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This study aims to determine the association between social jetlag and parameters of metabolic syndrome and type 2 diabetes (T2D) in a systematic review and meta-analysis. A systematic literature search was conducted in PubMed/Embase/Scopus until May 2022. Included studies described an association between social jetlag and parameters of the metabolic syndrome and/or T2D, were available full text and written in English or Dutch. Data extraction and quality assessment were performed on pre-piloted forms independently by two reviewers. Results were meta-analysed using random-effects analysis. A total of 6,290 titles/abstracts were screened, 176 papers were read full-text, 68 studies were included. Three studies were rated as low quality, 27 were moderate, and 38 were high quality. High quality studies showed that having social jetlag compared to no social jetlag was significantly associated with higher body mass index in 20 studies (0.49 kg/m2, 95% confidence interval [CI] 0.21–0.77; I2 = 100%), higher waist circumference in seven studies (1.11 cm, 95% CI 0.42–1.80; I2 = 25%), higher systolic blood pressure in 10 studies (0.37 mmHg, 95% CI 0.00–0.74; I2 = 94%) and higher glycated haemoglobin in 12 studies (0.42%, 95% CI 0.12– 0.72; I2 = 100%). No statistically significant associations were found for obesity, abdominal obesity, high- and low-density lipoprotein levels, cholesterol, triglycerides, diastolic blood pressure, hypertension, fasting glucose, homeostatic model assessment for insulin resistance, metabolic syndrome or T2D. Sensitivity analyses did not reduce heterogeneity. Despite substantial heterogeneity, social jetlag is associated with certain parameters of the metabolic syndrome and T2D, but not with prevalent metabolic syndrome or T2D. These findings should be interpreted with caution as the level of evidence is low and mostly based on cross-sectional data. Longitudinal studies are needed to further assess the direction of causality.

The causal effects of alcohol-in-moderation on cardiometabolic health are continuously debated. Mendelian randomization (MR) is an established method to address causal questions in observational studies. We performed a systematic review of the current evidence from MR studies on the association between alcohol consumption and cardiometabolic diseases, all-cause mortality and cardiovascular risk factors. We performed a systematic search of the literature, including search terms on type of design and exposure. We assessed methodological quality based on key elements of the MR design: use of a full instrumental variable analysis and validation of the three key MR assumptions. We additionally looked at exploration of non-linearity. We reported the direction of the studied associations. Our search yielded 24 studies that were eligible for inclusion. A full instrumental variable analysis was performed in 17 studies (71%) and 13 out of 24 studies (54%) validated all three key assumptions. Five studies (21%) assessed potential non-linearity. In general, null associations were reported for genetically predicted alcohol consumption with the primary outcomes cardiovascular disease (67%) and diabetes (75%), while the only study on all-cause mortality reported a detrimental association. Considering the heterogeneity in methodological quality of the included MR studies, it is not yet possible to draw conclusions on the causal role of moderate alcohol consumption on cardiometabolic health. As MR is a rapidly evolving field, we expect that future MR studies, especially with recent developments regarding instrument selection and non-linearity methodology, will further substantiate this discussion.

ObjectiveManagement of thoracic aortic aneurysms (TAAs) comprises regular diameter follow-up until the indication criterion for prophylactic surgery is reached. However, this approach is unable to predict the majority of acute type A aortic dissections (ATAADs). The current study aims to evaluate the diagnostic accuracy of ascending aortic diameter, length and volume for occurrence of ATAAD.MethodsThis two-centre observational cohort study retrospectively screened 477 consecutive patients who presented with ATAAD between 2009 and 2018. Of those, 25 (5.2%) underwent CT angiography (CTA) within 2 years before dissection onset. Aortic diameter, length and volume of these patients (‘pre-ATAAD’) were compared with those of TAA controls (n=75). Receiver operating curve analysis was performed to evaluate the predictive accuracy of the three different measurements.Results96% of patients with pre-ATAAD did not meet the surgical diameter threshold of 55 mm before dissection onset. Maximal aortic diameters (45 (40–49) mm vs 46 (44–49) mm, p=0.075) and volume (126 (95–157) cm3 vs 124 (102–136) cm3, p=0.909) were comparable between patients with pre-ATAAD and TAA controls. Conversely, ascending aortic length (84±9 mm vs 90±16 mm, p=0.031) was significantly larger in patients with pre-ATAAD. All three parameters had an area under the curve of >0.800. At the 55 mm cut-off point, the maximal diameter yielded a positive predictive value (PPV) of 20%. While maintaining same specificity levels, measurements of aortic volume and length showed superior diagnostic accuracy (PPV 55% and 70%, respectively).ConclusionMeasurements of aortic volume and length have superior diagnostic accuracy compared with the maximal diameter and could improve the timely identification of patients at risk for ATAAD.

Objective: Diabetic kidney disease is a microvascular complication of diabetes. Here, we assessed the association between skin microvascular function and renal hemodynamic function in a cohort of well-phenotyped adults with type 2 diabetes (T2D). Methods: We included 81 overweight/obese adults (age: 62 ± 8 years; BMI: 32 ± 4 kg/m2) with well-controlled T2D and no renal impairment. Skin microvascular function was assessed by nailfold capillary density in rest and after arterial occlusion (ie, peak capillary density). Renal hemodynamic functions (ie, measured glomerular filtration rate [mGFR], effective renal blood flow [ERBF], filtration fraction [FF], and effective renal vascular resistance [ERVR]) were assessed by combined inulin and para-aminohippurate clearances and blood pressure measurements. Results: Skin capillary density was 45 ± 10 capillaries/mm2 at baseline and 57 ± 11 capillaries/mm2 during post-occlusive peak; mGFR averaged 108 ± 20 ml/min. In multivariable regression analyses, positive associations between capillary density during post-occlusive peak and mGFR (β = 0.224; p = 0.022) and ERBF (β = 0.203; p = 0.020) and a positive trend for hyperemia and mGFR (β = 0.391; p = 0.053) were observed, while a negative association for post-occlusive capillary density with ERVR (β = −0.196; p = 0.027) was found. Conclusion: These findings indicate that microvascular dysfunction in overweight adults with T2D is associated with lower mGFR and ERPF and higher ERVR. We hypothesize that increased renal vascular resistance may contribute to glomerular dysfunction due to impaired renal perfusion.

In this paper we present practical protocols for secure ridge regression. We develop the necessary secure linear algebra tools, using only basic arithmetic over prime fields. In particular, we will show how to solve linear systems of equations and compute matrix inverses efficiently, using appropriate secure random self-reductions of these problems. The distinguishing feature of our approach is that the use of secure fixed-point arithmetic is avoided entirely, while circumventing the need for secure rational reconstruction at any stage as well. In fact, in recent follow-up works, our results have already been applied and extended to several other settings.

Atrial fibrillation (AF), the most common, progressive tachyarrhythmia is associated with serious complications, such as stroke and heart failure. Early recognition of AF, essential to prevent disease progression and therapy failure, is hampered by the lack of accurate diagnostic serum biomarkers to identify the AF stage. As we previously showed mitochondrial dysfunction to drive experimental and human AF, we evaluated whether cell-free circulating mitochondrial DNA (cfc-mtDNA) represents a potential serum marker. Therefore, the levels of two mtDNA genes, COX3 and ND1, were measured in 84 control patients (C), 59 patients undergoing cardiac surgery without a history of AF (SR), 100 paroxysmal (PAF), 116 persistent (PeAF), and 20 longstanding-persistent (LS-PeAF) AF patients undergoing either cardiac surgery or AF treatment (electrical cardioversion or pulmonary vein isolation). Cfc-mtDNA levels were significantly increased in PAF patients undergoing AF treatment, especially in males and patients with AF recurrence after AF treatment. In PeAF and LS-PeAF, cfc-mtDNA levels gradually decreased. Importantly, cfc-mtDNA in serum may originate from cardiomyocytes, as in vitro tachypaced cardiomyocytes release mtDNA in the medium. The findings suggest that cfc-mtDNA is associated with AF stage, especially in males, and with patients at risk for AF recurrence after treatment.

Genomic studies in African populations provide unique opportunities to understand disease etiology, human diversity, and population history. In the largest study of its kind, comprising genome-wide data from 6,400 individuals and whole-genome sequences from 1,978 individuals from rural Uganda, we find evidence of geographically correlated fine-scale population substructure. Historically, the ancestry of modern Ugandans was best represented by a mixture of ancient East African pastoralists. We demonstrate the value of the largest sequence panel from Africa to date as an imputation resource. Examining 34 cardiometabolic traits, we show systematic differences in trait heritability between European and African populations, probably reflecting the differential impact of genes and environment. In a multi-trait pan-African GWAS of up to 14,126 individuals, we identify novel loci associated with anthropometric, hematological, lipid, and glycemic traits. We find that several functionally important signals are driven by Africa-specific variants, highlighting the value of studying diverse populations across the region.

Metropolitan areas play an undetermined role in supporting migratory monarch butterfly (Danaus plexippus) populations despite providing habitat areas rich with milkweed (Asclepias spp.), the obligate host plants for monarch larvae. Researchers from the US Geological Survey and collaborating institutions have called for an “all hands on deck” approach to establishing monarch butterfly habitat by focusing on potential contributions from all land use sectors at levels necessary to sustain the eastern migratory monarch butterfly population. To understand the current and potential contribution of milkweed stems in metropolitan areas, our research teams surveyed milkweed densities using a new “metro-transect” protocol and conducted interviews and surveys across a diverse set of stakeholder groups in four major metropolitan areas (Chicago, Minneapolis-St. Paul, Kansas City, and Austin). We developed Geographic Information System (GIS) tools that use these data to model existing milkweed stems in metropolitan areas, and to estimate the potential to add additional milkweed stems with the adoption of milkweed-friendly planting practices across different land use classes (e.g., residential, institutional, and commercial). By extrapolating metropolitan Chicago milkweed densities across US Census urbanized areas in the northern US range of the eastern monarch butterflies, we estimate that approximately 29.8 million stems of milkweed can be added under modest “enhanced” milkweed densities, and up to 271 million stems may be added under “exemplary” milkweed densities. Both estimates are derived from a two percent “adoption rate,” or landowner conversion of green spaces. These findings show that metropolitan areas provide important habitat opportunities and should be included prominently in monarch conservation strategies when working toward national goals to increase the amount of milkweed stems and monarch habitat across the Midwest. Municipal decision-makers and planners can estimate their capacity to add stems across the metropolitan landscape by identifying where the biggest opportunities exist with help from our Urban Monarch Conservation Planning Tools.

It is well-established that cities need nature for critical ecosystem services—from storing carbon, to reducing temperatures, to mitigating stormwater—and there is growing momentum to seek out strategies for how these services can intersect with urban design and planning efforts. Social scientists and conservation planners increasingly point to urban residents' need to breathe fresh air, encounter the natural world, and have room to play. It is less obvious, perhaps, whether nature needs cities in order to thrive. The evidence from both urban planning and conservation planning is increasingly “yes.” As changes in land use and land cover sweep the planet, cities are becoming important refugia for certain wildlife populations. In recent years, urban planning has embraced the concept of “green infrastructure” as a way to embed green space across metropolitan landscapes to draw on the inherent benefits nature provides to cities, as well as to create habitat for wildlife. We explore this evolving view of cities and nature in the fields of urban and conservation planning. We argue the time is ripe to bring these worlds together, and, using our empirical work, establish that cities matter for monarch butterflies, other pollinators, and at-risk wildlife species.

Aims Therapeutic windows for residual platelet reactivity in patients with coronary artery disease on P2Y12 inhibitors were proposed in a consensus document. We aimed to explore the level of agreement between windows for different platelet function tests (PFTs) used to classify patients in low, optimal, and high on-treatment platelet reactivity categories, and to identify variables contributing to the level of agreement.Methods and results In this explorative clinical study, the VerifyNow P2Y12, Multiplate adenosine diphosphate (ADP), and light transmission aggregometry (LTA) 20 mu mol/L ADP were performed simultaneously in 145 consecutive vulnerable patients. Measurements were performed within 6 months of percutaneous intervention. Patients were considered vulnerable if they had >= 2 risk factors for bleeding or ischaemic events. Window-agreement between PFT pairs was slight to moderate. Multiplate-VerifyNow agreed in 72 patients (50%), kappa = 0.41; VerifyNow-LTA agreed in 76 patients (52%), kappa = 0.36; and LTA-Multiplate agreed in 64 patients (44%), kappa = 0.20. Several variables including the type of P2Y12 inhibitor, aspirin, haemoglobin level, platelet count, age, and previous stroke significantly influenced agreement between PFTs.Conclusions Our results suggest that the PFTs, with accompanying therapeutic windows, are not interchangeable when determining the response to antiplatelet therapy in vulnerable coronary artery disease patients on P2Y12 inhibitors. Hence, the type of PFT can directly affect the treatment strategy, which may be especially relevant for patients with multiple factors influencing individual PFTs and thereby test agreement.

The Gravity field and steady-state Ocean Circulation Explorer (GOCE) is the European Space Agency's (ESA)satellite gravity mission to determine the Earth's mean gravity field. GOCE delivers gravity gradients, anew type of satellite data. We study how these data can improve modeling of the Earth's lithosphere. We discuss the use of the original GOCE gravity gradients versus the use of gravity gradients in grids at satellite altitude or close the Earth's surface and conclude that grids are easier to handle than the original data because one does not have to deal with very different error characteristics of the different gradients, given in a rotating frame at varying heights. The downward continuation to the surface enhances signaland better reflects the near-surface geology. But this does not outweigh the amplification of noise and omission errors, which is why we recommend using the field at mean satellite altitude for lithospheric modeling. The North-East Atlantic region is ideal to analyze the additional value of GOCE gravity gradients because it is a well-studied region in terms of regional geophysics. We calculated the gradient sensitivity for crustal depth slices using a 3D lithospheric model. This reveals that especially interfaces with large density contrasts have a distinct signal in the gravity gradients, but that they are quite insensitive to intra-crustal density sources, which can have quite a large effect on surface gravity data. We also show thatthe satellite gradients have a depth sensitivity well suited to study the upper mantle density structure, making them complementary to gravity and seismic tomography. In the underexplored Rub'al-Khaliarea the GOCE vertical gradient was used to invert for crustal thickness. The updated Moho model givesa good fit to four of the six gradients and independent depths from seismic stations. The Moho modelwas used to update the heat flow model and source rock maturity maps, which are generally consistent with known source rock maturity trends in the surrounding regions. GOCE gradients are therefore usefulto map crustal thickness and deep regional structures for frontier areas. In combination with other data, heat flow can be modeled which is essential for basin maturity evaluation. © 2013 Elsevier B.V.

This paper focuses on the problem of controlling an ensemble of heterogeneous resources connected to an electrical grid at the same point of common coupling (PCC). The controller receives an aggregate power setpoint for the ensemble in real time and tracks this setpoint by issuing individual optimal setpoints to the resources. The resources can have continuous or discrete nature (e.g., heating systems consisting of a finite number of heaters that each can be either switched on or off) and/or can be highly uncertain (e.g., photovoltaic (PV) systems or residential loads). A naïve approach would lead to a stochastic mixed-integer optimization problem to be solved at the controller at each time step, which might be infeasible in real time. Instead, we allow the controller to solve a continuous convex optimization problem and compensate for the errors at the resource level by using a variant of the well-known error diffusion algorithm. We give conditions guaranteeing that our algorithm tracks the power setpoint at the PCC on average while issuing optimal setpoints to individual resources. We illustrate the approach numerically by controlling a collection of batteries, PV systems, and discrete loads.

Vijf MANP-studenten van Hogeschool Inholland in Amsterdam keken een week mee in de keuken van verscheidene verpleegkundig specialisten in de Verenigde Staten van Amerika. Zij liepen mee in enkele ziekenhuizen van de stad Columbia, in de staat South Carolina.

SummaryPatients with chronic kidney disease (CKD) have an increased risk of cardiovascular disease. Previous studies have suggested that patients with CKD have less therapeutic benefit of antiplatelet therapy. However, the relation between renal function and platelet reactivity is still under debate. On-treatment platelet reactivity was determined in parallel by ADP- and AA-induced light transmittance aggregometry (LTA) and the VerifyNow® System (P2Y12 and Aspirin) in 988 patients on dual antiplatelet therapy, undergoing elective coronary stenting. Patients were divided into two groups according to the presence or absence of moderate/severe CKD (GFRClinical Trial Registration: www.clinicaltrials.gov: NCT00352014.

To investigate the impact of genotypes on the basis of the loss-of-function variant CYP2C19*2 and the gain-of-function variant CYP2C19*17 on on-treatment platelet reactivity and on the occurrence of Thrombolysis in Myocardial Infarction (TIMI) major bleedings in 820 clopidogrel-treated patients who underwent elective coronary stenting.On-treatment platelet reactivity was quantified using ADP-induced light transmittance aggregometry (LTA) and the VerifyNow P2Y12 assay. Postdischarge TIMI major bleedings within 1 year after enrollment were recorded.In total, 25 major bleedings (3.0% of the study population) were observed. Patients with the CYP2C19*1/*17 and *17/*17 diplotypes exhibited a lower magnitude of platelet reactivity as compared with patients with the CYP2C19*1/*1 diplotype (for the light transmittance aggregometry-adjusted mean difference: -5.8%, 95% confidence interval: -9.6 to -2.1, P=0.002). Patients with the *1/*17 and *17/*17 genotype had a 2.7-fold increased risk in the occurrence of major bleedings [adjusted hazard ratio: 2.7, 95% confidence interval: 1.1-7.0, P=0.039]. The diplotypes *2/*17, *1/*2, and *2/*2 exhibited higher on-treatment platelet reactivity as compared with the wild type (P0.0001). However, this was not translated into an altered risk on major bleedings as compared with the wild type [hazard ratio: 1.3 (0.45-4.0), P=0.60]. Results have not been adjusted for multiple testing.Patients with the CYP2C19*1/*17 and *17/*17 diplotype have a lower magnitude of on-treatment platelet reactivity and are at a 2.7-fold increased risk of postdischarge TIMI major bleeding events after coronary stenting than patients with the *1/*1 genotype. The diplotypes *2/*17, *1/*2, and *2/*2 are associated with increased on-treatment platelet reactivity; however, this is not translated into a lower risk of bleeding events.

Background Previous studies have suggested that women do not accrue equal therapeutic benefit from antiplatelet medication as compared with men. The physiological mechanism and clinical implications behind this gender disparity have yet to be established. Methods On-treatment platelet reactivity was determined in 717 men and 234 women on dual antiplatelet therapy, undergoing elective coronary stent implantation. Platelet function testing was performed using arachidonic acid and adenosine diphosphate-induced light transmittance aggregometry (LTA) and the VerifyNow P2Y12 and Aspirin assays. Also the incidence of all-cause death, non-fatal acute myocardial infarction, stent thrombosis and ischaemic stroke was evaluated. Results Women had higher baseline platelet counts than men. Women exhibited a higher magnitude of on-aspirin platelet reactivity using LTA, but not using the VerifyNow Aspirin assay. The magnitude of on-clopidogrel platelet reactivity was significantly higher in women as compared with men with both tests used. The cut-off value to identify patients at risk as well as the incidence of clinical endpoints was similar between women and men (16/234[6.8%] vs. 62/717[8.6%], p = 0.38). Conclusion Although the magnitude of platelet reactivity was higher in women, the absolute difference between genders was small and both the cut-off value to identify patients at risk and the incidence of the composite endpoint were similar between genders. Thus, it is unlikely that the difference in platelet reactivity accounts for a worse prognosis in women.

Summary. Background: The pathophysiology of stent thrombosis (ST) has evolved from the identification of single causative factors to a complex multifactorial model. Objectives: The aim of the present study was to investigate whether patients with a history of ST exhibit heightened platelet reactivity to clopidogrel and aspirin. Patients/methods: Pretreatment and on-treatment platelet reactivity to clopidogrel and aspirin, as well as dual antiplatelet therapy resistance, was determined in 84 patients with a history of definite ST (cases: 41 early ST; 43 late ST) and in 103 control patients with a previously implanted coronary stent but no ST after the index procedure. Platelet function was evaluated with optical aggregometry, the VerifyNow P2Y12 and aspirin assays, the PFA-100 Innovance P2Y* cartridge, the flow cytometric vasodilator-stimulated phosphoprotein assay and urine 11-dehydrothromboxane B2 measurement before and after the administration of a 600-mg loading dose of clopidogrel and 100 mg of aspirin. The study was registered at ClinicalTrials.gov, number NCT01012544. Results: Patients with a history of early ST clearly demonstrated higher on-clopidogrel platelet reactivity than controls. Patients with both early and late ST exhibited heightened on-aspirin platelet reactivity status, and dual antiplatelet therapy resistance was more frequent. Conclusions: Patients with a history of early ST exhibit a poor response to clopidogrel. Furthermore, both early and late ST are strongly and independently associated with heightened on-aspirin platelet reactivity, and dual antiplatelet therapy resistance is more frequent.

Aim High on-clopidogrel platelet reactivity (HCPR) and high on-aspirin platelet reactivity (HAPR) are associated with atherothrombotic events following coronary stenting. There are, however, few data concerning high on-treatment platelet reactivity to both aspirin and clopidogrel simultaneously. The aim of the present study was to determine the incidence of dual high on-treatment platelet reactivity (DAPR) and its impact on clinical outcome. Methods On-treatment platelet reactivity was measured in parallel by ADP- and arachidonic acid-induced light transmittance aggregometry (LTA) (n¼921) and the point-of-care VerifyNow system (P2Y12 and aspirin) (n¼422) in patients on dual antiplatelet therapy undergoing elective stent implantation. HCPR and HAPR were established by receiver-operator characteristic curve analysis. The primary endpoint was a composite of all-cause death, non-fatal acute myocardial infarction, stent thrombosis and ischaemic stroke at 1-year follow-up. Results The incidence of DAPR varied between 14.7% and 26.9% depending on the platelet function test used. DAPR, assessed by LTA and the VerifyNow system, was highly associated with an adverse clinical outcome. At 1-year follow-up the primary endpoint occurred more frequently in patients with isolated HCPR (11.7%), isolated HAPR (9.6%) or DAPR (10.7%) compared with patients without high on-treatment platelet reactivity (4.2%, all p

Background The TRITON-TIMI 38 study has identified three subgroups of patients with a higher risk of bleeding during treatment with the thienopyridine prasugrel: patients with a history of stroke or transient ischaemic attack (TIA), patients >= 75 years and patients with a body weight = 75 years and a history of stroke were independent predictors of a higher on-treatment platelet reactivity. In contrast, a body weight = 75 years and patients with previous stroke, onclopidogrel platelet reactivity is increased. In contrast, in patients with a low body weight, on-clopidogrel platelet reactivity is decreased, suggesting that a stronger response to a thienopyridine might only lead to more bleeds in patients with low body weight

Summary. Background: High on-aspirin platelet reactivity (HAPR) is associated with atherothrombotic events following percutaneous coronary intervention (PCI). The aim of the present study was to identify the platelet function test sensitive for platelet cyclooxygenase-1 inhibition that best predicts atherothrombotic events. Methods and results: Nine hundred and fifty-one consecutive patients on dual antiplatelet therapy undergoing elective PCI were enrolled. On-aspirin platelet reactivity was measured in parallel by arachidonic acid (AA)-induced light transmittance aggregometry (AA-induced LTA), the VerifyNow® Aspirin Assay (VerifyNow® Aspirin Assay), the arachidonic acid prestimulated IMPACT-R (IMPACT-R AA) and the PFA-100 collagen/epinephrine cartridge (PFA COL/EPI). Cut-offs for HAPR were established by receiver-operator characteristic curve analysis. At 1-year follow-up, the composite of all-cause death, non-fatal acute myocardial infarction, stent thrombosis and ischemic stroke occurred more frequently in patients with HAPR when assessed by LTA [10.1% vs. 6.0%, P = 0.020 (n = 925)] and VerifyNow® [13.3% vs. 5.9%, P = 0.015 (n = 422)]. The VerifyNow® ASA assay (AUC = 0.78) and, to a lesser extent, AA-induced LTA (AUC = 0.73) added significantly to a model consisting of clinical and procedural risk factors in predicting atherothrombotic events. In contrast, the IMPACT-R (n = 791) and the PFA Collagen/Epinephrine (n = 719) were unable to discriminate between patients with and without primary endpoint at 1-year follow-up. None of the platelet function tests was able to identify patients at risk for bleeding. Conclusions: AA-induced LTA and the VerifyNow® ASA test were able to identify aspirin-treated patients undergoing PCI with stenting at risk for atherothrombotic events. The VerifyNow® Aspirin Assay had the highest predictive accuracy. None of the tests was able to identify patients at higher risk of bleeding.

The individual response to clopidogrel therapy is unpredictable, resulting in high on-treatment platelet reactivity in a substantial number of patients. Moreover, consistent findings across multiple investigations point out that a strong relationship exists between high on-treatment platelet reactivity and the occurrence of atherothrombotic events.This paper describes the current available methods of platelet function evaluation, including their advantages and drawbacks, reviews the evidence for the relation between high on-treatment platelet reactivity and clinical outcome, and discusses data concerning the clinical implications of platelet function testing in patients treated with thienopyridine therapy.The reader will be introduced to platelet function testing and its clinical applicability. The reader will gain a better understanding of the techniques used and will learn how to interpret the numerous data on platelet function testing and clinical outcome.Although a growing body of evidence demonstrates the promising potential of platelet function tests in predicting atherothrombotic events post stenting, platelet function testing should not yet be used routinely, as adequate treatment of high on-treatment platelet reactivity is unknown.

A simple and rapid point-of-care platelet function assay that guides antiplatelet responses to aspirin and clopidogrel may be of great clinical value for the individual tailoring of therapy. The Plateletworks assay is based on single platelet counting and has been described as a promising point-of-care assay for the monitoring of the effects of the GP IIb/IIIa antagonists. However, data about its utility and reliability in monitoring the effects of thienopyridines is limited. In the present study we assessed reproducibility of the Plateletworks assay over time. In addition, a comparison between the Plateletworks assay and optical aggregometry was performed in a large cohort of patients on maintenance therapy with aspirin and clopidogrel. The Plateletworks assay demonstrated a good agreement with optical aggregometry in measuring the response to clopidogrel. The results of Plateletworks are, however, highly time dependent which implicates that measurements should be performed within 10 min.

SummaryNovel P2Y12 inhibitors are in development to overcome the occurrence of atherothrombotic events associated with poor responsiveness to the widely used P2Y12 inhibitor clopidogrel. Cangrelor is an intravenously administered P2Y12 inhibitor that does not need metabolic conversion to an active metabolite for its antiplatelet action, and as a consequence exhibits a more potent and consistent antiplatelet profile as compared to clopidogrel. It was the objective of this study to determine the contribution of variation in the P2Y12 receptor gene to platelet aggregation after in vitro partial P2Y12 receptor blockade with the direct antagonist cangrelor. Optical aggregometry was performed at baseline and after in vitro addition of 0.05 and 0.25 μM cangrelor to the platelet-rich plasma of 254 healthy subjects. Five haplotype-tagging (ht)-SNPs covering the entire P2Y12 receptor gene were genotyped (rs6798347C>t, rs6787801T>c, rs9859552C>a, rs6801273A>g and rs2046934T>c [T744C]) and haplotypes were inferred. The minor c allele of SNP rs6787801 was associated with a 5% lower 20 μM ADP-induced peak platelet aggregation (0.05 μM cangrelor, p

The prodrug, clopidogrel, plays an important role in the prevention of thrombotic events in patients undergoing coronary stenting. However, a substantial number of atherothrombotic events still occur, which can partially be explained by heightened residual platelet reactivity. Several studies report that the genetic variation in CYP2C19 (*2) is associated with an impaired response to clopidogrel.To evaluate the effect of genetic variants affecting clopidogrel's absorption (ABCB1 C1236T, G2677T/A, C3435T), metabolism (CYP2C9*2, *3, CYP2C19*3, CYP3A4*1B, and CYP3A5*3), and pharmacodynamics (P2Y1 A1622G) on top of the influence of CYP2C19*2 on platelet reactivity in patients undergoing elective coronary stenting on dual antiplatelet therapy.Platelet function was assessed by light transmittance aggregometry and VerifyNow P2Y12 assay in 428 consecutive patients. Patients were either on chronic clopidogrel maintenance therapy (75 mg/day foror =5 days before the intervention) or received a 300 mg clopidogrel loading dose (1-5 days before the intervention, followed by 75 mg/day). Linear and logistic regressions were used to assess the associations between genetic variants and platelet reactivity and poor responder status.In both the treatment groups, CYP2C19*2-carriage was associated with higher platelet reactivity (P0.002) and poor responder status; 75 mg group: adjusted odds ratio (ORadj): 3.8, 95% confidence interval (CI): 2.0-7.2, 300 mg group: ORadj: 4.1, 95% CI: 1.6-10.4. In the 300 mg group, CYP2C9*3-carriage was associated with higher platelet reactivity (P0.05) and poor responder status (ORadj: 11.1, 95% CI: 1.6-78.8, P=0.016).Besides CYP2C19*2, the variant allele CYP2C9*3 plays an important role in the response to clopidogrel in patients on dual antiplatelet therapy undergoing coronary stenting.