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A new theory is proposed to describe spectral effects of the coupling between molecular rotations and OH···O motions in liquid water. The correlation function approach is employed together with a special type of development in which the coupling energy of these two motions is the expansion parameter. The isotropy of the liquid medium plays an essential role in this study. Based on this theory, a new infrared pump-probe experiment is described permitting a visualization of molecular rotations at subpicosecond time scales. Full curves relating the mean squared rotational angle and time, and not only the rotational relaxation time, are measured by this experiment. However, very short times where the incident pulses overlap must be avoided in this analysis. The lifetime of OH···O bonds in water is rotation-limited. [ABSTRACT FROM AUTHOR]

The two-dimensional IR (2D-IR) spectroscopy technique is employed to study the structure and dynamics of the sulfhydryl band of cysteines that are usually present in the hydrophobic core of proteins. The sulfhydryl group is shown to get highly polarized on being situated in an [alpha]-helix inside the protein.

OBJECTIVES: To perform a systematic review to provide rationale for intracoronary (IC) abciximab administration in patients with ST-segment elevation myocardial infarction (STEMI), to summarize recent studies comparing IC vs. intravenous (IV) abciximab administration in this setting and to define questions that need to be answered in future trials determining the optimal abciximab regimen. METHODS: A search covering the period from January 1993 to June 2011 was conducted by two independent investigators using MEDLINE, CENTRAL and Google Scholar databases. Proceedings from the scientific sessions of ACC, AHA, ESC, TCT and EuroPCR were also considered. RESULTS: IC administration allows one to obtain a much higher concentration of abciximab than IV injection at the culprit lesion. Therefore it is hypothesized that IC abciximab administration provides more efficient GP IIb/IIIa receptor inhibition and more pronounced additional dose-dependent antiplatelet, antithrombotic, and anti-inflammatory effects when compared to the IV route. Numerous observational and randomized studies comparing IC vs. IV abciximab in STEMI patients indicated improvement in different surrogate end points (infarct size, obstruction of coronary microcirculation, ST segment resolution, inflammatory mediators and markers of platelet activation) related to IC administration. The evidence supporting clinical benefits associated with IC injection of abciximab comes from one randomized and several non-randomized trials as most of the studies were underpowered to assess clinical outcomes. No difference in bleeding complications was observed between IC and IV regimens. Issues that need to be addressed in future studies include: the use of IC abciximab in combination with thrombectomy, the role of selective delivery systems, and the necessity of a prolonged IV infusion of abciximab after IC bolus administration. CONCLUSIONS: An accumulating body of evidence suggests the superiority of IC over IV abciximab administration in STEMI patients. However, further trials are warranted to establish the optimal strategy of abciximab treatment in this setting. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction-associated fatty liver disease (MAFLD) may progress to advanced liver fibrosis (ALF). We evaluated the diagnostic accuracy of a novel Liver Fibrosis Risk Index (LFRI) in MAFLD subjects using transient elastography (TE) as the reference method for liver fibrosis measurement and then the diagnostic performance of a new two-step non-invasive algorithm for the detection of ALF risk in MAFLD, using Fibrosis-4 (FIB-4) followed by LFRI and comparing it to the reference algorithm based on FIB-4 and TE. We conducted a prospective study on 104 MAFLD European adult subjects. All consenting subjects underwent TE and measurements of FIB-4 and LFRI. For FIB-4 and TE, validated cut-offs were used. An ROC analysis showed that LFRI diagnosed severe fibrosis with moderate accuracy in MAFLD subjects with a negative predictive value above 90%. Using the new algorithm with LFRI thresholds recommended by the manufacturer, the number of subjects classified into ALF risk groups (low, intermediate, or high) differed significantly when compared with the reference algorithm ( p = 0.001), with moderate agreement between them (weighted kappa (95% CI) = 0.59 (0.41-0.77)). To improve the performance of the LFRI-based algorithm, we modified cut-off points based on ROC curves obtained by dividing the study population according to the reference algorithm and observed no difference between algorithms ( p = 0.054) in categorizing ALF risk, with a slight increase in the total agreement (weighted kappa (95% CI) = 0.63 (0.44-0.82)). Our findings suggest that using the novel LFRI as a second-line test may represent a potential alternative for liver fibrosis risk stratification in MAFLD patients; however, modified cut-offs are needed to optimize its performance.

Background: Cardiac myosin-binding protein C (cMyC) is a novel cardio-specific biomarker of potential diagnostic and prognostic value for cardiovascular events. This study aims to determine reference values for cMyC and identify biological determinants of its concentration., Methods: A population of 488 presumably healthy adults were enrolled to define biological determinants which affect cMyC concentrations in serum. Concentrations of cMyC were assessed using enzyme-linked immunosorbent assays from commercially available kits. Eligibility for inclusion in this study evaluated all subjects' anthropometric, demographic and laboratory measurements. After applying strict inclusion criteria, a reference population (n=150) was defined and used to determine reference values. Reference values were derived using a robust method., Competing Interests: All the authors declare that they have no conflict of interest in this work.Conflict of Interest: The authors stated that they have no conflicts of interest regarding the publication of this article., (2023 Sylwester M. Kloska, Marek Kozinski, Anna Stefanska, Katarzyna Bergmann, Aneta Mankowska-Cyl, Joanna Siodmiak, Grazyna Sypniewska, Magdalena Krintus, published by CEON/CEES.)

Persistent Homology (PH) has been successfully used to train networks to detect curvilinear structures and to improve the topological quality of their results. However, existing methods are very global and ignore the location of topological features. In this paper, we remedy this by introducing a new filtration function that fuses two earlier approaches: thresholding-based filtration, previously used to train deep networks to segment medical images, and filtration with height functions, typically used to compare 2D and 3D shapes. We experimentally demonstrate that deep networks trained using our PH-based loss function yield reconstructions of road networks and neuronal processes that reflect ground-truth connectivity better than networks trained with existing loss functions based on PH.

Deep learning-based approaches to delineating 3D structure depend on accurate annotations to train the networks. Yet in practice, people, no matter how conscientious, have trouble precisely delineating in 3D and on a large scale, in part because the data is often hard to interpret visually and in part because the 3D interfaces are awkward to use. In this paper, we introduce a method that explicitly accounts for annotation inaccuracies. To this end, we treat the annotations as active contour models that can deform themselves while preserving their topology. This enables us to jointly train the network and correct potential errors in the original annotations. The result is an approach that boosts performance of deep networks trained with potentially inaccurate annotations.

We propose a novel, connectivity-oriented loss function for training deep convolutional networks to reconstruct network-like structures, like roads and irrigation canals, from aerial images. The main idea behind our loss is to express the connectivity of roads, or canals, in terms of disconnections that they create between background regions of the image. In simple terms, a gap in the predicted road causes two background regions, that lie on the opposite sides of a ground truth road, to touch in prediction. Our loss function is designed to prevent such unwanted connections between background regions, and therefore close the gaps in predicted roads. It also prevents predicting false positive roads and canals by penalizing unwarranted disconnections of background regions. In order to capture even short, dead-ending road segments, we evaluate the loss in small image crops. We show, in experiments on two standard road benchmarks and a new data set of irrigation canals, that convnets trained with our loss function recover road connectivity so well that it suffices to skeletonize their output to produce state of the art maps. A distinct advantage of our approach is that the loss can be plugged in to any existing training setup without further modifications.

Detection of curvilinear structures in images has long been of interest. One of the most challenging aspects of this problem is inferring the graph representation of the curvilinear network. Most existing delineation approaches first perform binary segmentation of the image and then refine it using either a set of hand-designed heuristics or a separate classifier that assigns likelihood to paths extracted from the pixel-wise prediction. In our work, we bridge the gap between segmentation and path classification by training a deep network that performs those two tasks simultaneously. We show that this approach is beneficial because it enforces consistency across the whole processing pipeline. We apply our approach on roads and neurons datasets.

Background Growth differentiation factor 15 (GDF-15) is an emerging cardiovascular biomarker, and a fully automated immunoassay has recently become available. The objectives of the study were to identify biological and lifestyle factors affecting serum GDF-15 concentrations and derive robust reference intervals, and to estimate GDF-15 within-subject biological variation and derived indices. Methods A presumably healthy population of 533 questionnaire-screened adults was used to identify the biological and lifestyle determinants of serum GDF-15. Following stringent exclusion criteria, a final group of 173 individuals was selected to establish GDF-15 reference interval. Twenty-six healthy volunteers were enrolled in the biological variation substudy. Results Using a multiple regression model, age, B-type natriuretic peptide and C-reactive protein as well as smoking status were significantly related to serum GDF-15 concentrations. The upper reference limit (URL) for serum GDF-15 concentrations (90% confidence interval [CI]) was 866 ng/L (733-999 ng/L), with no sex-related difference. Although GDF-15 tended to increase with age, the weak dependence of marker from age does not justify age-related URL. The within-subject CV was 6.3% (95% CI, 4.5%-8.5%), with no sex difference in intraindividual variances. The reference change value (RCV) for GDF-15 was 23%, and two are the specimens required to ensure that the mean GDF-15 result is within ±10% of the individual's homeostatic set point. Conclusions By identifying the main factors influencing serum GDF-15 concentrations, we robustly established the URL to be applied in adult population. As intraindividual variation of GDF-15 is relatively low, monitoring longitudinal changes in its concentrations over time using RCV can be a good alternative for interpreting GDF-15 in clinical setting.

Background: Midregional proadrenomedullin (MR-proADM) is emerging as a prognostic biomarker for detecting the failure of multiple organs. Establishment of scientifically robust reference intervals facilitates interpretation of laboratory test results. The objectives of this study were (i) to establish reliable reference intervals for plasma MR-proADM using a commercially available automated fluoroimmunoassay in apparently healthy individuals, and (ii) to identify biological determinants of MR-proADM concentrations., Methods: A total of 506 questionnaire-identified apparently healthy adults were enrolled in a single-center, cross-sectional study. A final reference group (n=172) was selected after exclusion of obese individuals, those with increased values of laboratory biomarkers indicating asymptomatic myocardial injury or dysfunction, ongoing inflammation, diabetes, dyslipidemia and renal dysfunction and outliers., Results: The 2.5th and 97.5th percentile intervals for MR-proADM values in the reference group (90% confidence interval) were 0.21 (0.19-0.23) and 0.57 (0.55-0.59) nmol/L, respectively. Although older age, higher values of HbA1c, C-reactive protein, B-type natriuretic peptide and body mass index, together with a history of smoking and a decreased estimated glomerular filtration rate were significantly associated with increasing concentrations of MR-proADM in both univariate and multivariate analyses, magnitudes of these relationships were modest and did not substantially influence MR-proADM reference intervals. Sex-dependent difference in MR-proADM reference intervals was not detected [0.19 (0.16-0.22)-0.56 (0.54-0.60) nmol/L in females vs. 0.22 (0.20-0.25)-0.58 (0.57-0.63) nmol/L in males]., Conclusions: Our study successfully established robust reference intervals for MR-proADM concentrations in plasma. Considering the negligible influence of potential biological determinants on plasma MR-proADM, we recommend the adoption of single reference intervals for adult population as a whole.

Background: Appropriately established reference intervals for laboratory biomarkers may help the interpretation of their results and facilitate clinical utilization., Objectives: i) To determine reference intervals for serum galectin-3 measured using the Architect STAT immunoassay, and ii) to identify factors affecting galectin-3 concentrations., Methods: We recruited 533 questionnaire-identified apparently healthy individuals, in which laboratory biomarkers were used to detect asymptomatic myocardial injury and dysfunction, ongoing inflammation, hyperglycemia, dyslipidemia, and renal dysfunction. A final reference group of 180 subjects was selected., Results: 2.5th and 97.5th percentiles of distribution of galectin-3 concentrations in the reference group (90% confidence interval) were 5.9 (5.0-6.8) and 18.1 (17.2-19.0) μg/L, respectively. Older age contributed to higher galectin-3 concentrations, but influenced derived reference intervals to a lesser extent. Other major determinants of galectin-3 concentrations observed in the questionnaire-screened population were not linked to galectin-3 in reference individuals. In aiming to decide if reference limits should be partitioned by age, we compared galectin-3 concentrations in subjects <40 (n=124) and ≥40years (n=56). Higher galectin-3 concentrations were found in older people (median, 12.4μg/L vs. 11.5μg/L, p=0.016). Accounting for manufacturer's declared imprecision at galectin-3 physiological concentrations of <10% (as CV) and the estimated URL for subjects ≥40 (18.8μg/L) and <40 (17.9μg/L), we recommend the adoption of a single URL for the overall adult population., Conclusions: We established reference intervals for galectin-3 in which the effects of biological determinants were irrelevant. Although in healthy subjects age may affect galectin-3 release, this does not appear to necessitate age-related reference limits., (Copyright © 2017. Published by Elsevier Inc.)

Implementation of cardiac troponin (cTn) assays has revolutionized the diagnosis, risk stratification, triage and management of patients with suspected myocardial infarction (MI). The Universal Definition of MI brought about a shift in the diagnostics of MI, from an approach primarily based on electrocardiography (ECG) to one primarily based on biomarkers. Currently, detection of a rise and/or fall in concentration or activity of myocardial necrosis biomarkers, preferentially cTns, with at least one value above the 99th percentile upper reference limit (URL), is the essential component for the diagnosis of MI. High-sensitivity cardiac troponin (hs-cTn) assays with their superior analytical performance were designed to further facilitate clinical decision making. The ability of hs-cTn assays to detect measurable cTn concentrations in at least 50% of healthy individuals, along with their improved precision (expressed as coefficient of variation ≤10% at the 99th percentile URL) associated with increased recognition of changing values, leads to enhanced risk stratification of patients with suspected MI, and also enables them to be used as prognostic tools potentially useful in other patient subsets. In this comprehensive review, we aim to integrate updated laboratory and clinical knowledge regarding hs-cTn assays in order to promote their optimal use in daily practice. We primarily focus on the role of hs-cTn assays in patients with suspected MI, discussing recommended diagnostic algorithms and result interpretation. Emphasis is also placed on the release of cTns following myocardial injury, the characteristics of antibodies used in available cTn immunoassays, and analytical performance of hs-cTn assays. In this paper, we also review potential challenges related to the selection of a healthy reference population in determining 99th percentile values, biological variation of hs-cTns, inequality between hs-cTn assays, and outline the current status of cTnI standardization. Finally, we discuss in detail the diagnostic and prognostic value of hs-cTn assays, including non-coronary causes of cTn elevation, the potential benefits and risks of point-of-care testing, and the unjustified skepticism of some clinicians regarding implementation of hs-cTn assays. In everyday clinical practice, hs-cTn assays are an important diagnostic advance, predominantly for patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS), with suspected non-ST-segment elevation myocardial infarction (NSTEMI). In the NSTE-ACS setting, recently introduced short diagnostic algorithms using hs-cTn assays integrated with careful clinical and ECG assessment were found to substantially reduce the time to final diagnosis, shorten visits to the emergency department and allow earlier safe discharge of low risk subjects. Hs-cTn assays have significantly higher sensitivity and negative predictive value for NSTEMI in comparison to contemporary cTn tests, particularly in early NSTE-ACS presenters. However, due to frequently occurring mild hs-cTn elevations, they are also associated with lower specificity and reduced positive predictive value when compared to previous generations of assays. Our review underscores the need for the education of clinicians and medical laboratory professionals regarding appropriate use and interpretation of hs-cTn assays. Adequate training and clinical experience in using these tests are essential to translate the improved analytical performance of hs-cTn assays into enhanced risk stratification and hopefully better patient outcomes.

Objectives: i) To assess the relationship between lipid markers and high-sensitivity C-reactive protein (hs-CRP), and high-sensitivity cardiac troponin I (hs-cTnI) in the reference population, and ii) to evaluate the impact of lipid markers and hs-CRP on the 99th percentile upper reference limit (URL) for hs-cTnI., Methods: 531 questionnaire-identified presumably healthy individuals were enrolled in a single-center, cross-sectional study. Surrogate biomarkers for diabetes, myocardial and renal dysfunction were used to refine the healthy cohort (n=408). Lipid profile, total cholesterol:high-density lipoprotein cholesterol (HDL-C) ratio, non-HDL-C, apolipoprotein AI (apoAI), apolipoprotein B (apoB), apoB:apoAI ratio, lipoprotein(a), small dense low-density lipoprotein cholesterol (LDL-C) and hs-CRP were determined., Results: Individuals with detectable vs. non-detectable hs-cTnI concentrations more often showed elevated LDL-C (60% vs. 46%; p=0.002), apoB (73% vs. 61%; p=0.008), apoB:apoAI ratio (53% vs. 40%; p=0.005) and lipoprotein(a) (15% vs. 7%; p=0.015). The apoB:apoAI ratio and to a lesser extent other lipid markers, but not hs-CRP, were positively associated with hs-cTnI concentration in univariate and multivariate analyses. Exclusion of individuals with elevated apoB:apoAI ratio or apoB, but not hs-CRP, lowered the 99th percentile URL in the healthy cohort respectively by 12.9% (6.2 vs. 5.4ng/L) and 14.5% (6.2 vs. 5.3ng/L). The corresponding reduction for both lipid biomarkers in the presumably healthy population was 24.0% (7.5 vs. 5.7ng/L)., Conclusion: Our study demonstrates that atherogenic lipid markers, particularly apoB:apoAI ratio or apoB, influence the 99th percentile URL for hs-cTnI., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objective: To establish and critically evaluate the 99th percentile upper reference limit (URL) for high-sensitivity cardiac troponin I (hs-cTnI) in a large healthy European cohort using different selection criteria., Methods: 1368 presumably healthy individuals from 9 countries were evaluated with surrogate biomarkers for diabetes (glycated hemoglobin [HbA1c] < 48 mmol/mol), myocardial (B-type natriuretic peptide [BNP] < 35 pg/mL) and renal dysfunction (estimated glomerular filtration rate [eGFR] >60 mL/min/1.73 m(2)), and dyslipidemia to refine the healthy cohort. The 99th percentile URLs were independently determined by the non-parametric and robust methods., Results: The use of biomarker selection criteria resulted in a decrease of the 99th percentile URL for hs-cTnI from 23.7 to 14.1 ng/L and from 11.2 to 7.1 ng/L, when using the non-parametric percentile and robust methods, respectively; a further reduction after exclusion of individuals with dyslipidemia was noted. Male gender, BNP, HbA1c and smoking status were independently associated with hs-cTnI concentration in the presumably healthy population, while the impact of age, present in the univariate analysis, decreased after adjustments for gender and surrogate biomarkers. The BNP-based inclusion criterion had the most pronounced effect on the 99th percentile URL, excluding 21% of the study participants and decreasing its value to 11.0 (7.1) ng/L according to the non-parametric (robust) method. Gender, but not age-specific, differences at 99th percentile URL have been identified., Conclusion: The selection of a reference population has a critical impact on the 99th percentile value for hs-cTnI. A uniform protocol for the selection of the healthy reference population is needed., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: International recommendations highlight the superior value of cardiac troponins (cTns) for early diagnosis of myocardial infarction along with analytical requirements of improved precision and detectability. In this multicenter study, we investigated the analytical performance of a new high sensitive cardiac troponin I (hs-cTnI) assay and its 99th percentile upper reference limit (URL)., Methods: Laboratories from nine European countries evaluated the ARCHITECT STAT high sensitive troponin I (hs-TnI) immunoassay on the ARCHITECT i2000SR/i1000SR immunoanalyzers. Imprecision, limit of blank (LoB), limit of detection (LoD), limit of quantitation (LoQ) linearity of dilution, interferences, sample type, method comparisons, and 99th percentile URLs were evaluated in this study., Results: Total imprecision of 3.3%-8.9%, 2.0%-3.5% and 1.5%-5.2% was determined for the low, medium and high controls, respectively. The lowest cTnI concentration corresponding to a total CV of 10% was 5.6 ng/L. Common interferences, sample dilution and carryover did not affect the hs-cTnI results. Slight, but statistically significant, differences with sample type were found. Concordance between the investigated hs-cTnI assay and contemporary cTnI assay at 99th percentile cut-off was found to be 95%. TnI was detectable in 75% and 57% of the apparently healthy population using the lower (1.1 ng/L) and upper (1.9 ng/L) limit of the LoD range provided by the ARCHITECT STAT hs-TnI package insert, respectively. The 99th percentile values were gender dependent., Conclusions: The new ARCHITECT STAT hs-TnI assay with improved analytical features meets the criteria of high sensitive Tn test and will be a valuable diagnostic tool.

Despite great progress in prevention strategies, pharmacotherapy and interventional treatment of coronary artery disease (CAD), cardiovascular events still constitute the leading cause of mortality and morbidity in the modern world. Traditional risk factors, including hypertension, diabetes mellitus, smoking, obesity, dyslipidemia, and positive family history account for the occurrence of the majority of these events, but not all of them. Adequate risk assessment remains the most challenging in individuals classified into low or intermediate risk categories. Inflammation plays a key role in the initiation and promotion of atherosclerosis and may lead to acute coronary syndrome (ACS) by the induction of plaque instability. For this reason, numerous inflammatory markers have been extensively investigated as potential candidates for the enhancement of cardiovascular risk assessment. This review aims to critically assess the clinical utility of well-established (C-reactive protein [CRP] and fibrinogen), newer (lipoprotein-associated phospholipase A2 [Lp-PLA2] and myeloperoxidase [MPO]) and novel (growth differentiation factor-15 [GDF-15]) inflammatory markers which, reflect different pathophysiological pathways underlying CAD. Although according to the traditional approach all discussed inflammatory markers were shown to be associated with the risk of future cardiovascular events in individuals with and without CAD, their clear clinical utility remains not fully elucidated. Current recommendations of numerous scientific societies predominantly advocate routine assessment of CRP in healthy people with intermediate cardiovascular risk. However, these recommendations substantially vary in their strength among particular societies. These discrepancies have a multifactorial background, including: (i) the strong prognostic value of CRP supported by solid scientific evidence and proven to be comparable in magnitude with that of total and high-density lipoprotein cholesterol, or hypertension, (ii) favourable analytical characteristics of commercially available CRP assays, (iii) lack of CRP specificity and causal relationship between CRP concentration and cardiovascular risk, and (iv) CRP dependence on other classical risk factors. Of major importance, CRP measurement in healthy men ≥50 years of age or healthy women ≥60 years of age with low-density lipoprotein cholesterol <130 mg/dL may be helpful in the selection of patients for statin therapy. Additionally, evaluation of CRP and fibrinogen or Lp-PLA2 may be considered to facilitate risk stratification in ACS patients and in healthy individuals with intermediate cardiovascular risk, respectively. Nevertheless, the clinical utility of CRP requires further investigation in a broad spectrum of CAD patients, while other promising inflammatory markers, particularly GDF-15 and Lp-PLA2, should be tested in individuals both with and without established CAD. Further studies should also focus on novel performance metrics such as measures of discrimination, calibration and reclassification, in order to better address the clinical utility of investigated biomarkers and to avoid misleadingly optimistic results. It also has to be emphasized that, due to the multifactorial pathogenesis of CAD, detailed risk stratification remains a complex process also involving, beyond assessment of inflammatory biomarkers, the patient's clinical characteristics, results of imaging examinations, electrocardiographic findings and other laboratory parameters (e.g. lipid profile, indices of renal function, markers of left ventricular overload and fibrosis, and biomarkers of myocardial necrosis, preferably cardiac troponins).

Several clinical and genetic variables are associated with influencing high on treatment platelet reactivity (HTPR). The aim of the study was to propose a path model explaining a concurrent impact among variables influencing HTPR and ischemic events. In this prospective cohort study polymorphisms of CYP2C19*2, CYP2C19*17, ABCB1, PON1 alleles and platelet function assessed by Multiple Electrode Aggregometry were assessed in 416 patients undergoing percutaneous coronary intervention treated with clopidogrel and aspirin. The rates of major adverse cardiac events (MACE) were recorded during a 12-month follow up. The path model was calculated by a structural equation modelling. Paths from two clinical characteristics (diabetes mellitus and acute coronary syndrome (ACS)) and two genetic variants (CYP2C19*2 and CYP2C19*17) independently predicted HTPR (path coefficients: 0.11 0.10, 0.17, and -0.10, respectively; p<0.05 for all). By use of those four variables a novel score for prediction of HTPR was built: in a factor-weighted model the risk for HTPR was calculated with an OR of 3.8 (95%CI: 3.1-6.8, p<0.001) for a score level of ≥1 compared with a score of <1. While MACE was independently predicted by HTPR and age in the multivariate model (path coefficient: 0.14 and 0.13, respectively; p<0.05), the coexistence of HTPR and age ≥75 years emerged as the strongest predictor of MACE. Our study suggests a pathway, which might explain indirect and direct impact of variables on clinical outcome: ACS, diabetes mellitus, CYP2C19*2 and CYP2C19*17 genetic variants independently predicted HTPR. In turn, age ≥75 years and HTPR were the strongest predictors of MACE.

Objectives: To perform a systematic up-to-date review and critical discussion of potential clinical applications of cangrelor based on its pharmacologic properties and the main findings from randomized clinical studies., Methods: A database search (PubMed, CENTRAL and Google Scholar) by two independent investigators, including proceedings from scientific sessions of ACC, AHA, ESC, TCT and EuroPCR, from January 1998 through December 2013., Results: Cangrelor is a potent, intravenous, direct-acting P2Y12 antagonist with rapid onset and quickly reversible action. In contrast to ticagrelor, cangrelor's interaction with thienopiridines requires termination of cangrelor infusion before switching to clopidogrel or prasugrel. According to randomized trials, a cangrelor-clopidogrel combination is relatively safe and more effective than the standard clopidogrel regimen in both urgent and elective percutaneous coronary intervention (PCI) settings, with the advantage of this drug combination fully evident when the universal definition of myocardial infarction is applied. In contrast to available antiplatelet drugs with delayed onset and offset of action, its favorable properties make cangrelor a desirable agent for ad hoc elective PCI, high risk acute coronary syndromes treated with immediate coronary stenting and for bridging those surgery patients who require periprocedural P2Y12 inhibition. Current evidence on cangrelor therapy is limited by the lack of adequately powered studies assessing cangrelor co-administration either with prasugrel or ticagrelor, suboptimal design of some of the trials favoring cangrelor, potentially attenuated benefits with modern stent design, and finally, by the lack of survival advantage., Conclusions: With its pharmacokinetic and pharmacodynamic advantages, allowing consistent and strong P2Y12 inhibition, and with its rapid onset and swift reversal of action devoid of need for an antidote, cangrelor might improve clinical outcomes in clopidogrel-treated patients by reducing ischemic events, while maintaining a favorable safety profile. However, further studies, addressing the safety and efficacy of cangrelor on top of novel oral P2Y12 inhibitors, are warranted.

Background: Recently, randomized controlled trials (RCTs) have shown that therapy with new oral activated factor X (Xa) inhibitors in acute coronary syndrome (ACS) yielded a reduction of ischemic events. However, this therapy was associated with a dose-related increase in major bleeding complications. We aimed to perform a systematic review and meta-analysis to appraise the clinical efficacy and safety of the lowest doses of oral factor Xa inhibitors compared with placebo in patients after a recent ACS., Methods: The primary endpoint was cardiovascular mortality. The rate of new myocardial infarction (MI) was the secondary efficacy endpoint, whereas major bleeding complications were recorded as a safety endpoint. Five RCTs were included in the meta-analysis enrolling a total of 25,643 patients., Results: There was no significant difference in mortality between patients treated with new antithrombotics compared with those receiving the standard therapy: odds ratio (OR), [95% confidence interval (CI)] = 0.97 [0.72-1.31], p = 0.86. Recurrent MI rates were decreased in the anti-Xa group: OR [95%CI] = 0.86 [0.76-0.98], p = 0.02, number needed to treat (NNT) = 189. The administration of new oral anticoagulants was associated with a strongly increased risk of major bleedings compared with the standard treatment: OR [95%CI] = 3.24 [2.29-4.59], p < 0.001, number needed to harm (NNH) = 104; similarly, intracranial bleeding rates were significantly higher in the anti-Xa arm., Conclusions: The addition of the new oral anticoagulants on top of standard therapy in the setting of ACS results in an excessive risk of major bleedings without any clear evidence of outweighing clinical benefits., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)