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Despite the continual improvements in dialysis treatments, mortality in end-stage kidney disease (ESKD) remains high. Many mortality prediction models are available, but most of them are not precise enough to be used in the clinical practice. We aimed to develop and validate two prediction models for 3-month and 1-year patient mortality after dialysis initiation in our population.Using population-based data of insurance claims in Taiwan, we included more than 210,000 patients who initiated dialysis between January 1, 2006, and June 30, 2015. We developed two prognostic models, which included 9 and 11 variables, respectively (including age, sex, myocardial infarction, peripheral vascular disease, cerebrovascular disease, dementia, chronic pulmonary disease, peptic ulcer disease, malignancy, moderate to severe liver disease, and first dialysis in intensive care unit).The models showed adequate discrimination (C-statistics were 0.80 and 0.82 for 3-month and 1-year mortality, respectively) and good calibration. In both our models, the first dialysis in the intensive care unit and moderate-to-severe liver disease were the strongest risk factors for mortality.The prediction models developed in our population had good predictive ability for short-term mortality in patients initiating dialysis in Taiwan and could help in decision-making regarding dialysis initiation, at least in our setting, supporting a patient-centered approach to care.

Background Little was know about the association between the CHA2DS2-VASc score and postoperative outcomes. Our purpose is to evaluate the effects of CHA2DS2-VASc score on the perioperative outcomes in patients with atrial fibrillation (AF). Methods We identified 47,402 patients with AF over the age of 20 years who underwent noncardiac surgeries between 2008 and 2013 from claims data of the National Health Insurance in Taiwan. The CHA2DS2-VASc score was used to evaluate postoperative complications, mortality and the consumption of medical resources by calculating adjusted odds ratios (ORs) and 95% confidence intervals (CIs). Results Compared with patients with a CHA2DS2-VASc score of 0, patients with scores ≥ 5 had an increased risk of postoperative septicemia (OR 2.76, 95% CI 2.00–3.80), intensive care (OR 2.55, 95% CI 2.12–3.06), and mortality (OR 2.04, 95% CI 1.14–3.64). There was a significant positive correlation between risk of postoperative complication and the CHA2DS2-VASc score (P Conclusion The CHA2DS2-VASc score was highly associated with postoperative septicemia, intensive care, and 30-day mortality among AF patients. Cardiologists and surgical care teams may consider using the CHA2DS2-VASc score to evaluate perioperative outcome risks in patients with AF.

The association between pancreatitis and acute myocardial infarction or stroke remains incompletely understood. This study aimed to evaluate the long-term risk of acute atherosclerotic cardiovascular disease (ASCVD) in people with acute and chronic pancreatitis. Using research database of Taiwan's National Health Insurance, we identified 2678 patients aged ≥ 20 years with newly diagnosed pancreatitis in 2000–2008. A cohort of 10,825 adults without pancreatitis was selected for comparison, with matching by age and sex. Both cohorts were followed from 2000 to the end of 2013, and incident acute ASCVD was identified during the follow-up period. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of acute ASCVD associated with pancreatitis were calculated. Compared with the comparison cohort, the adjusted HR of acute ASCVD were 1.76 (95% CI 1.47–2.12) and 3.42 (95% CI 1.69–6.94) for people with acute pancreatitis and chronic pancreatitis, respectively. A history of alcohol-related illness (HR 9.49, 95% CI 3.78–23.8), liver cirrhosis (HR 7.31, 95% CI 1.81–29.5), and diabetes (HR 6.89, 95% CI 2.18–21.8) may worsen the risk of acute ASCVD in patients with chronic pancreatitis. Compared with people had no pancreatitis, patients with acute pancreatitis who had alcohol-related illness (HR 4.66, 95% CI 3.24–6.70), liver cirrhosis (HR 4.44, 95% CI 3.05–6.47), and diabetes (HR 2.61, 95% CI 2.03–3.36) were at increased risk of acute ASCVD. However, the cumulative use of metformin was associated with a reduced risk of acute ASCVD in the acute pancreatitis cohort (HR 0.30, 95% CI 0.17–0.50). Compared with the control group, patients with acute or chronic pancreatitis were more likely to have an increased risk of acute ASCVD, while the use of metformin reduced the risk of acute ASCVD. Our findings warrant a survey and education on acute ASCVD for patients with acute and chronic pancreatitis.

The impact of heart failure (HF) on postoperative outcomes is not completely understood. Our purpose is to investigate complications and mortality after noncardiac surgeries in people who had HF. In the analyses of research data of health insurance in, we identified 32,808 surgical patients with preoperative HF and 32,808 patients without HF undergoing noncardiac surgeries. We used a matching procedure with propensity score and considered basic characteristics, coexisting diseases, and information of index surgery between patients with and without HF. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for complications and mortality after noncardiac surgeries in patients with HF were analyzed in multivariate logistic regressions. HF increased the risks of postoperative acute myocardial infarction (OR 2.51, 95% CI 1.99–3.18), pulmonary embolism (OR 2.46, 95% CI 1.73–3.50), acute renal failure (OR 1.97, 95% CI 1.76–2.21), intensive care (OR 1.93, 95% CI 1.85–2.01), and 30-day in-hospital mortality (OR 1.80, 95% CI 1.59–2.04). Preoperative emergency care, inpatient care, and injections of diuretics and cardiac stimulants due to heart failure were also associated with mortality after surgery. Patients with HF had increased complications and mortality after noncardiac surgeries compared with those without HF. The surgical care team may consider revising the protocols for perioperative care in patients with HF.

Patients with type 2 diabetes mellitus (T2DM) have a higher risk of chronic kidney disease (CKD) due to vascular complications and chronic inflammation. T2DM contributes to a higher risk of mortality and morbidity related to influenza. In Taiwan, influenza vaccination is recommended for patients with T2DM. A previous meta-analysis reported the efficacy of influenza vaccination in reducing hospitalization and mortality in patients with diabetes; however, the renal protective effect of the vaccine remains unclear. This study evaluated whether influenza vaccination could reduce the incidence of CKD and dialysis in patients with T2DM. The study cohort included all patients aged ≥55 years who were diagnosed as having T2DM between 1 January 2000 and 31 December 2012, by using data from Taiwan’s National Health Insurance Research Database. Each patient was followed up with to assess factors associated with CKD. A time-dependent Cox proportional hazard regression model after adjustment for potential confounders was used to calculate the hazard ratio (HR) of CKD in the vaccinated and unvaccinated patients. The study population comprised 48,017 eligible patients with DM; 23,839 (49.7%) received influenza vaccination and the remaining 24,178 (50.3%) did not. The adjusted HRs (aHRs) for CKD/dialysis decreased in the vaccinated patients compared with the unvaccinated patients (influenza season, noninfluenza season, and all seasons: aHRs: 0.47/0.47, 0.48/0.49, and 0.48/0.48, respectively, all p < 0.0001). We observed similar protective effects against CKD during the influenza and noninfluenza seasons. Regardless of comorbidities or drug use, influenza vaccination was an independent protective factor. Furthermore, aHRs for CKD/dialysis were 0.71 (0.65–0.77)/0.77 (0.68–0.87), 0.57 (0.52–0.61)/0.69 (0.56–0.70), and 0.30 (0.28–0.33)/0.28 (0.24–0.31) in the patients who received 1, 2–3, and ≥4 vaccinations during the follow-up period, respectively. This population-based cohort study demonstrated that influenza vaccination exerts a dose-dependent and synergistic protective effect against CKD in the patients with T2DM with associated risk factors.

Current cigarette smoking is associated with chronic kidney disease (CKD) or death from end-stage renal disease (ESRD). Mainstream cigarette smoke includes over 4000 compounds. Among the compounds present in tobacco smoke, nicotine is one of a large number of biologically stable and active compounds present in tobacco. However, the mechanisms by which nicotine exacerbates kidney disease progression have not been identified. It is known that the inflammasomes constitute an important innate immune pathway and contribute to the pathophysiology of diverse kidney diseases. The relationship between inflammasomes and nicotine-induced kidney damage still remains unclear. In the present study, we studied the mechanisms of nicotine-induced nephrotoxicity. We found that nicotine decreased cell viability and induced reactive oxygen species (ROS) generation in human kidney cells. Furthermore, nicotine significantly increased the expression of the alpha7 nicotinic acetylcholine receptor (&alpha, 7nAChR). Nicotine activated the NLRP6 inflammasome and induced endoplasmic reticulum (ER) stress. Nicotine caused mild apoptosis and necrosis but triggered significant autophagy in human kidney cells. In addition, nicotine induced the NLRP6 inflammasome and autophagy via &alpha, 7nAChR. In an animal model, the histological analysis in kidney showed evident changes and injury. The results indicated that &alpha, 7nAChR, IRE1&alpha, LC3 and NLRP6 expression in kidney sections was markedly increased in the nicotine groups. These findings suggest that nicotine causes kidney damage by modulating &alpha, 7nAChR, NLRP6 inflammasome, ER stress and autophagy.

The ventricular arrhythmia (VA)–chronic obstructive pulmonary disease (COPD) association and related risk factors remain unclear. Using 2001–2012 data from National Health Insurance Research Database, we retrospectively reviewed 71,838 patients diagnosed as having COPD and 71,838 age- and sex-matched controls. After adjustments for comorbidities, medication, urbanization level, and monthly income, patients with COPD had higher incidence rates of VA than did the controls (adjusted hazard ratio [aHR] [95% confidence interval (CI)]: 1.45 [1.25–1.68]). More hospitalization or emergency visits because of acute COPD exacerbation (aHRs [95% CIs] for first, second, and third visits: 1.28 [1.08–1.50], 1.75 [1.32–2.32], and 1.88 [1.46–2.41], respectively) and asthma–COPD overlap (aHR [95% CI]: 1.49 [1.25–1.79]) were associated with high VA risk in patients with COPD. In the multivariate analysis, heart failure (aHR [95% CI]: 2.37 [1.79–3.14]), diabetes (aHR [95% CI]:1.64 [1.29–2.08]), age ≥75 (aHR [95% CI]: 2.48 [1.68–3.67]), male (aHR [95% CI]: 1.69[1.34–2.12]), and class III antiarrhythmic drug use (aHR [95% CI]: 2.49 [1.88–3.28]) are the most significant risk factors of new onset of VA in patients with COPD.

BackgroundOnly few studies with inconsistent results comparing the relative risk of cardiac mortality between peritoneal dialysis (PD) and hemodialysis (HD). Switches between renal replacement therapy (RRT) modalities render objective assessment of survival benefits a greater challenge.MethodsData were retrieved from Taiwan’s National Health Insurance Database from 1 January 2006 to 31 December 2015. We included 13 662 and 41 047 long-term dialysis patients in a propensity score matching study design and a time-varying study design, respectively, to compare major adverse cardiovascular events (MACEs) between patients receiving PD and HD. We also included 109 256 dialysis patients to compare the all-cause mortality among different RRT modalities.ResultsFor MACE, the hazard ratio (HR) for PD patients compared to HD patients was 0.95 [95% confidence interval (CI) 0.89–1.02] in the propensity score study design and 1.06 (95% CI 1.01–1.12) in the time-varying study design. For all-cause mortality, the HR for PD patients compared to HD patients was 1.09 (95% CI 1.05–1.13) in the propensity score study design and 1.13 (95% CI 1.09–1.17) in the time-varying study design. The HR for death was higher at a level of statistical significance for females (1.21, 95% CI 1.15–1.28), patients ≥65 years old (1.30, 95% CI 1.24–1.36) and diabetes mellitus (DM; 1.28, 95% CI 1.22–1.34).ConclusionsThe HR for MACE is significantly higher among PD patients in time-varying design analysis. In addition, all-cause mortality was higher in PD patients compared to patients with HD, especially in those who were aged ≥65 years, female or DM.

Objective To evaluate the long-term risk of stroke and poststroke adverse outcomes in patients with heart failure (HF). Methods We used research data from Taiwan’s National Health Insurance Program from 2000 to 2005 and identified 20,072 adults aged ≥30 years who were newly diagnosed with HF. Frequency matching based on age and sex was used to select a comparison cohort consisting of 80,288 adults without HF. Events of incident stroke were identified from medical claims during the 2000–2013 follow-up period. The adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of the association of stroke with HF were calculated with a multiple Cox proportional hazard model. Another nested stroke cohort study of 480,604 hospitalized stroke patients determined the adjusted odds ratios (ORs) and 95% CIs for adverse events after stroke in patients with and without HF between 2000 and 2009. Results Compared with the non-HF cohort, HF patients had an increased risk of stroke (HR 2.32, 95% CI 2.21–2.43), including ischemic stroke and hemorrhagic stroke. The association between HF and stroke was significant in both sexes and in patients in all age groups and with various medical conditions. Previous HF was associated with poststroke mortality (OR 1.40, 95% CI 1.31–1.50), pneumonia (OR 1.33, 95% CI 1.28–1.38), and septicemia (OR 1.30, 95% CI 1.23–1.37). Conclusion HF was associated with a higher risk of stroke, and patients with HF had more complications and greater mortality after stroke.

Through population-based studies, associations have been found between coffee drinking and numerous health benefits, including a reduced risk of cardiovascular disease. Active ingredients in coffee have therefore received considerable attention from researchers. A wide variety of effects have been attributed to cafestol, one of the major compounds in coffee beans. Because cardiac hypertrophy is an independent risk factor for cardiovascular events, this study examined whether cafestol inhibits urotensin II (U-II)-induced cardiomyocyte hypertrophy. Neonatal rat cardiomyocytes were exposed only to U-II (1[Formula: see text]nM) or to U-II (1[Formula: see text]nM) following 12-h pretreatment with cafestol (1–10[Formula: see text][Formula: see text]M). Cafestol (3–10[Formula: see text][Formula: see text]M) pretreatment significantly inhibited U-II-induced cardiomyocyte hypertrophy with an accompanying decrease in U-II-induced reactive oxygen species (ROS) production. Cafestol also inhibited U-II-induced phosphorylation of redox-sensitive extracellular signal-regulated kinase (ERK) and epidermal growth factor receptor transactivation. In addition, cafestol pretreatment increased Src homology region 2 domains-containing phosphatase-2 (SHP-2) activity, suggesting that cafestol prevents ROS-induced SHP-2 inactivation. Moreover, nuclear factor erythroid-2-related factor 2 (Nrf2) translocation and heme oxygenase-1 (HO-1) expression were enhanced by cafestol. Addition of brusatol (a specific inhibitor of Nrf2) or Nrf2 siRNA significantly attenuated cafestol-mediated inhibitory effects on U-II-stimulated ROS production and cardiomyocyte hypertrophy. In summary, our data indicate that cafestol prevented U-II-induced cardiomycyte hypertrophy through Nrf2/HO-1 activation and inhibition of redox signaling, resulting in cardioprotective effects. These novel findings suggest that cafestol could be applied in pharmacological therapy for cardiac diseases.

// Pai-Feng Kao 1, 6, * , Ju-Chi Liu 1, 6, * , Yi-Ping Hsu 1 , Li-Chin Sung 1, 6 , Tsung-Yeh Yang 1 , Wen-Rui Hao 1 , Ying-Chin Lin 2, 3 and Szu-Yuan Wu 4, 5, 6, 7 1 Division of Cardiovascular Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan 2 Department of Family Medicine, Shung Ho Hospital, Taipei Medical University, New Taipei, Taiwan 3 Department of Family Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan 4 Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan 5 Department of Radiation Oncology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan 6 Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan 7 Department of Biotechnology, Hungkuang University, Taichung, Taiwan * These authors have contributed equally to this work Correspondence to: Szu-Yuan Wu, email: szuyuanwu5399@gmail.com Keywords: influenza vaccination; atrial fibrillation; ischemic stroke Received: June 11, 2017 Accepted: July 26, 2017 Published: November 09, 2017 ABSTRACT Purpose: Atrial fibrillation (AF) is associated with the risk of ischemic stroke, regardless of the administration of appropriate antithrombotic prophylaxis. This study investigated whether influenza vaccination is associated with the risk of ischemic stroke, to determine a solution to reduce this risk in patients with AF. Methods: We used data from the Taiwan National Health Insurance Research Database. The study cohort comprised all patients diagnosed as having AF (n = 14 454) before January 1, 2005; these patients were followed until December 31, 2012. The index date was January 1, 2005. A propensity score was derived using a logistic regression model to estimate the effect of vaccination by accounting for covariates that predict receiving the intervention (vaccine). A Cox proportional hazard model was used to calculate the hazard ratios (HRs) of ischemic stroke in vaccinated and unvaccinated patients with AF. Results: We included 6570 patients (2547 [38.77%] with and 4023 [61.23%] without influenza vaccination). The adjusted HRs (aHRs) of ischemic stroke were lower in the vaccinated patients than in the unvaccinated patients (influenza season, noninfluenza season, and all seasons: aHRs = 0.59, 0.50, and 0.55; P < 0.001, P < 0.001, and P < 0.001, respectively). Conclusions: Influenza vaccination might exert a dose-response effect against ischemic stroke in patients with AF who have risk factors for ischemic stroke by reducing the incidence of ischemic stroke, particularly in those aged 65–74 and ≥75 y.

An influenza vaccination might reduce the risk of incident peripheral arterial occlusive disease (PAOD) in patients with chronic kidney disease (CKD), but supporting evidence is limited. This case-crossover study analyzed data from Taiwan’s real-world National Health Insurance Research Database. This study included elderly (≥ 67 years old) patients with CKD having incident PAOD from January 1, 2006, to June 30, 2015. We defined 1 year before PAOD onset as the index date for the self-control group. A conditional logistic regression model was used to investigate exposure to an influenza vaccination for estimating the risk for incident PAOD following vaccination. In total, this study included 46,782 elderly patients with CKD having incident PAOD. The odds ratios for incident PAOD were 0.85 (95% confidence interval 0.77–0.94), 0.85 (0.79–0.92), 0.84 (0.79–0.90), and 0.85 (0.81–0.90) at 1, 2, 3, and 4 months after an influenza vaccination, respectively. We observed consistent results for the subgroups of patients with CKD and concomitant diabetes. However, we did not observe any beneficial effects of influenza vaccination in patients with advanced CKD or end-stage renal disease. This study demonstrated that influenza vaccination may be associated with a reduced risk of incident PAOD among patients with early-stage CKD.

Ta-Liang Chen,1,2,* Chao-Shun Lin,2–4 Jui-An Lin,1,2 Chun-Chieh Yeh,5,6 Li-Chin Sung,7 Yi-Cheng Chang,8 Chun-Chuan Shih,9,10,* Chien-Chang Liao2–4,11,12 1Department of Anesthesiology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; 2Department of Anesthesiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; 3Department of Anesthesiology, Taipei Medical University Hospital, Taipei, Taiwan; 4Anesthesiology and Health Policy Research Center, Taipei Medical University Hospital, Taipei, Taiwan; 5Department of Surgery, China Medical University Hospital, Taichung, Taiwan; 6Department of Surgery, University of Illinois, Chicago, IL, USA; 7Division of Cardiology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan; 8Division of Endocrinology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; 9School of Chinese Medicine for Post-Baccalaureate, College of Medicine, I-Shou University, Kaohsiung, Taiwan; 10Ph.D. Program in Clinical Drug Development of Herbal Medicine, College of Pharmacy, Taipei Medical University, Taipei, Taiwan; 11Research Center of Big Data and Meta-Analysis, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; 12School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan*These authors contributed equally to this workCorrespondence: Chien-Chang LiaoDepartment of Anesthesiology, Taipei Medical University Hospital, 252 Wuxing St., Taipei 11031, TaiwanTel +886-2-2737-2181, ext. 8310Fax +886-2-2736-7344Email jacky48863027@yahoo.com.twObjective: This study aimed to evaluate the risk of incident diabetes between people who used lovastatin and red yeast rice (RYR) prescriptions.Methods: A retrospective cohort study was performed to analyze the real-world database of Taiwan’s National Health Insurance. We identified the RYR cohort, which included 34,504 persons age 20 years or older who began their use of a RYR prescription in 2010–2014. A comparison cohort of 34,504 adults beginning the use of lovastatin was selected from the same dataset, which was matched by age and sex. Both cohorts had no diabetes before the use of the medications. Events of incident diabetes in 2000–2015 were ascertained from medical claims. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of incident diabetes associated with the use of RYR prescriptions were calculated.Results: The incidences of diabetes for the RYR cohort and the lovastatin cohort were 1.01 and 2.59 per 100 person-years, respectively (P < 0.0001). Compared with the lovastatin cohort, the adjusted HR of incident diabetes was 0.46 (95% CI 0.43–0.50) for people who used RYR prescriptions. The association between reduced incident diabetes and use of RYR prescriptions was significant in various subgroups. There was a dose-response relationship between RYR prescriptions and the reduced risk of incident diabetes.Conclusion: We raised the possibility that people who used RYR prescriptions may have a lower risk of incident diabetes compared with the lovastatin cohort.Keywords: diabetes, lovastatin, red yeast rice, risk

// Ju-Chi Liu 1, 4, * , Tsung-Yeh Yang 1, * , Yi-Ping Hsu 1 , Wen-Rui Hao 1 , Pai-Feng Kao 1, 4 , Li-Chin Sung 1, 4 , Chun-Chao Chen 1 , Szu-Yuan Wu 2, 3, 4, 5 1 Division of Cardiovascular Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan 2 Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan 3 Department of Radiation Oncology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan 4 Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan 5 Department of Biotechnology, Hungkuang University, Taichung, Taiwan * Co-first authors, These authors contributed equally to this work Correspondence to: Szu-Yuan Wu, email: szuyuanwu5399@gmail.com Keywords: statins, COPD, lung cancer Received: March 09, 2016 Accepted: July 09, 2016 Published: August 09, 2016 ABSTRACT Purpose: Chronic obstructive pulmonary disease (COPD) is associated with increased lung cancer risk. We evaluated the association of statin use with lung cancer risk in COPD patients and identified which statins possess the highest chemopreventive potential. Results: After adjustment for age, sex, CCI, diabetes, hypertension, dyslipidemia, urbanization level, and monthly income according to propensity scores, lung cancer risk in the statin users was lower than that in the statin nonusers (adjusted hazard ratio [aHR] = 0.37). Of the individual statins, lovastatin and fluvastatin did not reduce lung cancer risk significantly. By contrast, lung cancer risk in patients using rosuvastatin, simvastatin, atorvastatin, and pravastatin was significantly lower than that in statin nonusers (aHRs = 0.41, 0.44, 0.52, and 0.58, respectively). Statins dose-dependently reduced lung cancer risk in all subgroups and the main model with additional covariates (nonstatin drug use). Materials and Methods: The study cohort comprised all patients diagnosed with COPD at health care facilities in Taiwan ( n = 116,017) between January 1, 2001 and December 31, 2012. Our final study cohort comprised 43,802 COPD patients: 10,086 used statins, whereas 33,716 did not. Patients were followed up to assess lung cancer risk or protective factors. In addition, we also considered demographic characteristics, namely age, sex, comorbidities (diabetes, hypertension, dyslipidemia, and Charlson comorbidity index [CCI]), urbanization level, monthly income, and nonstatin drug use. The index date of statin use was the COPD confirmation date. To examine the dose–response relationship, we categorized statin use into four groups in each cohort: 365 cumulative defined daily doses (cDDDs). Patients receiving < 28 cDDDs were defined as nonstatin users. Conclusions: Statins dose-dependently exert a significant chemopreventive effect against lung cancer in COPD patients. Rosuvastatin, simvastatin, and atorvastatin exhibited the highest chemopreventive potential.

// Ju-Chi Liu 1, 4, * , Wen-Rui Hao 1, * , Yi-Ping Hsu 1 , Li-Chin Sung 1, 4 , Pai-Feng Kao 1, 4 , Chao-Feng Lin 1 , Alexander T.H. Wu 6 , Kevin Sheng-Po Yuan 7 , Szu-Yuan Wu 2, 3, 4, 5 1 Division of Cardiovascular Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei, Taiwan 2 Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan 3 Department of Radiation Oncology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan 4 Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan 5 Department of Biotechnology, Hungkuang University, Taichung, Taiwan 6 Ph.D. Program for Translational Medicine, Taipei Medical University, Taipei, Taiwan 7 Department of Otorhinolaryngology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan * These authors have contributed equally to this work Correspondence to: Szu-Yuan Wu, email: szuyuanwu5399@gmail.com Keywords: statins, chronic obstructive pulmonary disease, colon cancer Received: March 22, 2016 Accepted: June 27, 2016 Published: August 12, 2016 ABSTRACT Purpose: We evaluated the chemopreventive effect of statins on colon cancer in patients with chronic obstructive pulmonary disease (COPD) and identified the statin exerting the strongest chemopreventive effect. Methods: Using the National Health Insurance Research Database, we identified patients who received a COPD diagnosis in Taiwan between January 1, 2001, and December 31, 2012, and included them in the study cohort. Each patient was followed to assess the colon cancer risk and protective factors. A propensity score was derived using a logistic regression model to estimate the effect of statins by accounting for covariates predicted during the intervention (statins). To examine the dose–response relationship, we categorized statin doses into four groups in each cohort [ 365 cumulative defined daily dose]. Results: Compared with the statin nonusers, the adjusted hazard ratio (aHR) for colon cancer decreased in the statin users (aHR = 0.52, 95% confidence interval = 0.44, 0.62). Hydrophilic statins exerted a stronger preventive effect against colon cancer. Regarding the statin type, lovastatin, pravastatin, and fluvastatin nonsignificantly reduced the colon cancer risk in the patients with COPD. Compared with the statin nonusers, the aHRs for colon cancer decreased in the individual statin users (rosuvastatin, simvastatin, and atorvastatin: aHRs = 0.28, 0.64, and 0.65, respectively). In the sensitivity analysis, statins dose-dependently reduced the colon cancer risk. Conclusions: Statins dose-dependently exert significant chemopreventive effects on colon cancer in patients with COPD, with rosuvastatin exerting the largest chemopreventive effect.

[This corrects the article DOI: 10.1371/journal.pone.0206011.].

Diabetes-associated cardiac fibrosis is a severe cardiovascular complication. Momordicine I, a bioactive triterpenoid isolated from bitter melon, has been demonstrated to have antidiabetic properties. This study investigated the effects of momordicine I on high-glucose-induced cardiac fibroblast activation. Rat cardiac fibroblasts were cultured in a high-glucose (25 mM) medium in the absence or presence of momordicine I, and the changes in collagen synthesis, transforming growth factor-β1 (TGF-β1) production, and related signaling molecules were assessed. Increased oxidative stress plays a critical role in the development of high-glucose-induced cardiac fibrosis; we further explored momordicine I’s antioxidant activity and its effect on fibroblasts. Our data revealed that a high-glucose condition promoted fibroblast proliferation and collagen synthesis and these effects were abolished by momordicine I (0.3 and 1 μM) pretreatment. Furthermore, the inhibitory effect of momordicine I on high-glucose-induced fibroblast activation may be associated with its activation of nuclear factor erythroid 2-related factor 2 (Nrf2) and the inhibition of reactive oxygen species formation, TGF-β1 production, and Smad2/3 phosphorylation. The addition of brusatol (a selective inhibitor of Nrf2) or Nrf2 siRNA significantly abolished the inhibitory effect of momordicine I on fibroblast activation. Our findings revealed that the antifibrotic effect of momordicine I was mediated, at least partially, by the inhibition of the TGF-β1/Smad pathway, fibroblast proliferation, and collagen synthesis through Nrf2 activation. Thus, this work provides crucial insights into the molecular pathways for the clinical application of momordicine I for treating diabetes-associated cardiac fibrosis.

Specific data regarding the full range of stroke outcomes among patients with rheumatoid arthritis (RA) are lacking. This study aimed to investigate outcomes in RA patients hospitalized for a stroke. The study retrieved data from the Taiwan Longitudinal Health Insurance Database 2005. We identified 26,336 patients who were hospitalized for stroke treatment. Of these patients, 736 patients with a prior diagnosis of RA before the index hospitalization were selected as the study group. We selected 2208 age–sex-matched patients without RA as the comparison group. We performed conditional logistic regressions to calculate odds ratios (ORs) for in-hospital mortality and secondary diagnoses of pneumonia, urinary tract infections (UTIs), peptic ulcers, acute respiratory failure, and the use of mechanical ventilation to compare RA patients and comparison patients. We also compared the length of stay (LOS) and hospitalization costs between patients with RA and comparison patients. We found that RA patients had a significantly increased risk of peptic ulcer during the stroke hospitalization (OR = 1.52, 95% CI = 1.05–2.20). However, there were no significant differences between patients with RA and comparison patients in terms of in-hospital mortality, pneumonia, UTIs, acute respiratory failure, or the use of mechanical ventilation. Furthermore, the LOS of stroke hospitalization did not differ between the two groups. We concluded that RA patients hospitalized for a stroke do not have a significantly different risk of in-hospital mortality, pneumonia, UTIs, and mechanical ventilator use, but they have a higher risk of peptic ulcers. Additionally, among patients with a subarachnoid/intracerebral hemorrhagic stroke, RA patients were more likely to have received mechanical ventilation than comparison patients (adjusted OR = 1.89, 95% CI = 1.14–3.15).

PURPOSE: Chronic obstructive pulmonary disease (COPD) is associated with an increased cancer risk. We evaluated the chemopreventive effect of statins against all cancers in COPD patients and identified the statin with the strongest chemopreventive effect. PATIENTS AND METHODS: All patients diagnosed with COPD at health care facilities in Taiwan (n = 116,017) from January 1, 2001, to December 31, 2012, were recruited. Each patient was followed to assess the following protective and risk factors for all cancers: age; sex; comorbidities (diabetes, hypertension, dyslipidemia) and the Charlson comorbidity index [CCI]); urbanization level; monthly income; and nonstatin drug use. The index date of statins use was the date of COPD confirmation. Propensity scores (PSs) were derived using a logistic regression model to estimate the effect of statins by considering the covariates predicting intervention (statins) receipt. To examine the dose-response relationship, we categorized statin use into four groups in each cohort (365 cumulative defined daily dose). RESULTS: After PS adjustment for age, sex, CCI, diabetes, hypertension, dyslipidemia, urbanization level, and monthly income, we analyzed the all-cancer risk. The adjusted hazard ratios (aHRs) for the all-cancer risk were lower among statin users than among statin nonusers (aHR = 0.46, 95% confidence interval: 0.43 to 0.50). The aHRs for the all-cancer risk were lower among patients using rosuvastatin, simvastatin, atorvastatin, pravastatin, and fluvastatin than among statin nonusers (aHRs = 0.42, 0.55, 0.59, 0.66, and 0.78, respectively). Sensitivity analysis indicated that statins dose-dependently reduced the all-cancer risk. CONCLUSION: Statins dose-dependently exert a significant chemopreventive effect against various cancers in COPD patients. In particular, rosuvastatin has the strongest chemopreventive effect.

Background In this study, we evaluated the effects of various medications on the patency of vascular access (VA) for hemodialysis. Methods We analyzed data from the Longitudinal Health Insurance Database of Taiwan. We adopted a case–control study design within a cohort of patients who had received regular hemodialysis between 2002 and 2012; 34,354 patients with first VA failure were identified, and the duration from VA creation date to the first VA failure date was calculated. We then classified these patients into two groups, namely arteriovenous fistula (AVF, n = 25,933) and arteriovenous graft (AVG, n = 8,421). Each group was further divided into two subgroups, namely short-term (

Moderate coffee consumption is inversely associated with cardiovascular disease mortality; however, mechanisms underlying this causal effect remain unclear. Cafestol, a diterpene found in coffee, has various properties, including an anti-inflammatory property. This study investigated the effect of cafestol on cyclic-strain-induced inflammatory molecule secretion in vascular endothelial cells. Cells were cultured under static or cyclic strain conditions, and the secretion of inflammatory molecules was determined using enzyme-linked immunosorbent assay. The effects of cafestol on mitogen-activated protein kinases (MAPK), heme oxygenase-1 (HO-1), and sirtuin 1 (Sirt1) signaling pathways were examined using Western blotting and specific inhibitors. Cafestol attenuated cyclic-strain-stimulated intercellular adhesion molecule-1 (ICAM-1), monocyte chemoattractant protein- (MCP-) 1, and interleukin- (IL-) 8 secretion. Cafestol inhibited the cyclic-strain-induced phosphorylation of extracellular signal-regulated kinase and p38 MAPK. By contrast, cafestol upregulated cyclic-strain-induced HO-1 and Sirt1 expression. The addition of zinc protoporphyrin IX, sirtinol, or Sirt1 silencing (transfected with Sirt1 siRNA) significantly attenuated cafestol-mediated modulatory effects on cyclic-strain-stimulated ICAM-1, MCP-1, and IL-8 secretion. This is the first study to report that cafestol inhibited cyclic-strain-induced inflammatory molecule secretion, possibly through the activation of HO-1 and Sirt1 in endothelial cells. The results provide valuable insights into molecular pathways that may contribute to the effects of cafestol.

Cafestol, a diterpene molecule found in the berries of Coffea arabica L. (Rubiaceae), has been shown to exercise anti-angiogenic and anti-tumorigenic effects. However, cafestol's cellular mechanism has yet to be fully investigated. We previously demonstrated that urotensin II enhanced interleukin-8 secretion by endothelial cells, thereby increasing endothelial cell proliferation. Urotensin II may also participate in angiogenesis and tumor infiltration by macrophages. However, the effects of cafestol on urotensin II-induced interleukin-8 expression and cellular proliferation have not been determined. Here, we showed that pretreatment with cafestol inhibited urotensin II-stimulated endothelial cell proliferation. Further experiments demonstrated that cafestol increased translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and expression of enhanced heme oxygenase-1. Moreover, cafestol inhibited expression of urotensin II-induced interleukin-8. Cafestol's inhibitory effects on interleukin-8 expression and cellular proliferation induced by urotensin II were significantly abrogated by heme oxygenase-1 silencing, suggesting it may be involved in mediating the effects of cafestol. This study reports that cafestol inhibits urotensin II-induced interleukin-8 expression and cell proliferation via Nrf2/heme oxygenase-1-dependent mechanism in endothelial cells. These findings provide novel insight into the signaling pathways that may be important in mediating the effects of cafestol.

Nicorandil is an adenosine triphosphate-sensitive potassium channel opener with additional antioxidant properties. Doxorubicin (DOX) is an anticancer drug that exerts oxidation-mediated adverse cardiovascular effects. This study examined the effects of nicorandil on DOX-induced cytotoxicity in human umbilical vein endothelial cells (HUVECs) and underlying intracellular signaling mechanisms. Cultured HUVECs were pretreated with nicorandil (0.1, 0.3, 1, 3, and 10 μM) for 12 h and then treated with DOX (1 μM) for 24 h. Cell viability and cytotoxicity were measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and lactate dehydrogenase assays, respectively. Cell apoptosis was examined using a caspase-3 activity assay, and DNA fragmentation was detected through TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling) staining. Western blot analysis was conducted to determine the related protein expression. DOX markedly increased reactive oxygen species production, p53 expression, caspase-3 activity, cleaved caspase-3 levels, and TUNEL-positive cell numbers but reduced Bcl-2 expression and intracellular antioxidant enzyme levels; these effects were effectively antagonized through nicorandil (3 μM, 12 h) pretreatment, which resulted in HUVECs being protected from DOX-induced apoptosis. Activating transcription factor 3 (ATF3), a stress-induced transcription factor, was induced by nicorandil (3 μM). Furthermore, nicorandil (3 μM) enhanced nuclear factor erythroid 2–related factor 2 (Nrf2) translocation and heme oxygenase-1 (HO-1) expression. ATF3 short interfering RNA significantly attenuated nicorandil-mediated Nrf2 translocation, HO-1 expression, and inhibitory effects on DOX-stimulated reactive oxygen species production and cell apoptosis. In summary, nicorandil may protect HUVECs from DOX-induced apoptosis, in part through ATF3-mediated Nrf2/HO-1 signaling pathways, which potentially protect the vessels from severe DOX toxicity.

The authors of the published version of this article incorrectly presented the affiliation of Li-Chin Sung. The revised affiliation is now presented correctly in this article.

This study investigated how lycopene affected urotensin-II- (U-II-) induced cardiomyocyte hypertrophy and the possible implicated mechanisms. Neonatal rat cardiomyocytes were exposed to U-II (1 nM) either exclusively or following 6 h of lycopene pretreatment (1–10 μM). The lycopene (3–10 μM) pretreatment significantly inhibited the U-II-induced cardiomyocyte hypertrophy, decreased the production of U-II-induced reactive oxygen species (ROS), and reduced the level of NAD(P)H oxidase-4 expression. Lycopene further inhibited the U-II-induced phosphorylation of the redox-sensitive extracellular signal-regulated kinases. Moreover, lycopene treatment prevented the increase in the phosphorylation of serine-threonine kinase Akt and glycogen synthase kinase-3beta (GSK-3β) caused by U-II without affecting the protein levels of the phosphatase and tensin homolog deleted on chromosome 10 (PTEN). However, lycopene increased the PTEN activity level, suggesting that lycopene prevents ROS-induced PTEN inactivation. These findings imply that lycopene yields antihypertrophic effects that can prevent the activation of the Akt/GSK-3βhypertrophic pathway by modulating PTEN inactivation through U-II treatment. Thus, the data indicate that lycopene prevented U-II-induced cardiomyocyte hypertrophy through a mechanism involving the inhibition of redox signaling. These findings provide novel data regarding the molecular mechanisms by which lycopene regulates cardiomyocyte hypertrophy.

Background Vaccination against influenza may decrease the risk of an acute cardiovascular event in the elderly. The purpose of this study was to test the hypothesis that influenza vaccination could reduce hospitalizations for heart failure (HF) in patients with chronic obstructive pulmonary disease (COPD). Methods Using Taiwan National Health Insurance Research Dataset (NHIRD) 2000 to 2007, this cohort study comprised patients with a recorded diagnosis of COPD (n = 25,609) between January 1, 2000 and December 31, 2007. Each patient was followed up until the end of 2007. Cox proportional hazard regression analysis was used to evaluate the HF-free survival rates after adjusting for known confounding factors. Results We found that patients with COPD but no history of a cardiovascular event had a lower risk of hospitalization for HF after receiving influenza vaccination. After adjusting for potential confounders, there was a possible decrease in HF admission for the vaccinated group [hazard ratio (HR), 0.44, 95% confidence interval (CI), 0.35–0.55]. When stratified in terms of the patients' ages, the adjusted HR for hospitalization due to HF was 0.36 (95% CI, 0.28–0.46) for vaccinated patients over 64 years of age; however, the adjusted HR for HF in patients under 55 years of age who had received vaccination was not significant. Conclusion Our data show that there was a lower rate of hospitalization from HF in patients with COPD receiving influenza vaccination, but only in patients older than 65 years.

Background Carbon monoxide (CO) poisoning may cause toxicity to the cardiovascular system. However, the association between CO poisoning and the risk of major adverse cardiovascular events (MACE) remains unestablished. We investigated the incidence of MACE after CO poisoning in Taiwan and evaluated whether CO-poisoned individuals had a higher risk of MACE than did the general population. Methods Using Taiwan's National Health Insurance Research Database (NHIRD) during 2005-2013, a nationwide population-based cohort study was conducted among patients who experienced CO poisoning between 2005 and 2013. CO poisoning was defined according to the International Classification of Diseases, Ninth Revision, Clinical Modification codes. The study cohort comprised patients with CO poisoning between 2005 and 2010 (N = 13,939). Each patient was matched according to age, sex and index date with four randomly selected controls from the comparison cohort (N = 55,756). All patients were followed from the study date until MACE development, death, or the end of 2013. The hazard ratios for MACE were compared between the two cohorts by using Cox proportional hazards regressions analyses. Results Incident cases of MACE were identified from the NHIRD. After adjustment for potential confounders, the study cohort was independently associated with a higher MACE risk (adjusted hazard ratio, 2.00; 95% confidence interval, 1.83-2.18). Conclusion This population-based cohort study indicated that patients with CO poisoning have a higher risk of MACE than do individuals without CO poisoning.