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Abstract Background Concomitant use of clopidogrel and proton pump inhibitor (PPI) is common, but PPI may reduce the antiplatelet effects of clopidogrel in patients undergoing percutaneous coronary intervention (PCI). We evaluated the impact of PPI use on clinical outcomes in post-PCI patients, by incorporating P2Y12 reaction unit (PRU) and CYP2C19 genotyping results. Methods From a multicenter registry of patients who underwent PCI with drug-eluting stent implantation and received clopidogrel-based dual antiplatelet therapy (DAPT), patients who were prescribed a PPI at the time of PCI (PPI users) were compared to those who were not (non-users). The primary outcome included all-cause death, myocardial infarction, stent thrombosis, or cerebrovascular accident at 12 months. Major bleeding (Bleeding Academic Research Consortium [BARC] types 3–5) and gastrointestinal (GI) bleeding (BARC types 3–5) were important secondary outcomes. The adjusted outcomes were compared using a 1:1 propensity-score (PS) matching and competing risk analysis. Results Of 13,160 patients, 2,235 (17.0%) were prescribed PPI, with an average age of 65.4 years. PPI users had higher on-treatment PRU levels than non-users. After PS matching, the primary outcome occurred in 51 patients who were PPI users (cumulative incidence, 4.7%) and 41 patients who were non-users (cumulative incidence, 3.7%; log-rank p = 0.27). In carriers of both CYP2C19 loss-of-function alleles, PPI use was linked to an increased risk of the primary outcome (hazard ratio, 3.22; 95% confidence interval, 1.18–8.78). The incidence of major bleeding and GI bleeding (BARC types 3–5) was comparable between PPI users and non-users in the PS-matched cohort. Conclusions In post-PCI patients receiving clopidogrel-based DAPT, PPI use was not linked to an increased risk of adverse cardiac and cerebrovascular events, but there was a small but significant increase in on-treatment PRU. Future research using a more individualized approach would further elucidate these interactions and guide evidence-based clinical practices.

Aims: Calcium channel blockers (CCBs) are frequently co-administered with clopidogrel in cardiovascular disease. Although an inhibitory drug interaction exists between them, comprehensive large-scale studies for its validation are lacking. We investigated interactions between CCBs and clopidogrel using a large-scale national registry of patients who underwent percutaneous coronary intervention (PCI). Methods and Results: The Platelet function and genoType-Related long-term Prognosis-Platelet Function Test consortium investigates the association between platelet function test and long-term prognosis during dual antiplatelet therapy including clopidogrel in patients using drug-eluting stents. We compared the ex vivo platelet reactivity using the VerifyNow P2Y12 test and clinical outcomes between CCB users and non-users. Between 2003 and 2018, 11 714 patients were enrolled and categorized into two groups according to CCB usage. A composite endpoint encompassing all-cause mortality, myocardial infarction, stent thrombosis, or stroke was defined as a major adverse cardiac and cerebrovascular event (MACCE). During the 5-year follow-up period, no significant differences were observed in P2Y12 reaction units (215.8 ± 84.7 vs 218.4 ± 76.7, P = .156), MACCEs, major bleeding, or high platelet reactivity rates, even after adjusting for propensity score matching (PSM) and inverse probability of treatment weighting (IPTW). When limited to the high platelet reactivity cohort (≥252 PRU), the results remained consistent for MACCE [PSM-adjusted, HR: 0.923 (0.644-1.323), P -value .663; IPTW-adjusted, HR: 1.300 (0.822-2.056), P -value .262]. Conclusions: CCB and clopidogrel co-administration does not appear to significantly impact clopidogrel responsiveness or clinical outcomes. Despite these promising results, further investigation may be warranted. Clinical trial registration: Platelet Function and genoType-Related Long-term progGosis in DES-treated Patients: A Consortium From Multi-centered Registries [PTRG-DES]; NCT04734028

Abstract This study evaluated the association of atherogenic index of plasma (AIP) with platelet reactivity and clinical outcomes according to acute myocardial infarction (AMI). The composite of 3-year adverse outcomes of all-cause death, myocardial infarction, and cerebrovascular accident was evaluated in 10,735 patients after successful percutaneous coronary intervention with drug-eluting stents. AIP was defined as the base 10 logarithm of the ratio of triglyceride to high-density lipoprotein cholesterol concentration. High platelet reactivity (HPR) was defined as ≥ 252 P2Y12 reactivity unit. An increase of AIP (per-0.1 unit) was related to the decreased risk of HPR [odds ratio (OR) 0.97, 95% confidence interval (CI) 0.96–0.99; P = 0.001] in non-AMI patients, not in AMI patients (OR 0.98, 95% CI 0.96–1.01; P = 0.138). The HPR was associated with the increased risk of composite outcomes in both non-AMI and AMI patients (all-P

Summary: Background: Given the rapidly growing burden of cardiovascular disease (CVD) in Asia, this study forecasts the CVD burden and associated risk factors in Asia from 2025 to 2050. Methods: Data from the Global Burden of Disease 2019 study was used to construct regression models predicting prevalence, mortality, and disability-adjusted life years (DALYs) attributed to CVD and risk factors in Asia in the coming decades. Findings: Between 2025 and 2050, crude cardiovascular mortality is expected to rise 91.2% despite a 23.0% decrease in the age-standardised cardiovascular mortality rate (ASMR). Ischaemic heart disease (115 deaths per 100,000 population) and stroke (63 deaths per 100,000 population) will remain leading drivers of ASMR in 2050. Central Asia will have the highest ASMR (676 deaths per 100,000 population), more than three-fold that of Asia overall (186 deaths per 100,000 population), while high-income Asia sub-regions will incur an ASMR of 22 deaths per 100,000 in 2050. High systolic blood pressure will contribute the highest ASMR throughout Asia (105 deaths per 100,000 population), except in Central Asia where high fasting plasma glucose will dominate (546 deaths per 100,000 population). Interpretation: This forecast forewarns an almost doubling in crude cardiovascular mortality by 2050 in Asia, with marked heterogeneity across sub-regions. Atherosclerotic diseases will continue to dominate, while high systolic blood pressure will be the leading risk factor. Funding: This was supported by the NUHS Seed Fund (NUHSRO/2022/058/RO5+6/Seed-Mar/03), National Medical Research Council Research Training Fellowship (MH 095:003/008-303), National University of Singapore Yong Loo Lin School of Medicine's Junior Academic Fellowship Scheme, NUHS Clinician Scientist Program (NCSP2.0/2024/NUHS/NCWS) and the CArdiovascular DiseasE National Collaborative Enterprise (CADENCE) National Clinical Translational Program (MOH-001277-01).

Abstract Stent thrombosis (ST) is a fatal complication after percutaneous coronary intervention (PCI). The association between P2Y12 reaction unit (PRU) level and stent thrombosis occurrence remains unclear. Based on the multicenter, observational PTRG-DES (Platelet function and genoType-Related long-term proGnosis in DES-treated patients) registry of patients with drug-eluting stents (DES) implantation, a total of 11,714 patients with PRU values were analyzed. We sought to identify the predictors of early stent thrombosis (EST) and compared the primary outcome, a composite of cardiac death, myocardial infarction, and revascularization, between EST and non-EST groups. EST, defined as definite ST within 1 month after index PCI, occurred in 51 patients. PRU values were significantly higher in the EST group (263.5 ± 70.8 vs. 217.5 ± 78.7, p

Background Acute pulmonary thromboembolism (APTE) is often confused with myocardial infarction. Previous studies have shown that patients with APTE exhibit lower initial and peak cardiac troponin I (CTI) levels, but higher D-dimer (DD) levels, than patients with myocardial infarction. The present study aimed to reaffirm the tree model algorithm using an entirely new set of data. Methods We reviewed retrospective clinical and laboratory data from patients who were diagnosed with APTE or non-ST-elevation myocardial infarction (NSTEMI) between 2015 and 2016. Subjects who were not classified with a diagnosis or did not have their CTI or DD levels assessed were excluded. We categorized patients according to the previous algorithm and compared the outcomes with the previous test dataset. Results The analysis involved data from 156 patients with APTE and 363 patients with NSTEMI. In the validation data set, the APTE group showed higher initial DD levels (9.80±10.84 μg/mL) and lower initial CTI levels (0.17±0.54 μg/mL) than the NSTEMI group. The accuracy rate for the test dataset and the validation set were similar. The test set accuracy rate was 91.0%, while the accuracy rate in the validation set improved to 88.6%. Conclusions Patients with APTE exhibited lower initial and peak CTI levels, but higher DD levels than NSTEMI patients. The accuracy rate estimates were similar between the test set obtained from the tree model algorithm and the validation set. The study findings demonstrate that the assessment of cardiac biomarkers can be useful for differentiating between APTE and NSTEMI.

Background Carriers of CYP2C19 loss‐of‐function alleles have increased adverse events after percutaneous coronary intervention, but limited data are available for older patients. We aimed to evaluate the prognostic impact of CYP2C19 genotypes on clinical outcomes in older patients after percutaneous coronary intervention. Methods and Results The study included 1201 older patients (aged ≥75 years) who underwent percutaneous coronary intervention and received clopidogrel‐based dual antiplatelet therapy in South Korea. Patients were grouped on the basis of CYP2C19 genotypes. The primary outcome was 3‐year major adverse cardiac events, defined as a composite of cardiac death, myocardial infarction, and stent thrombosis. Older patients were grouped into 3 groups: normal metabolizer (36.6%), intermediate metabolizer (48.1%), and poor metabolizer (15.2%). The occurrence of the primary outcome was significantly different among the groups (3.1, 7.0, and 6.2% in the normal metabolizer, intermediate metabolizer, and poor metabolizer groups, respectively; P=0.02). The incidence rate of all‐cause death at 3 years was greater in the intermediate metabolizer and poor metabolizer groups (8.1% and 9.2%, respectively) compared with that in the normal metabolizer group (3.5%, P=0.03) without significant differences in major bleeding. In the multivariable analysis, the intermediate metabolizer and poor metabolizer groups were independent predictors of 3‐year clinical outcomes. Conclusions In older patients, the presence of any CYP2C19 loss‐of‐function allele was found to be predictive of a higher incidence of major adverse cardiac events within 3 years following percutaneous coronary intervention. This finding suggests a need for further investigation into an optimal antiplatelet strategy for older patients. Registration URL: https://clinicaltrials.gov. Identifier: NCT04734028.

Background Although age and body mass index (BMI) significantly affect platelet reactivity units and clinical outcomes after percutaneous coronary intervention, there are limited data on the relationship between high on‐treatment platelet reactivity (HPR) and clinical outcomes on age and BMI differences. Thus, we investigated the association of HPR with clinical outcomes according to age and BMI. Methods and Results The study analyzed 11 714 patients who underwent platelet function tests after percutaneous coronary intervention. The primary end point was the occurrence of major adverse cardiac and cerebrovascular events (MACCEs), whereas the secondary end point was major bleeding. HPR was defined as platelet reactivity units ≥252. Patients were categorized by age (22.6 kg/m2). Patients 22.6 kg/m2 had increases in MACCEs (adjusted HR, 1.387 [95% CI, 1.140–1.688]; P=0.001). No differences were shown in major bleeding. Conclusions HPR was linked to an increase in MACCEs or a decrease in major bleeding in patients after percutaneous coronary intervention, depending on age and BMI. This study is the first to observe that clinical outcomes in patients with HPR after percutaneous coronary intervention may vary based on age and BMI. Because the study is observational, the results should be viewed as hypothesis generating and emphasize the need for randomized clinical trials.

Abstract The authors evaluated the efficacy, safety, and characteristics of patients who respond well to standard dose triple combination therapy including chlorthalidone 25 mg with telmisartan 80 mg plus amlodipine 5 mg in hypertensive patients. This is a multicenter, double‐blind, active‐controlled, phase 3, randomized trial. Patients are randomized to triple combination (telmisartan 40 mg/amlodipine 5 mg/chlorthalidone 12.5 mg, TEL/AML/CHTD group) or dual combination (telmisartan 40 mg/amlodipine 5 mg, TEL/AML group) treatment and then dose up titration to TEL 80/AML5/CHTD25mg and TEL80/AML5, respectively. The primary endpoint is the change of mean sitting systolic blood pressure (MSSBP) at week 8. A Target BP achievement rate, a response rate, and the safety endpoints are also evaluated. Total 374 patients (mean age = 60.9 ± 10.7 years, male = 78.3%) were randomized to the study. The baseline MSSBPs/diastolic BPs were 149.9 ± 12.2/88.5 ± 10.4 mm Hg. After 8 weeks treatment, the change of MSSBPs at week 8 are −19.1 ± 14.9 mm Hg (TEL/AML/CHTD) and −11.4 ± 14.7 mm Hg (TEL/AML) (p

Abstract Background Diabetes mellitus (DM) is associated with thrombogenicity, clinically manifested with atherothrombotic events after percutaneous cutaneous intervention (PCI). This study aimed to investigate association between DM status and platelet reactivity, and their prognostic implication in PCI-treated patients. Methods The Platelet function and genoType-Related long-term Prognosis-Platelet Function Test (PTRG-PFT) cohort was established to determine the linkage of platelet function test (PFT) with long-term prognosis during dual antiplatelet therapy including clopidogrel in patients treated with drug-eluting stent (DES). We assessed platelet reactivity using VerifyNow and ‘high platelet reactivity (HPR)’ was defined as ≥ 252 P2Y12 reaction unit (PRU). Major adverse cardiac and cerebrovascular event (MACCE) was a composite of all-cause death, myocardial infarction, stent thrombosis or stroke. Results Between July 2003 and Aug 2018, DES-treated patients with available PFT were enrolled (n = 11,714). Diabetic patients demonstrated significant higher levels of platelet reactivity (DM vs. non-DM: 225.7 ± 77.5 vs. 213.6 ± 79.1 PRU, P

Introduction This study evaluated the efficacy and safety of a single-pill triple-combination of olmesartan/amlodipine/rosuvastatin (Olme/Amlo/Rosu) in comparison with a single-pill dual-combination of olmesartan/amlodipine (Olme/Amlo) in hypertensive patients with low-to-moderate cardiovascular risk. Methods This multicenter, active-control, randomized study included 106 hypertensive patients at low-to-moderate cardiovascular risk who were randomly assigned to receive either Olme/Amlo/Rosu 20/5/5 mg (Treatment 1), Olme/Amlo/Rosu 20/5/10 mg (Treatment 2), or Amlo/Olme 20/5 mg (Control) once daily for 8 weeks. The primary endpoint was the difference of the percent change in low-density lipoprotein cholesterol (LDL-C) level at 8 weeks from baseline in the 3 groups. Results The difference in the least square mean percent change (standard deviation) of LDL-C in the Treatment 1 and 2 groups compared with the Control group at 8 weeks was −32.6 (3.7) % and −45.9 (3.3) %, respectively ( P .05). Conclusion Single-pill triple-combination of olmesartan/amlodipine/rosuvastatin was superior to the single-pill dual-combination of amlodipine/olmesartan in LDLC-lowering effects, with excellent safety profiles and adherence rates, in hypertensive patients at low-to-moderate cardiovascular risk. Trial Registration: CLinicalTrials.gov identifier NCT04120753.

Abstract Background To assess the efficacy and safety of a combination therapy involving fimasartan, amlodipine, and rosuvastatin in patients with essential hypertension and dyslipidemia who fail to respond to fimasartan monotherapy. Methods This phase III, randomized, double-blind, multicenter study was conducted in adults aged 19–70 years. Patients who voluntarily consented were screened for eligibility to enroll in the study. Patients who failed to respond to 4 weeks of fimasartan monotherapy were randomized with a 1:1:1 ratio to the fimasartan 60 mg/amlodipine 10 mg + rosuvastatin 20 mg (FMS/ALD + RSV) as study group, fimasartan 60 mg/amlodipine 10 mg (FMS/ALD) as control 1 group, and fimasartan 60 mg + rosuvastatin 20 mg (FMS + RSV) as control 2 group. The primary efficacy endpoints were the change in the sitting systolic blood pressure and the rate of change in the low-density lipoprotein cholesterol (LDL-C) level from baseline to 8 weeks. The adverse events, adverse drug reactions, physical examination findings, laboratory test results, electrocardiograms, and vital signs were evaluated to assess safety in the study. Results Of 138 randomized patients, 131 were conducted efficacy analysis, and 125 completed the study. For the change in LDL-C and sitting SBP (SiSBP) as primary efficacy assessments, the change in LDL-C at week 8 was significantly reduce in the FMS/ALD + RSV group than in the control 1 group (P

Background Although high platelet reactivity (HPR) on clopidogrel is associated with higher ischemic events and lower bleeding events in patients who have undergone percutaneous coronary intervention with drug‐eluting stents, the differential risk of HPR in East Asian women versus men is unknown. Methods and Results We compared 11 714 patients enrolled in the PTRG‐DES (Platelet Function and Genotype‐Related Long‐Term Prognosis in Drug‐Eluting Stent–Treated Patients With Coronary Artery Disease) Consortium according to sex and the presence/absence of HPR on clopidogrel (defined as ≥252 P2Y12 reactivity units). The primary study end point was major adverse cardiac and cerebrovascular events (MACCEs; comprising all‐cause mortality, myocardial infarction, cerebrovascular accident, and stent thrombosis). HPR was more common in women (46.7%) than in men (28.1%). In propensity‐adjusted models, HPR was an independent predictor of MACCEs (men with HPR: hazard ratio [HR], 1.60 [95% CI, 1.20–2.12]; women with HPR: HR, 0.99 [95% CI, 0.69–1.42]) and all‐cause mortality (men with HPR: HR, 1.61 [95% CI, 1.07–2.44]; women with HPR: HR, 0.92 [95% CI, 0.57–1.50]) in men, although those associations were insignificant among women. In addition, a significant interaction between sex was noted in the associations between HPR and MACCE (Pinteraction=0.013) or all‐cause mortality (Pinteraction=0.025). Conclusions In this study, HPR was a differential risk factor for 1‐year MACCEs and all‐cause mortality in women and men. And it was an independent predictor of 1‐year MACCEs and all‐cause mortality in men but not in women. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT04734028. Registered July 9, 2003, https://clinicaltrials.gov/ct2/show/NCT04734028

Background Coronary computed tomography angiography (CCTA) is an imaging technique which can be used to evaluate and diagnose coronary artery stenosis. Dual-acquisition CCTA (DA-CCTA) with additional nitrate infusion is a promising alternative noninvasive diagnostic tool, as conventional CCTA has limitations in the diagnosis of variant angina compared to conventional angiographic coronary spasm tests. However, DA-CCTA may pose a potential risk due to radiation exposure. We compared the radiation dose between DA-CCTA and the coronary angiographic spasm provocation test. Methods Patients with clinically suspected variant angina at a single hospital between March 2013 and October 2018 were screened and underwent DA-CCTA or a coronary angiographic spasm provocation test. The effective radiation dose required for each approach was compared. Results In total, 211 suspected variant angina patients underwent DA-CCTA or the coronary angiographic spasm provocation test. Of these, 49 patients (mean age, 59.8 years; 67.3% men) received DA-CCTA and 162 patients (mean age, 60.5 years; 66.2% men) received a coronary angiographic spasm provocation test. There was meaningful difference in the effective radiation dose, with a median dose of 5.1 mSv (interquartile range [IQR], 4.1–9.2 mSv) required for DA-CCTA and a median dose of 10.9 mSv (IQR, 8.4–15.2 mSv) for the coronary angiographic spasm provocation test (p

Background and Objectives: Critically ill surgical patients are susceptible to various postoperative complications, including acute kidney injury (AKI) and multiorgan distress syndrome (MODS). These complications intensify patient suffering and significantly increase morbidity and mortality rates. This study aimed to identify the biomarkers for predicting AKI and MODS in critically ill surgical patients. Materials and Methods: We prospectively enrolled critically ill surgical patients admitted to the intensive care unit via the emergency department between July 2022 and July 2023. A total of 83 patients were recruited, and their data were used to analyze MODS. Three patients who showed decreased creatinine clearance at the initial presentation were excluded from the analysis for AKI. Patient characteristics and laboratory parameters including white blood cell (WBC) count, neutrophil count, delta neutrophil index, urine and serum β2-microglobulin, and urine serum mitochondrial DNA copy number (mtDNAcn) were analyzed to determine the reliable biomarker to predict AKI and MODS. Results: The following parameters were independently correlated with MODS: systolic blood pressure (SBP), initial neutrophil count, and platelet count, according to a logistic regression model. The optimal cut-off values for SBP, initial neutrophil count, and platelet count were 113 mmHg (sensitivity 66.7%; specificity 73.9%), 8.65 (X3) (109/L) (sensitivity 72.2%; specificity 64.6%), and 195.0 (X3) (109/L) (sensitivity 66.7%; specificity 81.5%), respectively. According to the logistic regression model, diastolic blood pressure (DBP) and initial urine mtDNAcn were independently correlated with AKI. The optimal cut-off value for DBP and initial urine mtDNAcn were 68.5 mmHg (sensitivity 61.1%; specificity 79.5%) and 1225.6 copies/μL (sensitivity 55.6%; specificity 95.5%), respectively. Conclusions: SBP, initial neutrophil count, and platelet count were independent predictors of MODS in critically ill patients undergoing surgery. DBP and initial urine mtDNAcn levels were independent predictors of AKI in critically ill surgical patients. Large-scale multicenter prospective studies are needed to confirm our results.

Abstract Background Multidrug-resistant organisms (MDROs) such as vancomycin-resistant enterococci (VRE) and carbapenemase-producing Enterobacteriaceae (CPE) are associated with prolonged hospitalisation, increased medical costs, and severe infections. Faecal microbiota transplantation (FMT) has emerged as an important strategy for decolonisation. This study aimed to evaluate the genetic response of MDROs to FMT. Methods A single-centre prospective study was conducted on patients infected with VRE, CPE, or VRE/CPE who underwent FMT between May 2018 and April 2019. Genetic response was assessed as the change in the expression of the resistance genes VanA, bla KPC, bla NDM, and bla OXA on days 1, 7, 14, and 28 by real-time reverse-transcription polymerase chain reaction. Results Twenty-nine patients received FMT, of which 26 (59.3%) were infected with VRE, 5 (11.1%) with CPE, and 8 (29.6%) with VRE/CPE. The mean duration of MDRO carriage before FMT was 71 days. Seventeen patients (63.0%) used antibiotics within a week of FMT. In a culture-dependent method, the expression of VanA and overall genes significantly decreased (p = 0.011 and p = 0.003 respectively). In a culture-independent method, VanA, bla NDM, and overall gene expression significantly decreased over time after FMT (p = 0.047, p = 0.048, p = 0.002, respectively). Similar results were confirmed following comparison between each time point in both the culture-dependent and -independent methods. Regression analysis did not reveal important factors underlying the genetic response after FMT. No adverse events were observed. Conclusion FMT in patients infected with MDROs downregulates the expression of resistance genes, especially VanA, and facilitates MDRO decolonisation.

BackgroundThe relationship between elevated serum uric acid (SUA) levels and cardiovascular outcomes after stent implantation remains uncertain. This study sought to evaluate the impact of SUA on 12-month cardiovascular outcomes after stent implantation.MethodsWe performed a retrospective study of patients who successfully underwent stent implantation and enrolled 3,222 patients with coronary artery disease (CAD) from a single center. SUA levels were measured before stent implantation. The patients were divided into six groups (

Abstract Background Coronavirus disease 2019 (COVID-19) is associated with acute respiratory distress syndrome, and corticosteroids have been considered as possible therapeutic agents for this disease. However, there is limited literature on the appropriate timing of corticosteroid administration to obtain the best possible patient outcomes. Methods This was a retrospective cohort study including patients with severe COVID-19 who received corticosteroid treatment from March 2 to June 30, 2020 in seven tertiary hospitals in South Korea. We analyzed the patient demographics, characteristics, and clinical outcomes according to the timing of steroid use. Twenty-two patients with severe COVID-19 were enrolled, and they were all treated with corticosteroids. Results Of the 22 patients who received corticosteroids, 12 patients (55%) were treated within 10 days from diagnosis. There was no significant difference in the baseline characteristics. The initial PaO2/FiO2 ratio was 168.75. The overall case fatality rate was 25%. The mean time from diagnosis to steroid use was 4.08 days and the treatment duration was 14 days in the early use group, while those in the late use group were 12.80 days and 18.50 days, respectively. The PaO2/FiO2 ratio, C-reactive protein level, and cycle threshold value improved over time in both groups. In the early use group, the time from onset of symptoms to discharge (32.4 days vs. 60.0 days, P = 0.030), time from diagnosis to discharge (27.8 days vs. 57.4 days, P = 0.024), and hospital stay (26.0 days vs. 53.9 days, P = 0.033) were shortened. Conclusions Among patients with severe COVID-19, early use of corticosteroids showed favorable clinical outcomes which were related to a reduction in the length of hospital stay.

Objectives The FOURIER trial reported that inhibition of PCSK9 with evolocumab on a background of statin therapy lowered low-density lipoprotein (LDL) cholesterol levels to a median of 30 mg per deciliter (0.78 mmol per liter) and reduced the risk of cardiovascular events. Here, we report data from a single center focusing on the effect of a PCSK9 inhibitor antibody on hyperlipidemia. Methods We enrolled 29 hypercholesterolemia patients who had LDL cholesterol levels ≥ 70 mg per deciliter or non-HDL cholesterol ≥ 100 mg per deciliter and were divided into two groups (placebo n = 14, evolocumab n = 15), and participated in a 72 – 96 week, randomized, double-blind, placebo-controlled trial with statin therapy. Patients were randomly assigned to receive evolocumab (140 mg every 2 weeks or 420 mg monthly) or matched placebo via subcutaneous injection. Lipid changes during follow-up were analyzed. Results The median LDL cholesterol level at baseline was 88 mg per deciliter, and the average LDL cholesterol level was 101.8 ± 20.0 mg per deciliter. At 4 weeks, the median LDL cholesterol level was 39 mg per deciliter, and the average LDL cholesterol level was 34.8 ± 51.8 mg per deciliter. Compared to placebo group, the LDL cholesterol levels were significantly reduced after treatment (P < 0.001), as well as total cholesterol, ApoB, and ApoB/ApoA1 levels. During follow-up, no discomfort was reported at local injection sites, and no cases of abnormal liver function were observed. Conclusions Evolocumab significantly reduced LDL cholesterol levels and was well tolerated.

Background/Aims Although statins are widely used to reduce the risk of cardiovascular disease (CVD) including stroke and myocardial infarction (MI), it is reported that statin use increases the incidence of herpes zoster (HZ) that is associated with increased risk of CVD. So, we evaluated the mediation effect of HZ caused by statin use on CVD. Methods We analyzed a prospective cohort from the National Health Insurance Service-database of South Korea. All individuals received a medical check-up and were followed-up from 2002 to 2013. Results A total of 275,382 individuals > 40 years old were followed up for 11 years from 2003. Of these, 11,415 people (4%) were classified as statin users and 263,967 (96%) as non-statin users. Those who used statins had significantly lower risks of cardiovascular events, stroke, and MI compared with non-statin users; the adjusted hazard ratios in the multivariate analysis were 0.90 (95% confidence interval [CI], 0.82 to 0.98), 0.88 (95% CI, 0.80 to 0.98), and 0.91 (95% CI, 0.79 to 1.07), respectively. When we calculated the mediating effect of cardiovascular events by statin use through HZ, 11.6% of the total beneficial effect of cardiovascular events by statin use was mitigated through the occurrence of HZ caused by statin use. This mediating effect was higher in the younger age group (< 60 years). Conclusions This study showed that statin use reduced CVD by 10%, but the protective effect of statin use against CVD was mitigated by approximately 10% through the development of HZ caused by statin use.

PurposeTo evaluate the imaging features of coronary spasm, including transluminal attenuation gradient (TAG) on coronary computed tomography angiography (CCTA), in patients with vasospastic angina (VA).MethodsA total of 43 patients with a high clinical likelihood of VA were included in the study. All the subjects underwent double CCTA acquisition: CCTA without a vasodilator ('baseline CT') and CCTA during continuous intravenous nitrate infusion ('IV nitrate CT'). A catheterized ergonovine provocation test was used to determine true VA patients. Coronary spasm is classified into focal- and diffuse-types according to morphological differences. We measured TAG and contrast enhancement of the proximal ostium (ProxHU) of each coronary artery for both the baseline and IV nitrate CT.ResultsTwenty-four patients (55.8%) showed positive results of coronary vasospasm on the provocation test. Thirty-eight vessels showed coronary spasms (29.5%): Focal-type in nine vessels (24%), and diffuse-type in 29 (76%). In the baseline CT, LCX showed significantly lower (steeper) TAG in spasm(+) vessels than in spasm(-) vessels, while LAD and RCA showed no significant differences in TAG. The ProxHU of LAD showed significantly lower values in spasm(+) vessels than in spasm(-) vessels, while the other vessels did not show significant differences in ProxHU. For IV nitrate CT, there were no significant differences in either the TAG and ProxHU between spasm(+) and (-) vessels for all the three vessel types. In subgroup analysis for spasm(+) vessels, diffuse spasms showed significantly lower TAG than focal spasms, while the ProxHU did not differ between the two types of spasm.ConclusionsA relatively large percentage of coronary spasms present as diffuse type, and the TAG values significantly differed according to the morphological type of the coronary spasm.

Matrix metalloproteinases (MMPs) are enzymes that decompose extracellular matrix (ECM) proteins. MMPs are thought to play important roles in cellular processes, such as cell proliferation, differentiation, angiogenesis, migration, apoptosis, and host defense. MMPs are distributed in almost all intraocular tissues and are involved in physiological and pathological mechanisms of the eye. MMPs are also associated with glaucoma, a progressive neurodegenerative disease of the eyes. MMP activity affects intraocular pressure control and apoptosis of retinal ganglion cells, which are the pathological mechanisms of glaucoma. It also affects the risk of glaucoma development based on genetic pleomorphism. In addition, MMPs may affect the treatment outcomes of glaucoma, including the success rate of surgical treatment and side effects on the ocular surface due to glaucoma medications. This review discusses the various relationships between MMP and glaucoma.

Abstract Background Hypertension is an important risk factor for cardiovascular disease, even in the elderly. Fimasartan is a new non-peptide angiotensin II receptor blocker with a selective type I receptor blocking effect. The objective of this study is to confirm the safety and the non-inferiority of the blood pressure–lowering effect of fimasartan compared with those of perindopril, which has been proven safe and effective in elderly patients with hypertension. Methods This is a randomized, double-blind, active-controlled, two-parallel group, optional-titration, multicenter, phase 3 study comparing the efficacy and safety of fimasartan and perindopril arginine. The study population consists of individuals 70 years old or older with essential hypertension. The primary outcome will be a change in sitting systolic blood pressure from baseline after the administration of the investigational product for 8 weeks. The secondary outcomes will be a change in sitting diastolic blood pressure from baseline and changes in sitting systolic blood pressure and diastolic blood pressure from baseline after the administration of the investigational product for 4, 16, and 24 weeks. The sample size will be 119 subjects for each group to confer enough power to test for the primary outcome. Discussion Research to confirm the efficacy and safety of a new medicine compared with those of previously proven anti-hypertensive drugs is beneficial to guide physicians in the selection of therapeutic agents. If it is confirmed that the new drug is not inferior to the existing drug, the drug will be considered as an option in the treatment of hypertension in elderly patients. Trial registration ClinicalTrials.gov Identifier: NCT03246555, registered on July 25, 2017.

Background: According to the new definition of septic shock, vasopressor therapy and hyperlactatemia are essential for diagnosis. However, there is controversy regarding the cutoff value for lactate, and prognostic factors in patients with septic shock and hypolactatemia. This study evaluated the prognostic significance of the cutoff value for lactate level in septic shock patients. Methods: The retrospective observational cohort study enrolled 1043 patients aged ≥18 years who meet the revised definition of septic shock. Clinical outcomes of patients with hyperlactatemia were compared with hypolactatemia. Results: Of the 1022 eligible patients, 369 had an arterial lactate level ≤2 mmol/L. More patients in the high lactate group had poor prognosis than in the low lactate group. A high Sequential Organ Failure Assessment score (SOFA) score group was significant (p

Abstract Background Aortic dilatation is a major risk factor for aortic dissection. The aim of the present study was to assess the relationship between left ventricular (LV) geometry and maximal ascending aorta (MAA). Methods We reviewed data from patients who were diagnosed with acute type A aortic dissection and who underwent surgical management from December 2002 to March 2016 at Dong-A University Hospital. Among 151 patients with non-Marfan aortic dissection in the study, 50 who had echocardiography preoperatively were investigated and MAA diameter was analyzed by LV geometric patterns. Results Patients’ mean age was 59.6 ± 13.5 years and 38.0% were male. The mean MAA diameter was 52.9 ± 8.5 mm. MAA diameter was significantly correlated with LV mass index (r = 0.62, P

Contrary to many reports that antiplatelet agents inhibit cancer growth and metastasis, new solid tumors have been reported in patients receiving long-term antiplatelet therapy. We investigated the effects of these agents directly on cancer cells in the absence of platelets to mimic the effects of long-term therapy. When four antiplatelet agents (aspirin, clopidogrel, prasugrel, and ticagrelor) were administered to colon cancer cells, cancer cell proliferation was inhibited similarly to a previous study. However, surprisingly, when cells were treated with a purinergic P2Y12 inhibitor (purinergic antiplatelet agent), the motility of the cancer cells was significantly increased. Therefore, gene expression profiles were identified to investigate the effect of P2Y12 inhibitors on cell mobility, and Serpin family 1 (SERPINE1) was identified as a common gene associated with cell migration and cell death in three groups. Antiplatelet treatment increased the level of SERPINE1 in cancer cells and also promoted the secretion of SERPINE1 into the medium. Increased SERPINE1 was found to induce MMP1 and, thus, increase cell motility. In addition, an increase in SERPINE1 was confirmed using the serum of patients who received these antiplatelet drugs. With these results, we propose that SERPINE1 could be used as a new target gene to prevent the onset and metastasis of cancer in patients with long-term antiplatelet therapy.

[This corrects the article DOI: 10.1371/journal.pone.0241169.].

BackgroundBrain abscess can be life-threatening and manifest various neurological findings, although the mortality rate has decreased recently. We investigated the risk factors for unfavorable outcomes of patients with brain abscess.MethodsA retrospective cohort study examined patients with brain abscess seen from May 2005 to December 2018 in a tertiary care hospital in Seoul, South Korea. We reviewed the medical records for clinical findings, therapeutic modalities, and prognostic factors of brain abscess. Unfavorable clinical outcomes were defined as death, moderate to severe disability with neurological deficits, or vegetative state at 1 year or at the time of discharge from outpatient follow-up.ResultsThe study enrolled 135 patients: 65.2% were males; the mean age was 56 years. 35.6% had unfavorable outcomes. In multivariate analysis, higher Sequential Organ Failure Assessment (SOFA) (p < 0.001), pre-existing hemiplegia (p = 0.049), and higher Charlson comorbidity index (CCI) (p = 0.028) were independently associated with unfavorable outcomes.ConclusionsHigher SOFA, pre-existing hemiplegia and higher Charlson comorbidity index were significant risk factors for unfavorable clinical outcomes in patients with brain abscess.

Background The CHA2DS2‐VASc score has been validated for stroke risk prediction in patients with atrial fibrillation (AF). Antithrombotic therapy is not recommended for low‐risk patients with AF (CHA2DS2‐VASc 0 [male] or 1 [female]). We studied a cohort of initially low‐risk patients with AF in relation to their development of incident comorbidities and their treatment on oral anticoagulation therapy. Methods and Results We assessed data from 14 441 low‐risk patients with AF (CHA2DS2‐VASc score of 0 [male] or 1 [female]) using the Korean National Health Insurance Service database, in relation to their development of incident stroke risk factors and adverse outcomes. The clinical end point was the occurrence of ischemic stroke, major bleeding, all‐cause death, or the composite outcome (ischemic stroke + major bleeding + all‐cause death). In our cohort, 2615 (29.1%) male and 1650 (30.3%) female patients acquired at least 1 new stroke risk factor during a mean follow‐up of 2.0 years. Among the patients with an increasing CHA2DS2‐VASc score ≥1, male and female patients treated with oral anticoagulants had a significantly lower risk of ischemic stroke (male: hazard ratio [HR], 0.62 [95% CI, 0.44–0.82; P=0.003]; female: HR, 0.65 [95% CI, 0.47–0.84; P=0.007]), all‐cause death (male: HR, 0.67 [95% CI, 0.49–0.88; P=0.009]; female: HR, 0.82 [95% CI, 0.63–1.02; P=0.185]), and composite outcomes (male: HR, 0.78 [95% CI, 0.61–0.95; P=0.042]; female: HR, 0.79 [95% CI, 0.62–0.96; P=0.045]) than patients not treated with oral anticoagulants. Conclusions Approximately 30% of patients acquired ≥1 stroke risk factor over a 2‐year follow‐up period. Low‐risk patients with AF should be regularly reassessed to adequately identify those with incident stroke risk factors that would merit thromboprophylaxis for the prevention of stroke and the composite outcome.

Novel coronavirus (named SARS-CoV-2) can spread widely in confined settings including hospitals, cruise ships, prisons, and places of worship. In particular, a healthcare-associated outbreak could become the epicenter of coronavirus disease (COVID-19). This study aimed to evaluate the effects of different intervention strategies on the hospital outbreak within a tertiary hospital. A mathematical model was developed for the COVID-19 transmission within a 2500-bed tertiary hospital of South Korea. The SEIR (susceptible-exposed-infectious-recovered) model with a compartment of doctor, nurse, patient, and caregiver was constructed. The effects of different intervention strategies such as front door screening, quarantine unit for newly admitted patients, early testing of suspected infected people, and personal protective equipment for both medical staff and visitors were evaluated. The model suggested that the early testing (within eight hours) of infected cases and monitoring the quarantine ward for newly hospitalized patients are effective measures for decreasing the incidence of COVID-19 within a hospital (81.3% and 70% decrease of number of incident cases, respectively, during 60 days). Front door screening for detecting suspected cases had only 42% effectiveness. Screening for prohibiting the admission of COVID-19 patients was more effective than the measures for patients before emergency room or outpatient clinic. This model suggests that under the assumed conditions, some effective measures have a great influence on the incidence of COVID-19 within a hospital. The implementation of the preventive measures could reduce the size of a hospital outbreak.

Hypothetically, diminished platelet reactivity (PR) during dual antiplatelet therapy (DAPT) should cause extra major bleeding events (MBE), although definite evidence is lacking. Multiple scores have been proposed to stratify bleeding risk, but their predictive value during DAPT is unclear. We compared the performance of the Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the ACC/AHA Guidelines (CRUSADE) with PR testing to predict MBE in Korean patients with acute coronary syndrome. We screened 1105, and included 903 consecutive patients who underwent coronary interventions. All patients received DAPT, while MBE were assessed by BARC scale. Admission platelet reactivity was assessed with VerifyNow Analyzer simultaneously with CRUSADE score, and MBE were collected at 1 month and at 1 year post stenting. There were a total of 113 (11%) MBE at 1 month, and extra 41(5%) MBE at 1 year. At 1 month MBE prediction was superior by CRUSADE score (AUC: 0.816, 95% CI: 0.79 0.84, p

Abstract Background The incidence of Proteus mirabilis antimicrobial resistance, especially that mediated by extended-spectrum β-lactamases (ESBLs), has increased. We investigated the impact of ESBL production on the mortality of patients with P. mirabilis bacteremia in Korea. Methods Patients diagnosed with P. mirabilis bacteremia between November 2005 and December 2013 at a 2000-bed tertiary care center in South Korea were included in this study. Phenotypic and molecular analyses were performed to assess ESBL expression. Characteristics and treatment outcomes were investigated among ESBL-producing and non-ESBL-producing P. mirabilis bacteremia groups. A multivariate analysis of 28-day mortality rates was performed to evaluate the independent impact of ESBLs. Results Among 62 P. mirabilis isolates from 62 patients, 14 expressed ESBLs (CTX-M, 2; TEM, 5; both, 6; other, 1), and the 28-day mortality rate of the 62 patients was 17.74%. No clinical factor was significantly associated with ESBL production. The 28-day mortality rate in the ESBL-producing group was significantly higher than that in the non-ESBL-producing group (50% vs. 8.3%, p = 0.001). A multivariate analysis showed that ESBL production (odds ratio [OR], 11.53, 95% confidence interval [CI], 2.11–63.05, p = 0.005) was independently associated with the 28-day mortality rate in patients with P. mirabilis bacteremia. Conclusions ESBL production is significantly associated with mortality in patients with bacteremia caused by P. mirabilis. Rapid detection of ESBL expression and prompt appropriate antimicrobial therapy are required to reduce mortality caused by P. mirabilis bacteremia.

Several reliable scales have been proposed for the management and prognosis in patients with acute coronary syndromes (ACS) treated with dual-antiplatelet therapy (DAPT). We sought to compare the performance of three conventional risk scores to predict major bleeding (MB; such as ACUITY or CRUSADE), or major adverse cardiovascular event (MACE for GRACE). This study included 904 consecutive post-ACS patients from the single Korean study center who underwent coronary interventions, and were treated with DAPT. All three scores were calculated based on admission data. MB and MACE were collected at 30-day and 1-year follow-ups. MB was defined according to the Bleeding Academic Research Consortium (BARC) criteria (types 3–5), and MACE included all-cause death, myocardial infarction, target vessel revascularization, and stroke. MB occurred in 114 patients (12.6%) during 30 days, and 65 patients (7.2%) from 30 days till 1-year follow-up. MACE occurred in 28 (3.1%) and 72 (8.0%) patients during 30 and 30 days till 1 year, respectively. For 30 days MB, the discriminatory ability of ACUITY (AUC: 0.83, 95% CI: 0.81–0.86) and CRUSADE (AUC: 0.82, 95% CI: 0.79–0.84) was similar, and more reliable than GRACE (AUC: 0.74, 95% CI: 0.71–0.77; p

Whether aggressive prolonged dual antiplatelet therapy (DAPT) promotes solid cancer risks remains a critical unsolved issue. Since the evidence from randomized trials, affiliated U.S. Food and Drug Administration (FDA) reviews, meta-analyses, and national registries is mixed, the search is ongoing. The FDA Adverse Event Reporting System (FAERS) is a global passive surveillance repository requiring mandatory updates for serious events. We assessed the frequencies of co-reporting any cancers with oral antiplatelet agent (OAA) strategies in FAERS. We examined the entire FAERS database (n = 8,604,889) with regard to monotherapy or DAPT with OAA, suspected causative role, and co-reporting any cancers (n = 433,111). We extracted cancer cases during monotherapy with aspirin (20,984 out of 462,371 or 4.54%), clopidogrel (2,797 out of 62,791 or 4.45%), prasugrel (119 out of 4,364 or 2.73%), and ticagrelor (144 out of 8.268 or 1.71%). DAPT with clopidogrel reported (2,453 out of 58,101, or 4.22%); prasugrel (162 out of 4,036, or 4.01%); and ticagrelor (195 out of 5,302 or 3.68%) cancer reports all on top of aspirin. We conclude that FAERS is currently unreliable for adequate assessment of cancer risks during DAPT. The retrieved evidence appears random and sporadic, while associated cancers are heavily underreported or/and missed. Without stricter rules, better surveillance, and enforcements, oncology outcome research options in FAERS are challenging.

Specific mechanisms underlying cardioprotective and anti-inflammatory effects of flavonoids remain unclear. The effects of two flavonoids—hesperidin and naringin—on endothelial nitric oxide synthase (eNOS) induction in human umbilical vein endothelial cells (HUVECs) were investigated here, and possible underlying molecular mechanisms using high glucose (HG) concentrations were examined. The flavonoids' effects on nitric oxide (NO) production and Ser-1177 and Thr-495 phosphorylation with or without mitogen-activated protein kinase (MAPK) signalling pathway inhibitors were determined. HG decreased eNOS mRNA and protein levels while pre-treatment with both flavonoids drastically increased the levels dose- and time-dependently, in HUVECs. Furthermore, HG altered eNOS phosphorylation at Ser1177 and Thr495. Naringin phosphorylated Ser1177 via the p-38 pathway and dephosphorylated Thr495 via the mitogen-activated protein kinase kinase (MEK) and c-Jun N-terminal kinase (JNK) pathways. Hesperidin phosphorylated Ser1177 via the MEK pathway and dephosphorylated Thr495 via the p-38 and JNK pathways. Thus, hesperidin and naringin regulate HG-induced eNOS expression via the MAPK signalling pathway.

Abstract Background The U.S. Food and Drug Administration (FDA) Adverse Event (AE) Reporting System (FAERS) is a global passive surveillance repository requiring mandatory updates by pharmaceutical manufacturers. Oral antiplatelet agents (OAAs) including aspirin (acetylsalicylic acid [ASA]) are broadly used to prevent thrombosis, at the expense of extra bleeding risks. However, the OAA filing quality and their comparative patterns in FAERS are unknown. We assessed completeness of original annual FAERS reports for OAA with special attention on ASA. Methods We extracted AE cases co-reported with OAA including ASA, clopidogrel, prasugrel, ticagrelor, vorapaxar, or their combination. The 2015 FAERS cases were examined based on OAA distribution, suspected causative role, missing gender or age, and most common AEs after ASA. Results A total of 1,187,729 reports qualified the inclusion criteria. The majority (n = 1,121,989) of the reports contain no reference of OAA, while 65,730 reports contain reference of at least one OAA, including 47,900 ASA cases. Therapy with ASA was heavily (>50%) underreported when used with prasugrel or ticagrelor, but still dominant (72.8%) among OAAs, followed by clopidogrel (18.7%), prasugrel (4.1%), ticagrelor (3.6%), and anecdotal vorapaxar (0.05%). Despite current recommendations, some (0.73%) reports contain multi-OAAs. The primary role of ASA in AE reporting was seldom (

Fishery acoustics (How to detect and monitor fish and other marine life [...]

Stent dislodgement is a rare complication of complex percutaneous coronary artery intervention and is often associated with significant morbidity. We report a case of stent dislodgement complicated by coronary artery dissection and acute total occlusion of left circumflex coronary artery. Direct expansion of the dislodged stent was performed using parallel wire technique and small balloon. An overlapping stent was implanted for remained coronary artery dissection. Coronary artery flow was restored and ST segment elevation was normalized after successful intervention.

AIM: To investigate the detailed microscopic anatomic structures of the lower eyelid in Korean cadavers.METHODS: Eight lower eyelids of 4 formalin-fixed Asian cadavers (4 males; age range, 48-69 years; mean age, 60.2 years) were examined. Three perpendicular dissected sections with a 2mm thickness were obtained from each eyelid to investigate anatomic shapes, size and relationship with surrounding structures. One section was obtained from the midline and 2 the other sections were obtained from a 3mm apart from the lateral and medial tarsus margins.RESULTS:The inferior tarsal muscle fibers were not directly attached to the tarsus but were only linked to the tarsus with enclosed fibrous fascia. The inferior tarsal muscles connected loosely with the capsulopalpebral fascia anteriorly and the conjunctiva posteriorly. The inferior tarsal muscle runs horizontally to the tarsus according to the shape of muscle fibers. The capsulopalpebral fascia consisted of an anterior and posterior layer. The anterior layer reached the orbital septum and subcutaneous fat but the posterior layer forwarded into the tarsus. Lockwood''s ligament was separated from the inferior tarsal muscle and capsulopalpebral fascia or fused into the capsulopalpebral fascia.CONCLUSION: This study suggests that the inferior tarsal muscle which runs horizontally and doesn’t insert directly into the tarsus, plays an important role in the movement and localization of the lower eyelid.

BACKGROUND:HIV-associated neurocognitive disorder (HAND) can occur in patients without prior AIDS defining illness and can be debilitating. This study aimed to evaluate the difference in the patterns of intrinsic brain activity between patients with or without HAND for deepening our understanding of HAND. METHODS:We evaluated 24 HIV-infected individuals, 12 with previously diagnosed HAND and 12 previously diagnosed without HAND, and 11 seronegative individuals. These individuals then underwent repeat NP testing and a functional brain MRI scan. For functional MRI analysis, seed-based analysis with bilateral precuneus cortex seed was applied. RESULTS:Among the 12 individuals with previously diagnosed HAND, 3 showed improvement of their neurocognitive function and 1 was excluded for worsening liver disease. Among the 12 patients who previously had normal neurocognitive function, 2 showed neurocognitive impairment. Overall, the HAND group, who had impaired cognitive function at the time of MRI scan, showed significant decrease of resting status functional connectivity between bilateral precuneus and prefrontal cortex (PFC) compared with nonHAND group, those who had normal neurocognitive function (Corrected P

This research, a new thrust-allocation algorithm based on penalty programming is developed to minimize the fuel consumption of offshore vessels/platforms with dynamic positioning system. The role of thrust allocation is to produce thruster commands satisfying required forces and moments for position-keeping, while fulfilling mechanical constraints of the control system. The developed thrust-allocation algorithm is mathematically formulated as an optimization problem for the given objects and constraints of a dynamic positioning system. Penalty programming can solve the optimization problems that have nonlinear object functions and constraints. The developed penalty-programming thrust-allocation method is implemented in the fully-coupled vessel–riser–mooring time-domain simulation code with dynamic positioning control. Its position-keeping and fuel-saving performance is evaluated by comparing with other conventional methods, such as pseudo-inverse, quadratic-programming, and genetic-algorithm methods. In this regard, the fully-coupled time-domain simulation method is applied to a turret-moored dynamic positioning assisted FPSO (floating production storage offloading). The optimal performance of the penalty programming in minimizing fuel consumption in both 100-year and 1-year storm conditions is demonstrated compared to pseudo-inverse and quadratic-programming methods.

The primary objective of this paper is to investigate the dynamic stability and survivability of a four-column classic TLP (tension-leg platform) under less-than-extreme storm conditions where one or more tendons have been lost due to damage or disconnect. The transient responses of the platform and tendon tensions at the moment of disconnection are particularly underscored. The numerical simulation is based on the BE-FE hybrid hull-tendon-riser coupled dynamic analysis in time domain. Compared to the common industry practice of checking the system without a failed tendon in the beginning, the maximum tension on the neighboring tendon can be significantly increased at the moment of disconnection due to the snap-like transient effects, which can lead to unexpected failure of the total system. It is also found that the transient effects can be reduced with the presence of TTRs (top-tensioned risers) with pneumatic tensioners. It is also seen that the TLP cannot survive in the 100-yr hurricane condition after losing one tendon.

Although human amniotic mesenchymal stem cells (AMMs) have been recognised as a promising stem cell resource, their therapeutic potential for wound healing has not been widely investigated. In this study, we evaluated the therapeutic potential of AMMs using a diabetic mouse wound model. Quantitative real-time PCR and ELISA results revealed that the angiogenic factors, IGF-1, EGF and IL-8 were markedly upregulated in AMMs when compared with adipose-derived mesenchymal stem cells (ADMs) and dermal fibroblasts. In vitro scratch wound assays also showed that AMM-derived conditioned media (CM) significantly accelerated wound closure. Diabetic mice were generated using streptozotocin and wounds were created by skin excision, followed by AMM transplantation. AMM transplantation significantly promoted wound healing and increased re-epithelialization and cellularity. Notably, transplanted AMMs exhibited high engraftment rates and expressed keratinocyte-specific proteins and cytokeratin in the wound area, indicating a direct contribution to cutaneous closure. Taken together, these data suggest that AMMs possess considerable therapeutic potential for chronic wounds through the secretion of angiogenic factors and enhanced engraftment/differentiation capabilities.