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Competing Interests: Funding Support and Author Disclosures The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Background: This study aimed to evaluate the performance of a modified U.S. (MUS) model for risk prediction of cardiovascular (CV) events in Asian patients and compare it to European and Japanese models., Methods: The MUS model, based on the US ACC/AHA 2018 lipid treatment guideline, was employed to stratify patients under primary or secondary prevention. Two multi-center prospective observational registry cohorts, T-SPARCLE and T-PPARCLE, were used to validate the scoring system, and the primary outcome was the time to first occurrence/recurrence of major adverse cardiac events (MACEs). The MUS model's performance was compared to other models from Europe and Japan., Results: A total of 10,733 patients with the mean age of 64.2 (SD: 11.9) and 36.5% female were followed up for a median of 5.4 years. The MUS model was validated, with an AUC score of 0.73 (95% CI 0.68-0.78). The European and Japanese models had AUC scores ranging from 0.6 to 0.7. The MUS model categorized patients into four distinct CV risk groups, with hazard ratios (HRs) as follows: very high- vs. high-risk group (HR = 1.91, 95% CI 1.53-2.39), high- vs. moderate-risk group (HR = 2.08, 95% CI 1.60-2.69), and moderate- vs. low-risk group (HR = 3.14, 95% CI 1.63-6.03). After adjusting for the MUS model, a history of atherosclerotic vascular disease (ASCVD) was not a significant predictor of adverse cardiovascular outcomes within each risk group., Conclusion: The MUS model is an effective tool for risk stratification in Asian patients with and without ASCVD, accurately predicting MACEs and performing comparably or better than other established risk models. Our findings suggest that patient management should focus on background risk factors instead of solely on primary or secondary prevention., Competing Interests: Conflicts of interest The authors declared no conflicts of interest., (© 2023 The Authors. Published by Elsevier B.V. on behalf of Chang Gung University. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)

Background: Classification of the type of calcaneal fracture on CT images is essential in driving treatment. However, human-based classification can be challenging due to anatomical complexities and CT image constraints. The use of computer-aided classification system in standard practice is additionally hindered by the availability of training images. The aims of this study is to 1) propose a deep learning network combined with data augmentation technique to classify calcaneal fractures on CT images into the Sanders system, and 2) assess the efficiency of such approach with differential training methods., Methods: In this study, the Principle component analysis (PCA) network was selected for the deep learning neural network architecture for its superior performance. CT calcaneal images were processed through PCA filters, binary hashing, and a block-wise histogram. The Augmentor pipeline including rotation, distortion, and flips was applied to generate artificial calcaneus fractured images. Two types of training approaches and five data sample sizes were investigated to evaluate the performance of the proposed system with and without data augmentation., Results: Compared to the original performance, use of augmented images during training improved network performance accuracy by almost twofold in classifying Sanders fracture types for all dataset sizes. A fivefold increase in the number of augmented training images improved network classification accuracy by 35%. The proposed deep CNN model achieved 72% accuracy in classifying CT calcaneal images into the four Sanders categories when trained with sufficient augmented artificial images., Conclusion: The proposed deep-learning algorithm coupled with data augmentation provides a feasible and efficient approach to the use of computer-aided system in assisting physicians in evaluating calcaneal fracture types., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Patients with chronic kidney diseases have multiple cellular dysfunctions leading to increased atherosclerosis, impaired immunity, and disturbed metabolism. However, it is unclear what is the fundamental signaling served as a marker or as a mediator for the dysregulated function in their leukocytes or tissues. Here we hypothesized that the N 6 -Methyladenosine (m 6 A) modification of the RNA in the leukocytes is responsible for the cellular dysfunction in chronic kidney diseases. Patients with chronic kidney diseases had significantly less m 6 A abundances in leukocytes and elevated RNA demethylase FTO proteins. The uremic toxin, indoxyl sulfate, activated the autophagy flux through modulation of FTO and m 6 A modifications in RNA. Notably, knockdown of FTO or inhibit the m 6 A by 3-deazaadenosine blocks the effects of indoxyl sulfate on autophagy activation in cells. These findings provide new insights into the mechanisms underlying chronic kidney disease-associated cellular dysfunction. Targeting RNA m 6 A modification may be a novel strategy for the treatment of chronic kidney diseases and autophagy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: The FTO (fat mass- and obesity-associated) gene variant is an established obesity-susceptibility locus. FTO protein is a nucleic acid demethylase and FTO genetic variants form long-range functional connections with IRX3, which regulates fat mass and metabolism in humans. From our previous results, we found FTO regulates the metabolism of triglyceride in adipocytes through demethylating Angptl4 (angiopoietin-like protein 4) mRNA in mice. We hypothesized that the FTO genetic variants regulate ANGPTL4 abundances in human adipose tissues and affect the outcome after bariatric surgery., Methods and Results: We recruited 188 obesity subjects with body mass indices (BMI)>35kg/m 2 and 102 non-obese subjects with BMI<30kg/m 2 from the OCEAN registry between 2011 and 2014. The distribution of FTO variants rs9939609 among participates was 73.79% TT, 23.79% AT, and 2.41% AA. The subjects with FTO variants AA or AT were correlated with higher BMI than those with FTO variants TT. The serum ANGPTL4 levels were significantly higher in obese subjects and positively correlated with the presence of FTO AA or AT haplotype. Of these participates, 84 obese subjects underwent bariatric surgery and adipose Angptl4 expressions were analyzed. The adipose Angptl4 mRNA levels and protein abundances were correlated with FTO AA or AT haplotype. The magnitude of excess body weight reduction 2 years after bariatric surgery was correlated with the adipose ANGPTL4 protein levels., Conclusion: Adipose ANGPTL4 abundances were affected by the presence of FTO obesity risk haplotype and correlated with excess weight loss percentage after bariatric surgery. These data signify the critical role of FTO variants and adipose ANGPTL4 in fatty acid metabolism and bariatric outcomes in humans., (Copyright © 2020 Asia Oceania Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.)

Patients with diabetes mellitus have up to a 15% lifetime risk of non-healing and poorly healing wounds. This work develops core-shell nanofibrous bioactive insulin-loaded poly-D-L-lactide-glycolide (PLGA) scaffolds that release insulin in a sustained manner for repairing wounds in diabetic rats. To prepare the biodegradable core-shell nanofibers, PLGA and insulin solutions were fed into two capillary tubes of different sizes that were coaxially electrospun using two independent pumps. The scaffolds sustainably released insulin for four weeks. The hydrophilicity and water-containing capacity of core-shell nanofibrous insulin/PLGA scaffolds significantly exceeded those of blended nanofibrous scaffolds. The nanofibrous core-shell insulin-loaded scaffold reduced the amount of type I collagen in vitro, increased the transforming growth factor-beta content in vivo, and promoted diabetic would repair. The core-shell insulin-loaded nanofibrous scaffolds prolong the release of insulin and promote diabetic wound healing., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: No randomized controlled trials evaluating metformin therapy efficacy in patients with type 2 diabetes mellitus (DM) and acute coronary syndrome (ACS) have been reported. We aimed to examine the mortality benefit of metformin therapy in patients with type 2 DM and ACS, compared with non-metformin anti-diabetes agents users., Methods: Data were extracted from the prospective nationwide ACS-DM Taiwan Society of Cardiology registry. Propensity score (PS) matching on baseline characteristics and treatment measures was performed for metformin versus non-metformin users. The Cox proportional hazards model was used to compare mortality outcomes among the PS-matched cohort as the primary analysis. The Cox proportional hazards models adjusting for all pre-determined covariates and quintiles of the PS among the overall population were performed as the secondary analyses., Results: Of 1157 patients with type 2 DM and ACS receiving anti-diabetes agents, 78 patients (6.7%) died over the 2-year follow-up period. After PS matching, 318 metformin users were matched with 318 non-metformin users. Metformin users had a lower all-cause mortality rate (adjusted hazard ratio [aHR] 0.50, 95% confidence interval [CI] 0.26-0.95) in the primary analysis. The survival benefit of metformin therapy was consistent in the secondary analyses (aHR 0.30, 95% CI 0.17-0.54 while adjusting for all pre-determined covariates, and aHR 0.34, 95% CI 0.19-0.59 while adjusting for quintiles of the PS)., Conclusions: Among patients with type 2 DM and ACS, metformin was associated with lower all-cause mortality. However, a detrimental effect of any of the comparators could not be excluded., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Angina pectoris (AP) is one of common symptoms of heart disease. The prevalence of AP varies by genders, age and ethnics. This study aimed to estimate the AP prevalence in adults and its change between surveys., Methods: Data was derived from the Nutrition and Health Survey in Taiwan (NAHSIT) between 1993 and 1996, and between 2005 and 2008. Participants aged ≥19 years old and grouped according to sex and age range (19-44.9, 45-64.9, and ≥65 years). The national weight prevalence rates in three types of AP (possible, definite, and confirmed) were estimated and we also estimated its change between surveys., Results: A total of 5031(1993-1996) and 4686 (2005-2008) adults were enrolled for this study. The aged-adjusted prevalence of possible, definite, and confirmed AP was 9.2%, 5.6%, and 2.1%, respectively, in 1993-1996, and 4.7%, 3.5%, and 1.1%, respectively, in 2005-2008. The age-adjusted prevalence of definite AP significantly declined from 5.6 (1993-1996) to 3.5 (2005-2008). Women had greater decline in the prevalence for possible (5.8% vs. 3.2%), definite (2.9% vs. 1.3%) and confirmed (1.6% vs. 0.5%) AP than men in both surveys. All AP prevalence rates increased by age in men in both surveys, however, the positive association between AP prevalence and age groups among women only was in 1993-1996., Conclusions: The AP prevalence significantly declined from 1993 to 1996 to 2005-2008. The AP prevalence in women was higher. The prevalence increased with age in men, but not in women. Continuous monitoring of AP prevalence is recommended to better understand the disease burden., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Irisin is an exercise-related myokine. The abundance of irisin is associated with many diseases, such as myocardial infarction, chronic kidney disease, metabolic syndrome, obesity, and diabetes mellitus. In cardiomyocytes, irisin modulates the mitochondrial thermogenesis, regulates ischemic responses, and affects calcium signaling. Previous studies suggested that irisin increases cardiomyoblast mitochondrial functions and protects ischemic and reperfusion injury in ex vivo murine heart. In human, clinical studies have shown that acute myocardial infarction patients with more elevated serum irisin abundances are associated with increased major adverse cardiovascular events. However, the mechanisms responsible for this discrepancy between in myocardial infarction patients and ex vivo murine heart is unclear. Based on the clinical observations, we hypothesized that excessive irisin might lead to mitochondrial dysfunctions and cardiomyocyte damages. Our data showed that overexpression of irisin in mice with the adenovirus resulted in enhanced mitochondrial respiration with a higher oxygen consumption rate. Enhanced irisin expression in heart and irisin treatment in cardiomyocytes increased reactive oxygen species production. Furthermore, irisin treatment in cardiomyocytes enhanced the apoptosis and the cleaved caspase 9 levels in hypoxic condition. Pathway analysis in the murine heart with the overexpression of irisin showed that angiopoietin-Tie2, IL-8, IL-13, TGF-β, and thrombopoietin signaling were affected by irisin. Collectively, these results supported that excessive irisin causes mitochondrial overdrive with a higher reactive oxygen species production, which results in increased apoptosis of cardiomyocytes in a hypoxic environment., (Copyright © 2018 Elsevier Inc. All rights reserved.)

A novel bifurcation stent coated with bioabsorbable nanofibers that deliver the extended and controlled release of rosuvastatin and paclitaxel was developed. Bioabsorbable bifurcation stents, consisting of a double-slit tubular main body and two spiral branches, were manufactured. Bi-layered poly (lactic-co-glycolic acid) nanofibers that contained rosuvastatin and paclitaxel were used for treating the stents. Various properties of the fabricated stents, including compression strengths, collapse pressure, water contact angle and flow properties within a circulation model, were quantified. In vitro nanofibrous elution chromatography assays from the drug-loading bifurcation stents were carried out for the release patterns of pharmaceuticals. The effectiveness of eluted rosuvastatin and paclitaxel in inhibiting the adhesion of platelets as well as the proliferation of smooth muscle cells (SMCs) were studied, respectively. The experimental results suggest that bioabsorbable nanofibrous bifurcation stents released high concentrations of rosuvastatin and paclitaxel for 27 and 70 days, respectively. The eluted drugs of rosuvastatin and paclitaxel effectively reduced adherent platelets and the proliferation of SMCs. The developed bioabsorbable nanofibrous bifurcation stents herein may provide a promising means of treating cardiovascular bifurcation lesions., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Irisin, a recently identified myokine, regulates mitochondrial function and energy expenditure. The concentration of irisin is significantly altered after ST-elevation myocardial infarction (STEMI). We hypothesized that serum irisin concentration is associated with adverse cardiovascular outcomes after myocardial infarction. Serum irisin concentrations were measured using enzyme-linked immunosorbent assay (ELISA) in 399 patients 28d after the onset of STEMI in a prospective single-center cohort study. We assessed the association between irisin concentrations and adverse cardiovascular events during a 3-year follow-up. The excess risks of cardiovascular mortality, stroke, heart failure, and revascularization were predominantly seen among those with the highest concentrations of irisin, with concentrations higher than 75th percentile of the overall distribution had a ~4-fold increase in risk (hazard ratio=3.96, 95% confidence interval 1.55 to 10.11, P<0.01). Our findings showed that serum concentrations of irisin are elevated in post-STEMI patients with increased risk for adverse cardiovascular events. Novel therapies targeting irisin may represent a new direction in the treatment of STEMI., (Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.)

Background: Data on a large patient population regarding very long-term outcomes after bare metal stent (BMS) implantation in diabetic patients are lacking. The aim of this study was to evaluate the very long-term (8-17 years) clinical and 6-month angiographic outcomes of BMS implantations in patients with and without type 2 diabetes., Methods and Results: A total of 2391 patients (579 with and 1812 without diabetes) who received BMS implantations between November 1995 and May 2004 were enrolled from the Cardiovascular Atherosclerosis and Percutaneous TrAnsluminal INterventions (CAPTAIN) registry into this study. During a mean follow-up period of 152±53months, the diabetic patients had higher rates of all-cause mortality (28% vs. 15%, p<0.001), re-infarction (6% vs. 5%, p=0.284), target lesion revascularization (13% vs. 10%, p=0.049), and a lower cardiovascular event-free survival rate (42% vs. 56%, p<0.001) compared to the patients without diabetes. The diabetic patients also had a higher restenosis rate (26% vs. 18%, p<0.001) at 6-month angiographic follow-up. The multivariate analysis of risk factors for cardiac event-free survival included age (hazard ratio [HR]: 1.011; p=0.001), hypertension (HR: 1.168; p=0.011), diabetes mellitus (HR: 1.353; p<0.001), pre-existing coronary artery disease (HR: 1.341; p<0.001), and left ventricular ejection fraction (LVEF) (HR: 0.992; p=0.002) (Table 7). The Kaplan-Meier analysis showed a significant difference in cardiovascular event-free survival rate between the two groups (p<0.001)., Conclusion: The clinical and angiographic outcomes of diabetic patients with BMS implantations were worse than those of patients without diabetes after a very long-term follow-up period., (Copyright © 2017 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.)

Background: Predictive value of the Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile international normalized ratio, Elderly, Drugs or alcohol use (HAS-BLED) score for clinical outcomes has been investigated in patients with and without atrial fibrillation. Many factors in the HAS-BLED model have been reported to be prognostic predictors in patients with post-myocardial infarction (MI). However, few studies have investigated the predictive value of HAS-BLED score on long-term survival in patients with post-MI., Methods: A total of 617 patients with non-ST elevation MI (NSTEMI) without atrial fibrillation were enrolled. The Thrombolysis In Myocardial Infarction (TIMI), Global Registry of Acute Coronary Events (GRACE), Can Rapid Risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA guidelines (CRUSADE), and HAS-BLED risk scores were calculated for each patient., Results: The C-statistics of TIMI, GRACE, CRUSADE, and HAS-BLED scores for 3-year survival were 0.658, 0.749, 0.756, and 0.765, respectively. For 3-year survival prediction, GRACE, CRUSADE, and HAS-BLED scores, respectively demonstrated superior performance than TIMI score and there was no significant difference between these three scores (GRACE vs. TIMI: z=1.615, p=0.027; CRUSADE vs. TIMI: z=1.371, p=0.043; HAS-BLED vs. TIMI: z=1.899, p=0.014; CRUSADE vs. GRACE: z=0.078, p=0.234; HAS-BLED vs. GRACE: z=0.435, p=0.166; HAS-BLED vs. CRUSADE: z=0.353, p=0.181). Multivariate analysis showed left ventricular ejection fraction <40%, old age, stroke history, bleeding history, and abnormal renal and liver function were independent predictors for 3-year mortality., Conclusions: HAS-BLED scoring system is similar to the GRACE and CRUSADE systems but better than TIMI system to predict long-term survival outcomes in patients with NSTEMI without atrial fibrillation. However, HAS-BLED score is easier to calculate than GRACE and CRUSADE scores., (Copyright © 2016 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Compared to bare metal stent (BMS) implantation, drug-eluting stents (DES) is significantly better in attenuating intimal hyperplasia and reducing the rate of revascularization. However, the requirement of prolonged dual antiplatelet therapy (DAPT) and the economic cost have been the major disadvantages of DES. Studies have shown that the use of DES in small vessels decrease revascularization rate, but the results in large vessels vary. Previous studies have shown that the extent of late loss is unrelated to vessel diameter, and that late loss is easily accommodated in large vessels, thus resulting in decreased clinical benefit of DES in this setting. No definite cut-off point value of the vessel size has yet been demonstrated. Series studies aimed at evaluating the clinical outcomes of DES versus BMS in large vessels, but their results have been controversial. In this review, we evaluate the latest studies on clinical outcomes for different vessel sizes and clinical conditions. Nonetheless, further large clinical trials are warranted to address the clinical results of newer stents in different size vessels, especially in large vessels., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Polymicrobial sepsis is a potentially fatal condition and a significant burden on health care systems. Acute lung injury is the most common complication of sepsis and results in high mortality. However, there has been no recent significant progress in the treatment of sepsis or acute lung injury induced by sepsis. Here we show that mice deficient in the circadian protein CLOCK had better survival than wild-type mice after induction of polymicrobial sepsis by cecal ligation and puncture. Inflammatory cytokine production was attenuated and bacterial clearance was improved in CLOCK-deficient mice. Moreover, acute lung injury after induction of sepsis was significantly decreased in CLOCK-deficient mice. Genome-wide profiling analysis showed that inhibin signaling was reduced in CLOCK-deficient mice. These data establish the importance of circadian CLOCK-inhibin signaling in sepsis, which may have potential therapeutic implications., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: To investigate the cardiovascular (CV) outcomes of drug-eluting stents (DESs) versus bare-metal stents (BMSs) in patients with acute myocardial infarction (AMI) complicated by cardiogenic shock (CS)., Methods: Data from the Taiwan National Health Insurance Research Database was analyzed between January 1, 2007 and December 31, 2011. A total of 3051 AMI patients in CS were selected as the study cohort. Their clinical outcomes were evaluated by comparing 1017 subjects who used DESs to 2034 matched subjects who used BMSs., Results: The risk of the primary composite outcome (i.e., death, myocardial infarction, stroke, and coronary revascularization) was significantly lower in the DES group compared with the BMS group [56.1% vs. 66.2%, hazard ratio (HR), 0.74; 95% CI, 0.67-0.81] with a mean follow-up of 1.35years. The patients who received DESs had a lower risk of coronary revascularization (HR, 0.78; 95% CI, 0.67-0.91) and death (HR, 0.70; 95% CI, 0.62-0.79) than those who used BMSs. However, the risks of myocardial infarction (HR, 0.89; 95% CI, 0.66-1.18), ischemic stroke (HR, 1.02; 95% CI, 0.67-1.53) and major bleeding (HR, 0.80; 95% CI, 0.56-1.14) were similar between the two groups., Conclusions: Among patients with CS complicating AMI, DES implantation significantly reduced the risk of percutaneous coronary revascularization and death compared to BMS implantation., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

The circadian rhythm regulates blood pressure and maintains fluid and electrolyte homeostasis with central and peripheral clock. However, the role of circadian rhythm in the pathogenesis of tubulointerstitial fibrosis remains unclear. Here, we found that the amplitudes of circadian rhythm oscillation in kidneys significantly increased after unilateral ureteral obstruction. In mice that are deficient in the circadian gene Clock, renal fibrosis and renal parenchymal damage were significantly worse after ureteral obstruction. CLOCK-deficient mice showed increased synthesis of collagen, increased oxidative stress, and greater transforming growth factor-β (TGF-β) expression. TGF-β mRNA expression oscillated with the circadian rhythms under the control of CLOCK-BMAL1 heterodimers. The expression of cyclooxygenase 2 was significantly higher in kidneys from CLOCK-deficient mice with ureteral obstruction. Treatment with a cyclooxygenase 2 inhibitor celecoxib significantly improved renal fibrosis in CLOCK-deficient mice. Taken together, these data establish the importance of the circadian rhythm in tubulointerstitial fibrosis and suggest CLOCK/TGF-β signaling as a novel therapeutic target of cyclooxygenase inhibition., (Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Methylation of RNA N(6)-methyladenosine has fundamental cellular functions, including translation regulation, RNA export, and stem cells renewal. However, the regulation of RNA N(6)-methyladenosine methylation is poorly understood. Here, we observed a robust circadian rhythm in N(6)-methyladenosine modifications of RNA. Deficiency of core mammalian clock genes, cryptochromes, decreased the levels of N(6)-methyladenosine in RNA. Cryptochrome1/2 knockout mice had significantly lower N(6)-methyladenosine methylation of RNA and lost the circadian rhythm of N(6)-methyladenosine levels in RNA. Global analysis of the circadian methylomes of N(6)-methyladenosine in RNA revealed that gene transcription, translation regulation, and RNA metabolism were highly correlated with N(6)-methyladenosine oscillation. Our findings extended a fundamental link between the circadian rhythm and N(6)-methyladenosine modification of RNA and suggested that this link is critical in controlling post-transcriptional gene expression and RNA metabolism., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Variations in the human fat mass and obesity-associated gene, which encodes FTO, an 2-oxoglutarate-dependent nucleic acid demethylase, are associated with increased risk of obesity. These FTO variations were recently shown to affect IRX3 and the exact function of FTO is still controversial. Obesity is closely linked to circadian rhythm. To understand the role of FTO in circadian rhythm, we analyzed the circadian rhythm of FTO deficient mice. FTO deficient mice had robust circadian locomotor activity rhythms with prolonged periods. The light-induced phase shifts of circadian rhythms were also significantly affected in FTO deficient mice. Tissue explants of FTO deficient mice maintained robust peripheral rhythms with prolonged period. Overexpress of FTO represses the transcriptional activation by CLOCK and BMAL1. Core clock genes expression of mRNA and protein were also altered in FTO deficient mice. Furthermore, FTO co-immunoprecipitated with CRY1/2 in a circadian manner. These results indicate a fundamental link between the circadian rhythm and FTO and extend the function of FTO to the core clockwork machinery., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: The cardiovascular safety and efficacy of sitagliptin, a dipeptidyl peptidase 4 (DPP-4) inhibitor, in type 2 diabetic patients with chronic kidney disease (CKD) after acute myocardial infarction (AMI) are unclear., Methods: We analyzed data from the Taiwan National Health Insurance Research Database between March 1st, 2009 and December 31st, 2011. A total of 1025 AMI patients with diabetes with chronic kidney disease were selected as the study cohort. The study evaluated the cardiovascular safety and efficacy of sitagliptin by comparing 205 subjects (20%) who use sitagliptin to 820 matched subjects (80%) who do not. The primary outcomes included myocardial infarction, ischemic stroke or cardiovascular death., Results: Primary composite outcomes occurred in 54 patients in the sitagliptin group (26.3%) and in 164 patients in the comparison group (20.0%) (HR, 1.32; 95% CI, 0.97-1.79; P=0.079) during the mean follow-up of 1.02years (SD=0.71years). The sitagliptin group had similar risks of ischemic stroke, all-cause mortality or hospitalization for heart failure (HF) compared to the non-sitagliptin group (P=0.938, 0.523 and 0.795 respectively). However, sitagliptin use was associated with increased risks of recurrent myocardial infarction (HR, 1.73; 95% CI, 1.15-2.58; P=0.008) and percutaneous coronary revascularization (HR, 1.43; 95% CI, 1.04-1.95; P=0.026)., Conclusions: Among type 2 diabetic patients with CKD after AMI, the use of sitagliptin was not associated with an increased risk of cardiovascular death, ischemic stroke or hospitalization for HF but was associated with increased risks of recurrent MI and percutaneous coronary revascularization., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Myofibroblasts have a key role in wound healing by secreting growth factors and chemoattractants to create new substrates and proteins in the extracellular matrix. We have found that galectin-1, a β-galactose-binding lectin involved in many physiological functions, induces myofibroblast activation; however, the mechanism remains unclear. Here, we reveal that galectin-1-null (Lgals1(-/-)) mice exhibited a delayed cutaneous wound healing response. Galectin-1 induced myofibroblast activation, migration, and proliferation by triggering intracellular reactive oxygen species (ROS) production. A ROS-producing protein, NADPH oxidase 4 (NOX4), was upregulated by galectin-1 through the neuropilin-1/Smad3 signaling pathway in myofibroblasts. Subcutaneous injection of galectin-1 into wound areas accelerated the healing of general and pathological (streptozotocin-induced diabetes mellitus) wounds and decreased the mortality of diabetic mice with skin wounds. These findings indicate that galectin-1 is a key regulator of wound repair that has therapeutic potential for pathological or imperfect wound healing.

Circadian clocks are fundamental machinery in organisms ranging from archaea to humans. Disruption of the circadian system is associated with premature aging in mice, but the molecular basis underlying this phenomenon is still unclear. In this study, we found that telomerase activity exhibits endogenous circadian rhythmicity in humans and mice. Human and mouse TERT mRNA expression oscillates with circadian rhythms and are under the control of CLOCK-BMAL1 heterodimers. CLOCK deficiency in mice causes loss of rhythmic telomerase activities, TERT mRNA oscillation, and shortened telomere length. Physicians with regular work schedules have circadian oscillation of telomerase activity while emergency physicians working in shifts lose the circadian rhythms of telomerase activity. These findings identify the circadian rhythm as a mechanism underlying telomere and telomerase activity control that serve as interconnections between circadian systems and aging., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Long-term (>3 years) outcomes of drug-eluting stents (DES) versus bare-metal stents (BMS) in large coronary arteries were not conclusive. In addition, large coronary vessels were defined using a wide size range (≥3.0 mm) in previous studies. The aim of this study was to assess the long-term efficacy of DES versus BMS in subgroups of different vessel sizes., Methods: A total of 1096 patients (1342 lesions) who underwent either DES or BMS implantation in large coronary vessels was followed for a mean duration of 4.5 years. Patients were divided into 4 subgroups by the reference vessel diameters (Q1: 3.0-3.25 mm, Q2: 3.26-3.50 mm, Q3: 3.51-3.75 mm, and Q4: 3.76-4.50 mm). The primary endpoint was major adverse cardiac events (MACE), defined as a composite of cardiac death, myocardial infarction, target vessel revascularization, and stent thrombosis. The propensity score-adjusted Cox regression method was applied., Results: In the 3 subgroups with smaller vessel sizes, the adjusted risk of MACE in DES recipients was reduced by 82% in Q1 (hazard ratio [HR]: 0.18, 95% confidence interval [CI]: 0.09-0.38), 49% in Q2 (HR: 0.51, 95% CI: 0.26-0.98), and 67% in Q3 (HR: 0.33, 95% CI: 0.15-0.73). However, in the largest vessel subgroup (>3.75 mm), all clinical outcomes were not significantly different irrespective of the stent type used., Conclusions: The incidence of MACE in 3.0-3.75 mm vessels was significantly reduced by the use of DES than by the use of BMS during a long-term follow-up. However, DES lost its benefit in >3.75 mm vessels., (© 2013.)

Background: In Taiwan, the prevalence of head and neck cancer is relatively high. Because radiation-associated carotid stenosis is a significant risk factor for stroke, carotid artery stenting (CAS), instead of carotid endarterectomy, is indicated in patients with radiation-associated carotid stenosis. We sought to evaluate the effect of neck radiotherapy (XRT) on the long-term outcome of patients undergoing CAS., Methods: From March 2001 to November 2011, 147 CAS procedures were performed on 129 patients (n = 43 for XRT, n = 86 for non-XRT). Mean follow-up was 42.7 ± 20.5 months (median: 52 months; range: 1-60 months). Duplex velocity criterion for > 50% restenosis after CAS was defined as peak systolic velocity > 175 cm/s. Endpoints included 5-year freedom from mortality, ipsilateral recurrent stroke, and major adverse cardiovascular events (MACE)., Results: The mean age of XRT patients was significantly lesser than that of non-XRT patients (61 ± 8 vs. 71 ± 8, p < 0.001). There was significantly less coronary artery disease and other cardiovascular co-morbidities in XRT patients. No significant differences were noted in the composite 30-day ipsilateral stroke/myocardial infarction/mortality (XRT: 8.6% vs. non-XRT: 6%, p > 0.05) and 5-year freedom from mortality, ipsilateral recurrent stroke, and MACE (p > 0.05) between the two groups. Intra-stent carotid restenosis > 50% was significantly higher in the XRT group on follow-up., Conclusion: Long-term outcomes of CAS for radiation-associated stenosis were not altered by a history of neck XRT, except for asymptomatic carotid restenosis.

Introduction: The numbers of vessels obstructed in patients with coronary artery disease (CAD) is an important prognostic factor. Pulse wave velocity (PWV), ankle-brachial index (ABI) and the estimated glomerular filtration rate (eGFR) are associated with increasing CAD risks; however, the association between the numbers of vessels obstructed and PWV, ABI and eGFR is not clear., Methods: PWV, ABI and eGFR of 58 patients underwent coronary angiography for angina pectoris and acute coronary syndrome were measured. The variables that may be related to the number of vessels involved were analyzed using univariate linear regression followed by stepwise multivariate linear regression to determine the best-fit model., Results: The average PWV, ABI and eGFR were 1523 ± 281 cm/sec, 1.16 ± 0.06 and 76.0 ± 16.7 mL/min/1.73 m(2) for patients with no CAD; 1496 ± 230 cm/sec, 1.14 ± 0.09 and 82.3 ± 12.4 mL/min/1.73 m(2) for 1-vessel CAD; 1733 ± 298 cm/sec, 1.07 ± 0.17 and 63.0 ± 26.3 mL/min/1.73 m(2) for 2-vessel CAD and 1996 ± 664 cm/sec, 0.99 ± 0.19 and 56.2 ± 27.3 mL/min/1.73 m(2) for 3-vessel CAD. Age, diabetes, hypertension, pulse pressure, serum creatinine, eGFR, ABI and PWV were correlated with the numbers of vessel obstructed in univariate regression. In stepwise multivariate linear regression, diabetes, PWV and ABI was independently linked to the numbers of vessels obstructed (P=0.021, 0.004 and 0.025)., Conclusion: Noninvasive indexes for atherosclerotic vascular disease including PWV and ABI are linked to the number of vessels obstructed in patients with CAD.

Background: Cardiac tamponade associated with hypothyroidism has been reported, but few studies address the clinical features. This study aims to identify the patient characteristics and to propose a reasonable clinical approach for hypothyroid cardiac tamponade., Method: Patients admitted to Chang Gung Memorial Hospital between September 1998 and September 2008 with pericardial effusion secondary to hypothyroidism were enrolled. Cases involving cardiac tamponade were investigated. The clinical data, electrocardiography, echocardiography and aspirated fluid were examined., Results: Thirty-six patients with moderate or large amount of pericardial effusion as a result of hypothyroidism were examined. Eight patients (22.2%) with both clinical and echocardiographic signs of tamponade were identified and were treated by pericardiocentesis or creation of pleural-pericardial window. These patients were characterized with normal sinus rhythm (80.75 ± 13.45 beats/min), low voltage over limb leads (6 of 8, 75.0%), flat T wave (6 of 8, 75.0%) and clear yellowish pericardial fluid (7 of 8, 87.5%). Their heart rates were significantly lower (80.75 ± 13.45 beats/min versus 112.75 ± 12.87 beats/min, P < 0.01) than those of patients with cardiac tamponade from malignancy, autoimmune disease, tuberculosis and iatrogenic insult. Their interventricular septa were also significantly thicker (15.71 ± 6.70 mm versus 11.70 ± 2.11 mm, P = 0.02). Ten patients (27.8%) had echocardiographic signs of tamponade without paradoxical pulse and were successfully treated with thyroxine without pericardial drainage., Conclusion: For patients diagnosed with cardiac tamponade without sinus tachycardia, hypothyroidism should be highly suspected. Although emergent pericardiocentesis should be performed in clinical cardiac tamponade, patients with echocardiographic tamponade signs without a paradoxical pulse should be treated with thyroxine initially.

Background: Coronary artery disease (CAD) is the most important cause of mortality and morbidity in patients who have undergone carotid artery endovascular or surgical intervention. Metabolic syndrome (MetS) and hyperhomocysteinemia (HHCY) have been reported to be associated with CAD. However, no study has investigated the association between MetS or HHCY and the severity of CAD in patients with carotid stenosis., Methods: Total of 148 consecutive patients with at least 1 side of the extracranial internal carotid artery were enrolled. Further, on the basis of the results of coronary angiography, the patients were divided into the CAD group (n = 85) and the non-CAD group (n = 63)., Results: Multiple regression analysis revealed that CAD was independently associated with HHCY (odds ratio: 4.07; 95% confidence interval: 1.93-8.57; P < 0.0001) and MetS (odds ratio: 3.38; 95% confidence interval: 1.56-7.29; P = 0.002). Furthermore, multivariate stepwise linear regression revealed that the MetS score and total plasma homocysteine level were significantly correlated with affected vessel number in CAD and the extent of coronary atherosclerosis., Conclusions: MetS and HHCY can predict the presence of CAD in patients with carotid stenosis. Furthermore, the MetS score and total plasma homocysteine level are significantly associated with the extent of coronary atherosclerosis.

Background: This study assesses the prognostic values of left ventricular (LV) filling patterns, as determined by tissue Doppler imaging (TDI), on cardiac events in patients with LV systolic dysfunction. Normally observed in patients with an advanced form of cardiac disease, an abnormal diastolic pattern by Doppler echocardiography reflects a poor prognosis. Recent studies using TDI have significantly contributed to efforts to evaluate diastolic function and demonstrate the prognostic importance of TDI-derived indices of the LV function., Methods and Results: One hundred seventy-three consecutive adult patients, mean (standard deviation) age of 62.4 (14.3), with a diagnosis of dilated cardiomyopathy and LV ejection fraction <45% were enrolled. During a follow-up period of 321 +/- 100 days, 9 patients expired from cardiac complications and 29 underwent readmission for decompensated heart failure. In multivariate analysis, only the mean value of early (Em) and late (Am) diastolic velocities ratio assessed by TDI, and LV end-diastolic pressure were found to be independent predictors of a cardiac event. The optimal cutoff value for forecasting cardiac event was Em/Am > or = 0.74 with an area under the receiver operating characteristic curve of 0.82; sensitivity and specificity were 84% and 76%, respectively (P < 0.001; standard error = 0.046)., Conclusions: Em/Am ratio is the important predictor of cardiac event, which allows normalization for other risk factors in patients with a clinical diagnosis of chronic heart failure with LV dysfunction comparing with conventional Doppler echocardiography.

Aims: To evaluate the utility of multidetector computed tomography (MCT) in assessing tumor size and nodal status in patients with advanced breast cancers before and after the neoadjuvant chemotherapy., Methods: Twenty-eight proven locally advanced breast cancer patients with 30 tumors were enrolled in this study. MCT was used to assess tumor size and axillary lymph nodes before and after the neoadjuvant chemotherapy. The correlation between tumor size on MCT and gross tumor size was tested., Results: The MCT measurements documented complete response in 3, partial response in 18, non-response in 8 and progressed in 1. The mean tumor diameters on pathology and post-chemotherapy MCT were 3.6cm (S.D.=+/-2.9cm) and 3.1cm (S.D.=+/-2.6cm), respectively. The Pearson correlation coefficient was 0.76 (p<0.001). The sensitivity, specificity, positive predictive valve, negative predictive valve and accuracy of MCT in diagnosing the axillary lymph node metastases after pre-operative neoadjuvant chemotherapy were counted, respectively, to 72%, 40%, 85.7%, 22.2% and 66.7%. All the 5 downstaged axillary nodal statuses from node-positive to node-negative on MCT had micrometastases., Conclusion: MCT can be used to evaluate tumor size and nodal status in patients with advanced breast cancer. As there is a baseline MCT before chemotherapy for comparison, we are potentially aware of the possibility of false negative nodal micrometastases on the post-chemotherapy MCT.

Background: This study assesses hemodynamic and angiographic changes in patients with a patent infarct-related artery (IRA) after acute myocardial infarction (AMI)., Methods: One hundred and seventy-seven patients with first AMI, who received a predischarge stenting to the IRA and sustained a patent IRA over 3 years, were stratified into 3 groups according to the baseline left ventricular ejection fraction (LVEF): group A included 63 patients with a LVEF of >49%, group B 73 patients with a LVEF of 40%-49%, and group C 41 patients with a LVEF of <40%. The hemodynamic and angiographic parameters were compared at baseline, 6-month and 3-year follow-up., Results: The LV end-diastolic volume index increased 1, 4 and 4 ml/m(2) at 6 months and 4, 5 and 10 ml/m(2) at 3 years, respectively in group A, B and C. The LVEF increased 4%, 7% and 12% at 6 months and 6%, 8% and 14% at 3 years, respectively in group A, B and C. The stroke volume index increased 3, 7 and 12 ml/m(2) at 6 months and 6, 8 and 15 ml/m(2) at 3 years, respectively in group A, B and C. The LV wall motion score decreased 2, 3 and 3 at 6 months and was unchanged at 3 years, respectively in group A, B and C. The LV end-diastolic pressure decreased 2, 3 and 4 mm Hg, respectively in group A, B and C, at 6-month follow-up and remained stable at 3 years., Conclusions: Long-term beneficial effects in patients receiving a late predischarge intracoronary stenting following first AMI were seen and these may be related to patent IRA. A progressive improvement in left ventricular remodeling occurs in all patients regardless of their initial left ventricular function and the improvement continues for at least 3 years.

Background: Although previous studies have suggested that aortic valve sclerosis (AVS) shares common histologic features with atherosclerosis and is an indicator of significant coronary artery disease (CAD), many patients with aortic valve disease do not have coexisting coronary atherosclerotic disease and vice versa. It is important to find the subjects with AVS who are most likely to have concomitant CAD and require aggressive evaluation., Hypothesis: We hypothesized that the systemic inflammatory marker, high-sensitive C-reactive protein (hs-CRP), may be associated with AVS, and may be helpful before coronary angiography in identifying the presence of concomitant CAD in patients with AVS., Methods: This study included 227 patients with suspected CAD undergoing transthoracic echocardiography and coronary angiography. AVS was defined as a focal area of increased echogenicity and thickening of the aortic valve leaflets without restriction in motion. Data of atherosclerotic risk factors including hs-CRP were collected., Results: Technically satisfactory ultrasound recordings were obtained in 217 subjects (96% of enrolled patients). Patients with AVS were older (65+/-10 vs. 60+/-10 years old; P=0.0004), had higher serum creatinine levels (115.2+/-79.7 vs. 88.6 +/-35.4 micromol/L; P=0.04), and had greater prevalence of obstructive CAD (75% vs. 53%; P=0.001) than those with normal aortic valves. CRP levels were not associated with AVS, and failed to predict concomitant CAD in patients with AVS. Additionally, none of the established risk factors were independent predictors of the presence of CAD in AVS patients., Conclusion: Hs-CRP levels appear to not be associated with AVS, and are of little value in terms of predicting the presence of concurrent CAD before coronary procedure.

Percutaneous transluminal coronary angioplasty in ostial lesions is technically difficult and is associated with a lower procedural success rate, higher complication rate and restenosis rate as compared to nonostial lesions. The safety, feasibility, immediate and 6-month angiographic, and long-term clinical outcomes of stenting in aorto-ostial, left anterior descending artery (LAD)-ostial and nonostial stenoses, were retrospectively compared in 19 patients with 20 aorto-ostial lesions (group A), 97 with 97 LAD-ostial lesions (group B) and 1778 with 2242 nonostial lesions (group C). The major adverse cardiac events during hospitalization were similar among the three groups (p = 0.816). Twelve patients with 12 lesions in group A, 75 with 75 lesions in group B and 1384 with 1749 lesions in group C underwent a 6-month follow-up coronary angiography. There were no differences in acute gain (2.04 +/- 0.46 vs. 2.34 +/- 0.50 vs. 2.39 +/- 0.54 mm, respectively, p = 0.057) and net gain (0.89 +/- 1.02 vs. 1.26 +/- 1.08 vs. 1.34 +/- 0.76 mm, respectively, p = 0.105) among the three groups. Group B had a larger late loss than group A and C (1.15 +/- 1.01 vs. 1.22 +/- 0.76 vs. 1.04 +/- 0.65 mm, respectively, p = 0.048) and group A had a larger loss index than group B and C (0.59 +/- 0.50 vs. 0.52 +/- 0.31 vs. 0.48 +/- 0.29, respectively, p = 0.027). The binary restenosis rate among the three groups was 33%, 29% and 20%, respectively, (p = 0.072). Group B had higher restenotic rate as compared to group C (p = 0.036). During a long-term follow-up period of 42+/-21 months, major adverse cardiac events were similar among the three groups (15.8% vs. 25.8% vs. 20.1%, respectively, p = 0.362), but group B had a higher incidence of recurrent angina as compared to group C (17.5% vs. 10.9%, p = 0.039). The cardiac event-free survival rate, as determined by Kaplan-Meier analysis, was similar among the three groups (56% vs. 57% vs. 67%, respectively, p = 0.149); a borderline significance was noted as compared group B to group C (p = 0.051). In conclusion, stenting in aorto-ostial or LAD-ostial lesions is safe, feasible and has a similar acute result as compared to stenting in nonostial lesions; however, it still has a higher 6-month angiographic restenosis rate. LAD-ostial stenoses may have a less favorable long-term clinical outcome than nonostial stenoses.

Radiofrequency ablation therapy was conducted in 86 consecutive children and young patients with a mean age of 14 +/- 3 years (range = 3-18). Fifty-two patients had Wolff-Parkinson-White syndrome, one had re-entry tachycardia incorporating a nodoventricular fiber, 22 had atrioventricular node re-entry tachycardia, two had atrial tachycardia and nine had idiopathic ventricular tachycardia. Radiofrequency ablation was successful in 50 of the 52 patients (96%) with Wolff-Parkinson-White syndrome and the one with nodoventricular fiber. Radiofrequency modification of the atrioventricular node using the inferior approach was successful in eliminating atrioventricular node re-entry tachycardia in 20 of the 22 patients (91%). Radiofrequency ablation in the two patients with atrial tachycardia was unsuccessful. Of the nine patients with idiopathic ventricular tachycardia, eight from the left ventricle and one from the right ventricular outflow tract, eight were successfully ablated (88%). Follow-up over a period ranging from 1 to 46 months (21 +/- 13) revealed a recurrence of tachycardia in seven patients; a late electrophysiological study in 38 patients revealed the induction of tachycardia in 11 patients (seven with accessory pathway-mediated tachycardia, three with atrioventricular node re-entry tachycardia and one with idiopathic ventricular tachycardia). All 11 patients were successfully ablated by a second trial. In conclusion, radiofrequency ablation therapy is effective and safe in pediatric patients with supraventricular and ventricular tachycardia and should be considered as the therapy of choice in this group of patients.