic obstructive pulmonary disease (COPD), previous hip fracture, osteoporosis, dementia, and previous respiratory failure had higher medical costs and a high mortality rate.

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

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

Digital, Background: Two glucagon-like peptide-1 (GLP-1) receptor agonists reduced renal outcomes in people with type 2 diabetes at risk for cardiovascular disease. We assessed the long-term effect of the GLP-1 receptor agonist dulaglutide on renal outcomes in an exploratory analysis of the REWIND trial of the effect of dulaglutide on cardiovascular disease. Methods: REWIND was a multicentre, randomised, double-blind, placebo-controlled trial at 371 sites in 24 countries. Men and women aged at least 50 years with type 2 diabetes who had either a previous cardiovascular event or cardiovascular risk factors were randomly assigned (1:1) to either weekly subcutaneous injection of dulaglutide (1·5 mg) or placebo and followed up at least every 6 months for outcomes. Urinary albumin-to-creatinine ratios (UACRs) and estimated glomerular filtration rates (eGFRs) were estimated from urine and serum values measured in local laboratories every 12 months. The primary outcome (first occurrence of the composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes), secondary outcomes (including a composite microvascular outcome), and safety outcomes of this trial have been reported elsewhere. In this exploratory analysis, we investigate the renal component of the composite microvascular outcome, defined as the first occurrence of new macroalbuminuria (UACR >33·9 mg/mmol), a sustained decline in eGFR of 30% or more from baseline, or chronic renal replacement therapy. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01394952. Findings: Between Aug 18, 2011, and Aug 14, 2013, 9901 participants were enrolled and randomly assigned to receive dulaglutide (n=4949) or placebo (n=4952). At baseline, 791 (7·9%) had macroalbuminuria and mean eGFR was 76·9 mL/min per 1·73 m2 (SD 22·7). During a median follow-up of 5·4 years (IQR 5·1-5·9) comprising 51 820 person-years, the renal outcome developed in 848 (17·1%) participants at an incidence rate of 3·5 per 100 person-years in the dulaglutide group and in 970 (19·6%) participants at an incidence rate of 4·1 per 100 person-years in the placebo group (hazard ratio [HR] 0·85, 95% CI 0·77-0·93; p=0·0004). The clearest effect was for new macroalbuminuria (HR 0·77, 95% CI 0·68-0·87; p, Ciencias Médicas y de la Salud

Digital, Background Three different glucagon-like peptide-1 (GLP-1) receptor agonists reduce cardiovascular outcomes in people with type 2 diabetes at high cardiovascular risk with high glycated haemoglobin A1c (HbA1c) concentrations. We assessed the effect of the GLP-1 receptor agonist dulaglutide on major adverse cardiovascular events when added to the existing antihyperglycaemic regimens of individuals with type 2 diabetes with and without previous cardiovascular disease and a wide range of glycaemic control. Methods This multicentre, randomised, double-blind, placebo-controlled trial was done at 371 sites in 24 countries. Men and women aged at least 50 years with type 2 diabetes who had either a previous cardiovascular event or cardiovascular risk factors were randomly assigned (1:1) to either weekly subcutaneous injection of dulaglutide (1·5 mg) or placebo. Randomisation was done by a computer-generated random code with stratification by site. All investigators and participants were masked to treatment assignment. Participants were followed up at least every 6 months for incident cardiovascular and other serious clinical outcomes. The primary outcome was the first occurrence of the composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes (including unknown causes), which was assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01394952. Findings Between Aug 18, 2011, and Aug 14, 2013, 9901 participants (mean age 66·2 years [SD 6·5], median HbA1c 7·2% [IQR 6·6–8·1], 4589 [46·3%] women) were enrolled and randomly assigned to receive dulaglutide (n=4949) or placebo (n=4952). During a median follow-up of 5·4 years (IQR 5·1–5·9), the primary composite outcome occurred in 594 (12·0%) participants at an incidence rate of 2·4 per 100 person-years in the dulaglutide group and in 663 (13·4%) participants at an incidence rate of 2·7 per 100 person-years in the placebo group (hazard ratio [HR] 0·88, 95% CI 0·79–0·99; p=0·026). All-cause mortality did not differ between groups (536 [10·8%] in the dulaglutide group vs 592 [12·0%] in the placebo group; HR 0·90, 95% CI 0·80–1·01; p=0·067). 2347 (47·4%) participants assigned to dulaglutide reported a gastrointestinal adverse event during follow-up compared with 1687 (34·1%) participants assigned to placebo (p, Ciencias Médicas y de la Salud

Few studies have investigated the risk of physiological sequelae in living kidney donors (KDs). We conducted a population-based cohort study using the National Health Insurance Research Database of Taiwan, which covers more than 99% of citizens. We comprehensively investigated the risk of medical disorders after kidney donation in living KDs using a maximum follow-up of 13 years. From January 1997 to December 2010, 1081 living KDs and 1082 age- and sex-matched non-KDs were eligible. Primary outcomes comprised end-stage renal disease, chronic kidney disease, stroke, cancer, acute myocardial infarction, acute renal failure (ARF), and diabetes. The adjusted hazard ratios (HRs) for developing ARF, diabetes, hyperlipidemia, hypertension, cancer, end-stage renal disease, acute myocardial infarction, and stroke were similar between the KD and non-KD cohorts (P > .05). Although differences in the adjusted HRs of ARF were nonsignificant, the cumulative incidence rate of ARF 13 years after donation was 7.48 per 1000 person-years in the KD cohort compared with 3.46 in the matched non-KD cohort. The incidence rate ratio for ARF between donors and nondonors significantly increased to 2.16 (95% confidence interval, 1.61–2.71). Living KDs experienced no significant health disorders following kidney donation but should be alert to the higher incidence rate of ARF.

Atypical antipsychotics, such as olanzapine, are commonly prescribed to patients with schizophrenic symptoms and other psychiatric disorders. However, weight gain and metabolic disturbance cause adverse effects, impair patient compliance and limit clinical utility. Thus, a better understanding of treatment-acquired adverse effects and identification of targets for therapeutic intervention are believed to offer more clinical benefits for patients with schizophrenia. Beyond its nutritional effects, studies have indicated that supplementation of chromium brings about beneficial outcomes against numerous metabolic disorders. In this study, we investigated whether olanzapine-induced weight gain and metabolic disturbance involved chromium dynamic mobilization in a female Sprague-Dawley rat model, and whether a dietary supplement of chromium improved olanzapine-acquired adverse effects. Olanzapine medicated rats experienced weight gain and adiposity, as well as the development of hyperglycemia, hyperinsulinemia, insulin resistance, hyperlipidemia, and inflammation. The olanzapine-induced metabolic disturbance was accompanied by a decrease in hepatic Akt and AMP-activated Protein Kinase (AMPK) actions, as well as an increase in serum interleukin-6 (IL-6), along with tissue chromium depletion. A daily intake of chromium supplements increased tissue chromium levels and thermogenic uncoupling protein-1 (UCP-1) expression in white adipose tissues, as well as improved both post-olanzapine weight gain and metabolic disturbance. Our findings suggest that olanzapine medicated rats showed a disturbance of tissue chromium homeostasis by inducing tissue depletion and urinary excretion. This loss may be an alternative mechanism responsible for olanzapine-induced weight gain and metabolic disturbance.

Aims This study investigated whether patients with alcoholic cirrhosis have a high risk of hemorrhagic stroke. Methods In this study, 17,094 patients diagnosed with cirrhosis between 2000 and 2010 were identified using the Taiwan National Health Insurance claims data. Identified patients were randomly selected and propensity score matched with individuals without cirrhosis according to age, sex, comorbidities and index year. Results The overall incidence rate of stroke was 4.41 and 12.1 per 1000 person-years in the chronic liver disease and cirrhosis (CLDC) with hepatitis B virus (HBV) or hepatitis C virus (HCV) cohort and the alcoholic CLDC cohort, respectively. The alcoholic CLDC cohort exhibited a 4.53-fold higher risk of hemorrhagic stroke (adjusted subhazard ratio [aSHR] = 4.53, 95% confidence interval [CI] = 3.05-6.71) than did the non-CLDC cohort, and the CLDC with HBV or HCV cohort exhibited a 1.40-fold higher risk of hemorrhagic stroke (aSHR = 1.40, 95% CI = 1.10-1.78) than did the non-CLDC cohort. The alcoholic CLDC cohort and the CLDC with HBV or HCV cohort showed an aSHR of 1.80 (95% CI = 1.36-2.40) and 0.95 (95% CI = 0.83-1.07) for ischemic stroke, respectively, compared with the non-CLDC cohort. Conclusion Alcoholic patients with CLDC had a higher risk of hemorrhagic stroke compared with non-alcoholic patients with CLDC and patients without CLDC.

Background: Air pollution has been associated with autoimmune diseases. Nephrotic syndrome is a clinical manifestation of immune-mediated glomerulopathy. However, the association between nephrotic syndrome and air pollution constituents remains unknown. We conducted this nationwide retrospective study to investigate the association between PM2.5 and nephrotic syndrome. Methods: We used the Longitudinal Health Insurance Database (LHID) and the Taiwan Air Quality-Monitoring Database (TAQMD). We combined and stratified the LHID and the TAQMD data by residential areas of insurants linked to nearby air quality-monitoring stations. Air pollutant concentrations were grouped into four levels based on quartile. Univariable and multivariable Cox proportional hazard regression models were applied. Findings: Relative to Q1-level SO2, subjects exposed to the Q4 level were associated with a 2.00-fold higher risk of nephrotic syndrome (adjusted HR = 2.00, 95% CI = 1.66&ndash, 2.41). In NOx, relative to Q1 NOx concentrations, the adjusted HRs of nephrotic syndrome risk were 1.53 (95% CI = 1.23&ndash, 1.91), 1.30 (95% CI = 1.03&ndash, 1.65), and 2.08 (95% CI = 1.69&ndash, 2.56) for Q2, Q3, and Q4 levels, respectively. The results revealed an increasing trend for nephrotic syndrome risk correlating with increasing levels of NO, NO2, and PM2.5 concentrations. Interpretation: High concentrations of PM2.5, NO, NO2, and SO2 are associated with increased risk of nephrotic syndrome.

Simple Summary In addition to their role in hemostasis and thrombosis, platelets have been implicated in cancer malignancy and thrombocytosis in cancer patients and have been associated with an adverse prognosis. These phenomena indicate that antiplatelet drugs may be useful as an anticancer therapy. Using K562-differentiated megakaryocytes and murine platelets, conditioned medium and exosomes obtained from megakaryocytes and platelets contained high-mobility group box 1 (HMGB1) and promoted cancer cell survival, as well as protected cancer cells from doxorubicin cytotoxicity. Data of tumor-bearing mice established by Lewis lung carcinoma (LLC) cells and C57BL/6 mice revealed that antiplatelet drug dipyridamole and exosome release inhibitor GW4869 mitigated tumor growth and ameliorated concurrent alterations in blood circulation and tumor tissues, as well as platelet infiltration in tumor tissues. Therefore, exosomes and exosomal HMGB1 appear to have roles in platelet-driven cancer malignancy and represent targets of antiplatelet drugs in anticancer treatment. Abstract Reciprocal crosstalk between platelets and malignancies underscores the potential of antiplatelet therapy in cancer treatment. In this study, we found that human chronic myeloid leukemia K562 cell-differentiated megakaryocytes and murine platelets produced bioactive substances and these are released into the extracellular space, partly in their exosomal form. High-mobility group box 1 (HMGB1) is a type of exosomal cargo, and the antiplatelet drugs aspirin and dipyridamole interfered with its incorporation into the exosomes. Those released substances and exosomes, along with exogenous HMGB1, promoted cancer cell survival and protected cells from doxorubicin cytotoxicity. In a tumor-bearing model established using murine Lewis lung carcinoma (LLC) cells and C57BL/6 mice, the tumor suppressive effect of dipyridamole correlated well with decreased circulating white blood cells, soluble P-selectin, TGF-β1 (Transforming Growth Factor-β1), exosomes, and exosomal HMGB1, as well as tumor platelet infiltration. Exosome release inhibitor GW4869 exhibited suppressive effects as well. The suppressive effect of dipyridamole on cancer cell survival was paralleled by a reduction of HMGB1/receptor for advanced glycation end-products axis, and proliferation- and migration-related β-catenin, Yes-associated protein 1, Runt-related transcription factor 2, and TGF- β1/Smad signals. Therefore, exosomes and exosomal HMGB1 appear to have roles in platelet-driven cancer malignancy and represent targets of antiplatelet drugs in anticancer treatment.

Background The relationship between postprandial hyperglycaemia and diabetic peripheral neuropathy (DPN), whether painful or painless, has yet to be determined. Thus, the aim of this study was to investigate the relationship in patients with type 2 diabetes (T2D). Methods This cross-sectional study was conducted in adults with T2D between January and October 2013. Blood samples were collected after overnight fasting every 3 months prior to enrolment. For this study, increased postprandial glycaemic exposure was defined as high glycated haemoglobin (HbA1c) and near-normal mean fasting plasma glucose (FPG) levels. Both painless and painful DPN were evaluated using two validated tools, the Michigan Neuropathy Screening Instrument (MNSI) and Douleur Neuropathique 4 (DN4) questionnaire. Results This study included 1040 participants with mean FPG levels Conclusion This study is the first to reveal that increased postprandial glycaemic exposure, as assessed by high HbA1c and near-normal FPG levels, is associated with an increased risk of painful DPN in adults with T2D.