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BACKGROUND: For patients with oral anticoagulants (OAC) undergoing percutaneous coronary intervention (PCI), European guidelines have recently changed their recommendations to dual antithrombotic therapy (DAT; P2Y12 inhibitor and OAC) without aspirin.AIMS: The prospective WOEST 2 registry was designed to obtain contemporary real-world data on antithrombotic regimens and related outcomes after PCI in patients with an indication for OAC.METHODS: In this analysis, we compare DAT (P2Y12 inhibitor and OAC) to triple antithrombotic therapy (TAT; aspirin, P2Y12 inhibitor, and OAC) on thrombotic and bleeding outcomes after one year. Clinically relevant bleeding was defined as Bleeding Academic Research Consortium classification (BARC) grade 2, 3, or 5; major bleeding as BARC grade 3 or 5. Major adverse cardiac and cerebrovascular events (MACCE) was defined as a composite of all-cause mortality, myocardial infarction, stent thrombosis, ischaemic stroke, and transient ischaemic attack.RESULTS: A total of 1,075 patients were included between 2014 and 2021. Patients used OAC for atrial fibrillation (93.6%) or mechanical heart valve prosthesis (4.7%). Non-vitamin K oral anticoagulant (NOAC) was prescribed in 53.1% and vitamin K antagonists in 46.9% of patients. At discharge, 60.9% received DAT, and 39.1% TAT. DAT was associated with less clinically relevant and similar major bleeding (16.8% vs 23.4%; pCONCLUSIONS: Dual antithrombotic therapy is associated with a substantially lower risk of clinically relevant bleeding without a statistically significant penalty in ischaemic events.

The POPular Genetics trial demonstrated that a CYP2C19 genotype-guided P2YIn this analysis, we aimed to evaluate the cost effectiveness of a genotype-guided strategy compared with standard treatment with ticagrelor or prasugrel.A 1-year decision tree based on the POPular Genetics trial in combination with a lifelong Markov model was developed to compare costs and quality-adjusted life-years (QALYs) between a genotype-guided and a standard P2YBase-case analysis with a hypothetical cohort of 1000 subjects demonstrated 8.98 QALYs gained and €725,550.69 in cost savings for the genotype-guided strategy (dominant). The deterministic and probabilistic sensitivity analysis confirmed the robustness of the model and the cost-effectiveness results. In scenario analyses, the genotype-guided strategy remained dominant.In patients undergoing primary PCI, a CYP2C19 genotype-guided strategy compared with standard treatment with ticagrelor or prasugrel resulted in QALYs gained and cost savings.Clinicaltrials.gov number: NCT01761786, Netherlands trial register number: NL2872.

Aims The aim of this study was to systematically assess the effects of antiplatelets on clinical outcomes in patients with atrial fibrillation (AF), treated and not-treated with oral anticoagulation. Methods and results We searched MEDLINE, Embase, and CENTRAL from inception until September 2020. From 5446 citations, we selected randomized trials allocating patients with AF to antiplatelet therapy vs. control. We applied random-effects models for meta-analysis and assessed potential effect modification with background anticoagulation use. Eighteen trials including 21 518 participants met our prespecified eligibility criteria. In 10 studies without background anticoagulation, antiplatelets reduced all-cause stroke [486/6165 (events/patients) vs. 621/6061; risk ratio (RR) 0.77, 95% confidence interval (CI) 0.69–0.86, I2 = 0%]. In eight studies with background anticoagulation, there was a signal for an increase in all-cause stroke with antiplatelets (97/4608 vs. 72/4684; RR 1.33, 95% CI 0.98–1.79, I2 = 0%, P-value for interaction Conclusions In patients with AF not receiving oral anticoagulation, antiplatelet therapy modestly reduced stroke. There was a corresponding signal for harm when used on top of anticoagulation. Irrespective of background anticoagulation use, antiplatelet therapy significantly increased bleeding, moderately reduced myocardial infarction, and did not affect mortality.

It is unknown whether patients undergoing primary percutaneous coronary intervention (PCI) benefit from genotype-guided selection of oral P2YWe conducted a randomized, open-label, assessor-blinded trial in which patients undergoing primary PCI with stent implantation were assigned in a 1:1 ratio to receive either a P2YFor the primary analysis, 2488 patients were included: 1242 in the genotype-guided group and 1246 in the standard-treatment group. The primary combined outcome occurred in 63 patients (5.1%) in the genotype-guided group and in 73 patients (5.9%) in the standard-treatment group (absolute difference, -0.7 percentage points; 95% confidence interval [CI], -2.0 to 0.7; P0.001 for noninferiority). The primary bleeding outcome occurred in 122 patients (9.8%) in the genotype-guided group and in 156 patients (12.5%) in the standard-treatment group (hazard ratio, 0.78; 95% CI, 0.61 to 0.98; P = 0.04).In patients undergoing primary PCI, a

The study of membrane protein function and structure requires their successful detection, expression, solubilization, and/or reconstitution, which poses a challenging task and relies on the availability of suitable tools. Several research groups have successfully applied Nanobodies in the purification, as well as the functional and structural characterization of membrane proteins. Nanobodies are small, single-chain antibody fragments originating from camelids presenting on average a longer CDR3 which enables them to bind in cavities and clefts (such as active and allosteric sites). Notably, Nanobodies generally bind conformational epitopes making them very interesting tools to stabilize, dissect, and characterize specific protein conformations. In the clinic, several Nanobodies are under evaluation either as potential drug candidates or as diagnostic tools. In recent years, we have successfully generated high-affinity, conformation-sensitive anti-γ-secretase Nanobodies. γ-Secretase is a multimeric membrane protease involved in processing of the amyloid precursor protein with high clinical relevance as mutations in its catalytic subunit (Presenilin) cause early-onset Alzheimer's disease. Advancing our knowledge on the mechanisms governing γ-secretase intramembrane proteolysis through various strategies may lead to novel therapeutic avenues for Alzheimer's disease. In this chapter, we present the strategies we have developed and applied for the screening and characterization of anti-γ-secretase Nanobodies. These protocols could be of help in the generation of Nanobodies targeting other membrane proteins.

Buried unexploded ammunition is a major problem on arable land in former battle areas. Many battlefields of the First World War (WWI) still contain a lot of unexploded shells just below the plough layer, posing serious threats to soil editors and trenchers. Electromagnetic induction (EMI) sensors have been used for a variety of agricultural and archaeological purposes to map the natural soil variability and to locate buried archaeological remains. Besides its sensitivity to variations in soil texture and anthropogenic disturbances, EMI proves to respond strongly to metal objects in the soil. Most EMI sensors rely on a single signal, with magnitude and sign of the metal anomalies differing according to the instruments coil distance and separation. The multi-coil EMI sensor, the DUALEM-21S, provides four simultaneous apparent electrical conductivity ( ECa ) signals enhancing significantly the possibilities for signal processing. To calibrate our instrument, we buried different masses of metal at different depths. The four ( ECa measurements showed a response to the metal objects down to 1.2 m. The measurements were subtracted by their gradual trend to obtain the local anomalies (Δ( ECa ). A combination of these four Δ( ECa ’s was used to amplify the signal response to metal, influenced by both depth and mass of the buried objects. At an intensively shelled former WWI battle field near Ypres (Belgium), a detailed prospection was conducted with the DUALEM-21S. Based on our multi-signal procedure, we located 40 positions, 20 where we predicted buried metal and 20 where we expected that no metal was present within 1.2 m depth. There were no false negative predictions and at the 20 locations where we expected metal, shells up to 90 kg were excavated. As a final outcome we produced a map with predictions of the mass of metal objects in the soil assuming a fixed depth and alternatively a map with predictions of the depth of metal objects assuming a given mass. Apart from their potential for agricultural and archaeological investigations, multi-( ECa signals were shown to be useful for locating metal objects, like unexploded WWI shells, in the top 1.2 m of soil.