Explore the vast range of titles available.

Circulating microRNAs (miRNAs) have been described as potential diagnostic biomarkers in cardiovascular disease and in particular, coronary artery disease (CAD). Few studies were undertaken to perform analyses with regard to risk stratification of future cardiovascular events. miR-126, miR-197 and miR-223 are involved in endovascular inflammation and platelet activation and have been described as biomarkers in the diagnosis of CAD. They were identified in a prospective study in relation to future myocardial infarction. The aim of our study was to further evaluate the prognostic value of these miRNAs in a large prospective cohort of patients with documented CAD. Levels of miR-126, miR-197 and miR-223 were evaluated in serum samples of 873 CAD patients with respect to the endpoint cardiovascular death. miRNA quantification was performed using real time polymerase chain reaction (RT-qPCR). The median follow-up period was 4 years (IQR 2.78-5.04). The median age of all patients was 64 years (IQR 57-69) with 80.2% males. 38.9% of the patients presented with acute coronary syndrome (ACS), 61.1% were diagnosed with stable angina pectoris (SAP). Elevated levels of miRNA-197 and miRNA-223 reliably predicted future cardiovascular death in the overall group (miRNA-197: hazard ratio (HR) 1.77 per one standard deviation (SD) increase (95% confidence interval (CI) 1.20; 2.60), p = 0.004, C-index 0.78; miRNA-223: HR 2.23 per one SD increase (1.20; 4.14), p = 0.011, C-index 0.80). In ACS patients the prognostic power of both miRNAs was even higher (miRNA-197: HR 2.24 per one SD increase (1.25; 4.01), p = 0.006, C-index 0.89); miRA-223: HR 4.94 per one SD increase (1.42; 17.20), p = 0.012, C-index 0.89). Serum-derived circulating miRNA-197 and miRNA-223 were identified as predictors for cardiovascular death in a large patient cohort with CAD. These results reinforce the assumption that circulating miRNAs are promising biomarkers with prognostic value with respect to future cardiovascular events.

Background Despite increased atherothrombotic risk in type 2 diabetes mellitus, (T2DM) the best preventative antithrombotic strategy remains undetermined. We defined the effects of three antiplatelet agents on functional readout and biomarker kinetics in platelet activation and coagulation in patients with T2DM. Materials and methods 56 patients with T2DM were randomised to antiplatelet monotherapy with aspirin 75 mg once daily (OD), clopidogrel 75 mg OD or prasugrel 10 mg OD during three periods of a crossover study. Platelet aggregation (PA) was determined by light-transmittance aggregometry and P-selectin expression by flow cytometry. Markers of fibrin clot dynamics, inflammation and coagulation were measured. Plasma levels of 14 miRNA were assessed by quantitative polymerase chain reactions. Results Of the 56 patients, 24 (43%) were receiving aspirin for primary prevention of ischaemic events and 32 (57%) for secondary prevention. Prasugrel was the strongest inhibitor of ADP-induced PA (mean ± SD maximum response to 20μmol/L ADP 77.6 ± 8.4% [aspirin] vs. 57.7 ± 17.6% [clopidogrel] vs. 34.1 ± 14.1% [prasugrel], p < 0.001), P-selectin expression (30 μmol/L ADP; 45.1 ± 21.4% vs. 27.1 ± 19.0% vs. 14.1 ± 14.9%, p < 0.001) and collagen-induced PA (2 μg/mL; 62.1 ± 19.4% vs. 72.3 ± 18.2% vs. 60.2 ± 18.5%, p < 0.001). Fibrin clot dynamics and levels of coagulation and inflammatory proteins were similar. Lower levels of miR-24 (p = 0.004), miR-191 (p = 0.019), miR-197 (p = 0.009) and miR-223 (p = 0.014) were demonstrated during prasugrel-therapy vs. aspirin. Circulating miR-197 was lower in those cardiovascular disease during therapy with aspirin (p = 0.039) or prasugrel (p = 0.0083). Conclusions Prasugrel monotherapy in T2DM provided potent platelet inhibition and reduced levels of a number of platelet-associated miRNAs. miR-197 is a potential marker of cardiovascular disease in this population. Clinical outcome studies investigating prasugrel monotherapy are warranted in individuals with T2DM. Trial registration EudraCT, 2009-011907-22. Registered 15 March 2010, https://www.clinicaltrialsregister.eu/ctr-search/trial/2009-011907-22/GB .

Cardiovascular (CV) risk assessment is based on the utilization of risk scores, enabling clinicians to estimate an individual’s risk to develop CV pathologies and events. Such risk scores comprise classic CV risk factors such as smoking, diabetes, hypertension, and blood cholesterol levels. Recently, other CV biomarkers such as cardiac troponins have been suggested and evaluated as alternative biomarkers not only in the acute diagnostic setting of myocardial infarction, but also as markers for risk stratification in the general population. In this review, we summarize the current knowledge on biomarkers in the field of primary prevention in cardiovascular disease (CVD). Furthermore, we present potential alternative biomarker-based strategies for CV risk assessment. In this respect we provide an outlook on the potential use of genomic variation as well as circulating non-coding RNAs to complement current risk assessment strategies so as to further personalize risk stratification in CVD.

In many situations, governments have sector-specific tax and regulation policies at their disposal to influence the market outcome after a national or an international merger has taken place. In this paper we study the implications for merger policy when countries non-cooperatively deploy production-based taxes and firms may be partly owned by foreigners. We find that when foreign firm ownership is low in the pre-merger situation, non-cooperative tax policies are more efficient after a national merger, and smaller synergy effects are needed for this type of merger to be proposed and cleared. In contrast, cross-border mergers dominate when the degree of foreign firm ownership is high initially. These results suggest a link between increasing international portfolio diversification and the rising share of cross-border mergers.

The generation of a robot program can be seen as a collection of sub-problems, where many combinations of some of these sub-problems are well studied. The performance of a robot program is strongly conditioned by the location of the tasks. However, the scope of previous methods does not include workspace layout design, likely missing high-quality solutions. In industrial applications, designing robot workspace layout is part of the commissioning. We broaden the scope and show how to model a dual-arm multi-tool robot assembly problem. Our model includes more robot programming sub-problems than previous methods, as well as workspace layout design. We propose a constraint programming formulation in MiniZinc that includes elements from scheduling and routing, extended with variable task locations. We evaluate the model on realistic assembly problems and workspaces, utilizing the dual-arm YuMi robot from ABB Ltd. We also evaluate redundant constraints and various formulations for avoiding arm-to-arm collisions. The best model variant quickly finds high-quality solutions for all problem instances. This demonstrates the potential of our approach as a valuable tool for a robot programmer.

BackgroundPrevious studies have shown that differential exposure to lifestyle factors may mediate the association between education and coronary heart diseases (CHD). However, few studies have examined the potential roles of allostatic load (AL) or differential susceptibility.Methods25 310 men and 26 018 women aged 35–74 and CHD free at baseline were identified from 21 European cohorts and followed for a median of 10 years, to investigate the mediating role of AL, as well as of smoking, alcohol use and body mass index (BMI), on educational differences in CHD incidence, applying marginal structural models and three-way decomposition.ResultsAL is a mediator of the association between educational status and CHD incidence, with the highest proportion mediated observed among women and largely attributable to differential exposure, (28% (95% CI 19% to 44%)), with 8% (95% CI 0% to 16%) attributable to differential susceptibility. The mediating effects of smoking, alcohol and BMI, compared with AL, were relatively small for both men and women.ConclusionOverall, the educational inequalities in CHD incidence were partially mediated through differential exposure to AL. By contrast, the mediation of the educational gradient in CHD by investigated lifestyle risk factors was limited. As differential susceptibility in men was found to have a predominant role in the accumulation of AL in low educational classes, the investigation of AL-related risk factors is warranted.

Fast tacrolimus (Tac) metabolism is associated with reduced survival rates after renal transplantation (RTx), mainly due to cardiovascular events. Because dyslipidemia is a leading cause of cardiovascular death, we hypothesized that most RTx patients do not achieve recommended target low-density lipoprotein cholesterol (LDL-C) levels (European cardiology society guidelines) and that fast Tac metabolizers have higher dyslipidemia rates. This study included RTx recipients who received initial immunosuppression with immediate-release tacrolimus (IR-Tac), mycophenolate, and prednisolone. Patients were grouped according to their Tac concentration-to-dose ratio (C/D ratio) 3 months after RTx. Dyslipidemia parameters were analyzed at RTx, 3 months, and 12 months after RTx. Statin use and renal function were documented in a 12-month follow-up, and death was documented in a 60-month follow-up. Ninety-six RTx recipients were divided into two groups: 31 fast Tac metabolizers (C/D ratio < 1.05 ng/mL·1/mg) and 65 slow metabolizers (C/D ratio ≥ 1.05 ng/mL·1/mg). There were no differences in triglyceride or cholesterol levels between groups at RTx, 3, and 12 months after RTx. A total of 93.5% of fast and 95.4% of slow metabolizers did not achieve target LDL-C levels (p = 0.657). Fast metabolizers developed lower renal function compared to slow metabolizers 12 months after RTx (p = 0.009). Fast metabolizers showed a 60 month survival rate of 96.8% compared to 94.7% in the slow metabolizer group (p = 0.811). As most RTx recipients do not reach recommended target LDL-C levels, individualized nutritional counseling and lipid-lowering therapy must be intensified. Fast Tac metabolism is associated with lower renal function after RTx, but does not play a significant role in dyslipidemia.

RationaleNon-coding RNAs (ncRNAs), including microRNAs (miRNAs), circular RNAs (circRNA) and long non-coding RNAs (lncRNA), have been implicated as novel cardiac biomarkers.ObjectiveTo compare the tissue-specificity and release kinetics of ncRNAs and protein biomarkers after induced myocardial injury by transcoronary ablation of septal hypertrophy (TASH).Methods and resultsUpon screening the relative abundance of 109 circRNA and 21 lncRNAs in human cardiac tissue, 12 circRNAs and 11 lncRNAs were selected for further analyses. Human myocardial tissue was spiked into plasma from healthy individuals and the expression levels of ncRNAs were compared to a panel of miRNAs, including muscle- (miR-1, miR-133a) and cardiac-enriched miRNAs (miR-208a, miR-208b, miR-499). Curve fitting analyses of each of the three ncRNA classes with the highest R2 values revealed no significant differences in the regression coefficients compared with high sensitive troponin T and I (hs-cTnT, hs-cTnI) and cardiac myosin-binding protein C (cMyC). At low spike-in concentrations, however, significantly higher regression coefficients were observed for all ncRNA species (Mann Whitney test: miRNAs vs. proteins p<0.0001, fold-change 2.6; circRNAs vs proteins p=0.0028, fold change 2.8; lncRNAs vs. proteins p=0.0028, fold-change 1.6). To assess whether ncRNAs allow earlier detection of myocardial injury, circulating ncRNAs were quantified in patients undergoing TASH before and at 1 hour, 8 hours, 24 hours after the procedure. Unlike cardiac proteins, miR-1 and miR-133a showed the steepest rise within the first hour after cardiac injury. These muscle-enriched miRNAs were also more readily detectable in plasma than the cardiac-specific miRNAs, miR-208b and miR-499. In contrast, cardiac circRNAs remained undetectable in plasma even after myocardial injury. Putative cardiac lncRNAs, including the Long Intergenic Non-Coding RNA Predicting Cardiac Remodelling And Survival (LIPCAR) were abundant in plasma but failed to show significant changes after TASH, refuting a predominant cardiac origin. Finally, the stability of ncRNAs was assessed in plasma. Degradation of cardiac/muscle-enriched miRNAs was observed in plasma left at room temperature for 1 hour and reduced by treatment with RNAse inhibitors. As expected, circRNAs were less susceptible to degradation. Mitochondrial-derived lncRNAs such as LIPCAR increased after 1 hour of incubation in plasma, while non-mitochondrial lncRNAs showed a degradation pattern similar to miRNAs.ConclusionsOur results demonstrate that circulating heart-associated ncRNAs may enhance early detection of myocardial injury. All three ncRNA classes demonstrated superior release kinetics in vitro compared with established cardiac protein biomarkers. At early time points after TASH, however, a higher sensitivity was only observed for muscle-enriched miRNAs, but not for circRNAs or lncRNAs.