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Enzymatically oxygenated phospholipids (eoxPL) from lipoxygenases (LOX) or cyclooxygenase (COX) are prothrombotic. Their generation in arterial disease, and their modulation by cardiovascular therapies is unknown. Furthermore, the Lands cycle acyl-transferases that catalyze their formation are unidentified. eoxPL were measured in platelets and leukocytes from an atherosclerotic cardiovascular disease (ASCVD) cohort and retrieved human arterial thrombi from three anatomical sites. The impact of age, gender, and aspirin was characterized in platelets from healthy subjects administered low-dose aspirin. The role of lysophosphatidylcholine acyltransferase 3 (LPCAT3) in eoxPL biosynthesis was tested using an inhibitor and a cell-free assay. Platelets from ASCVD patients generated lower levels of COX-derived eoxPL but elevated 12-LOX-diacyl forms, than platelets from healthy controls. This associated with aspirin and was recapitulated in healthy subjects by aspirin supplementation. P2Y12 inhibition had no impact on eoxPL. LPCAT3 inhibition selectively prevented 12-LOX-derived diacyl-eoxPL generation. LPCAT3 activity was not directly altered by aspirin. P2Y12 inhibition or aspirin had little impact on eoxPL in leukocytes. Complex aspirin-dependent gender and seasonal effects on platelet eoxPL generation were seen in healthy subjects. Limb or coronary (ST-elevation myocardial infarction, STEMI) thrombi displayed a platelet eoxPL signature while carotid thrombi had a white cell profile. EoxPL are altered in ASCVD by a commonly used cardiovascular therapy, and LPCAT3 was identified as the acyltransferase generating aspirin-sensitive 12-LOX diacyl forms. These changes to the phospholipid composition of blood cells in humans at risk of thrombosis may be clinically significant where the procoagulant membrane plays a central role in driving elevated thrombotic risk., Competing Interests: Conflict of interest P. C. receives research funding from CSL Behring, Haemonetics Corp, Werfen, and consultancy from CSL Behring. The other authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Although data suggests ad hoc percutaneous coronary intervention (PCI) results in similar patient outcomes compared to planned PCI in nonselected patients, data for ad hoc unprotected left main stem PCI (uLMS-PCI) are lacking., Aim: To determine if in-hospital outcomes of uLMS-PCI vary by ad hoc versus planned basis., Methods: Data were analyzed from all patients undergoing uLMS-PCI in the United Kingdom 2006-2018, and patients grouped into uLMS-PCI undertaken on an ad hoc or a planned basis. Patients who presented with ST-segment elevation, cardiogenic shock, or with an emergency PCI indication were excluded., Results: In total, 8574 uLMS-PCI procedures were undertaken with 2837 (33.1%) of procedures performed on an ad hoc basis. There was a lower likelihood of intervention for stable angina (28.8% vs. 53.8%, p < 0.001) and a higher rate of potent P2Y12 inhibitor use (16.4% vs. 12.1%, p < 0.001) in the ad hoc PCI group compared to the planned PCI group. Patients undergoing uLMS-PCI on an ad hoc basis tended to undergo less complex procedures. Acute procedural complications including slow flow (odds ratio [OR]: 1.70, 95% confidence interval [CI]: 1.01-2.86), coronary dissection (OR: 1.41, 95% CI: 1.12-1.77) and shock induction (OR: 2.80, 95% CI: 1.64-4.78) were more likely in the ad hoc PCI group. In-hospital death (OR: 1.65, 95% CI: 1.19-2.27) and in-hospital major adverse cardiac or cerebrovascular events (OR: 1.50, 95% CI: 1.13-1.98) occurred more frequently in the ad hoc group. In sensitivity analyses, these observations did not differ when several subgroups were separately examined., Conclusions: Ad hoc PCI for uLMS disease is associated with adverse outcomes compared to planned PCI. These data should inform uLMS-PCI procedural planning., (© 2024 The Author(s). Catheterization and Cardiovascular Interventions published by Wiley Periodicals LLC.)

Background: Clotting, leading to thrombosis, requires interactions of coagulation factors with the membrane aminophospholipids (aPLs) phosphatidylserine and phosphatidylethanolamine. Atherosclerotic cardiovascular disease (ASCVD) is associated with elevated thrombotic risk, which is not fully preventable using current therapies. Currently, the contribution of aPL to thrombotic risk in ASCVD is not known. Here, the aPL composition of circulating membranes in ASCVD of varying severity will be characterized along with the contribution of external facing aPL to plasma thrombin generation in patient samples., Methods: Thrombin generation was measured using a purified factor assay on platelet, leukocyte, and extracellular vesicles (EVs) from patients with acute coronary syndrome (n=24), stable coronary artery disease (n=18), and positive risk factor (n=23) and compared with healthy controls (n=24). aPL composition of resting/activated platelet and leukocytes and EV membranes was determined using lipidomics., Results: External facing aPLs were detected on EVs, platelets, and leukocytes, elevating significantly following cell activation. Thrombin generation was higher on the surface of EVs from patients with acute coronary syndrome than healthy controls, along with increased circulating EV counts. Thrombin generation correlated significantly with externalized EV phosphatidylserine, plasma EV counts, and total EV membrane surface area. In contrast, aPL levels and thrombin generation from leukocytes and platelets were not impacted by disease, although circulating leukocyte counts were higher in patients., Conclusions: The aPL membrane of EV supports an elevated level of thrombin generation in patient plasma in ASCVD. Leukocytes may also play a role although the platelet membrane did not seem to contribute. Targeting EV formation/clearance and developing strategies to prevent the aPL surface of EV interacting with coagulation factors represents a novel antithrombotic target in ASCVD., Competing Interests: None.

Aminophospholipids (aPL) such as phosphatidylserine are essential for supporting the activity of coagulation factors, circulating platelets, and blood cells. Phosphatidylthreonine (PT) is an aminophospholipid previously reported in eukaryotic parasites and animal cell cultures, but not yet in human tissues. Here, we evaluated whether PT is present in blood cells and characterized its ability to support coagulation. Several PT molecular species were detected in human blood, washed platelets, extracellular vesicles, and isolated leukocytes from healthy volunteers using liquid chromatography-tandem mass spectrometry. The ability of PT to support coagulation was demonstrated in vitro using biochemical and biophysical assays. In liposomes, PT supported prothrombinase activity in the presence and absence of phosphatidylserine. PT nanodiscs strongly bound FVa and lactadherin (nM affinity) but poorly bound prothrombin and FX, suggesting that PT supports prothrombinase through recruitment of FVa. PT liposomes bearing tissue factor poorly generated thrombin in platelet poor plasma, indicating that PT poorly supports extrinsic tenase activity. On platelet activation, PT is externalized and partially metabolized. Last, PT was significantly higher in platelets and extracellular vesicle from patients with coronary artery disease than in healthy controls. In summary, PT is present in human blood, binds FVa and lactadherin, supports coagulation in vitro through FVa binding, and is elevated in atherosclerotic vascular disease. Our studies reveal a new phospholipid subclass, that contributes to the procoagulant membrane, and may support thrombosis in patients at elevated risk., Competing Interests: Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Despite advances in stent technology for percutaneous coronary intervention (PCI) in the treatment of coronary disease, these procedures can be complicated by stent failure manifested as intracoronary stent restenosis (ISR). Even with advances in stent technology and medical therapy, this complication is reported to affect around 10% of all percutaneous coronary intervention (PCI) procedures. Depending on stent type (drug-eluting versus bare metal), ISR has subtle differences in mechanism and timing and offers different challenges in diagnosing etiology and subsequent treatment options., Areas Covered: This review will be visiting the definition, pathophysiology, and risk factors of ISR., Expert Opinion: The evidence behind management options has been illustrated with the aid of real life clinical cases and summarized in a proposed management algorithm.

Purpose of the Study: In 2010, the National Institute for Health and Care Excellence (NICE) recommended the use of anticoagulants rather than aspirin as pharmacological thromboprophylaxis after hip fracture. We examine the impact of implementing this change in guidance on the clinical incidence of deep vein thrombosis (DVT)., Study Design: Demographic, radiographic and clinical data were retrospectively collected for 5039 patients admitted to a single tertiary centre in the UK for hip fracture between 2007 and 2017. We calculated rates of lower-limb DVT and examined the impact of the June 2010 change of departmental policy, from use of aspirin to use of low-molecular-weight heparins (LMWH) in hip fracture patients., Results: Doppler scans were performed in 400 patients in the 180 days after a hip fracture, and identified 40 ipsilateral and 14 contralateral DVTs (p<0.001). The rate of DVT reduced significantly following the 2010 change in departmental policy from aspirin to LMWH in these patients (1.62% vs 0.83%, p<0.05)., Conclusions: The rate of clinical DVT halved following the change from aspirin to LMWH for pharmacological thromboprophylaxis, but the number needed to treat was 127. A figure of <1% for the incidence of clinical DVT in a unit that routinely uses LMWH monotherapy following hip fracture provides a context for discussions of alternative strategies, and for power calculations for future research. These figures are important to policy makers and to researchers as they will inform the design of the comparative studies on thromboprophylaxis agents for which NICE has called., (© The Author(s) 2022. Published by Oxford University Press on behalf of Postgraduate Medical Journal. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aim: Bifurcation-PCI is performed frequently, although without extensive evidence to back up a definitive solution for its complexity. We set out to identify factors associated with 1- and 12-month mortality after bifurcation-PCI between 2017 and 2021 in our tertiary center in Wales, UK. Results: Of 732 bifurcation PCI cases (mean age 69; 25% female), 67% were in ACS, 42% were left main PCI and 25.3% involved two-stent strategy. 30-day and 12-month mortality were 1.9 and 8.2%, respectively. Age, diabetes, smoking and renal failure are associated with mortality after bifurcation-PCI, while the choice between provisional and 2-stent strategies did not impact mortality/TLR. Conclusion: Awareness of 'real-world' outcomes of bifurcation-PCI should be used for appropriate patient selection, technique planning and procedural consent.

Introduction: Left main stem percutaneous coronary intervention (LMS-PCI) is a complex high-risk procedure which can be performed as an alternative to coronary artery bypass graft (CABG) procedure in surgical turn-down patients or where there is equipoise in percutaneous versus surgical strategies. Current guidelines suggest that PCI is an appropriate alternative to CABG in patients with unprotected LMS disease and low SYNTAX score. However, "real world" data on outcomes of LMS-PCI remain limited. This study aims to quantify and determine predictors of mortality following LMS-PCI., Methods: Using local coronary angioplasty registries from two UK centers, all LMS-PCI cases were identified from 2016 to 2020. Descriptive statistics and multivariate logistic regressions were used to examine the association between baseline and procedural characteristics with 30-day and 12-month mortality., Results: We identified 484 cases of LMS-PCI between 2016 and 2020. There was a year-on-year increase in the number of LMS-PCI, the highest being in 2020. Covariates associated with higher 30-day mortality were age (OR 1.07, 95% CI: 1.02-1.12) and shock preprocedure (OR 23.88, 95% CI: 7.90-72.20). Covariates associated with higher 12-month mortality were age (OR 1.04, 95% CI: 1.01-1.08), acute coronary syndrome (ACS) (OR 2.50, 95% CI: 1.08-5.80), renal disease (OR 5.24, 95% CI: 1.47-18.68), and shock preprocedure (OR 7.93, 95% CI: 3.30-19.05). Overall, 30-day and 12-month mortality in this contemporary data set were 9.5% and 16.7%, respectively, with significantly lower rates in elective cases (p < 0.01)., Conclusions: Older age and cardiogenic shock preprocedure were associated with increased 30-day mortality after LMS-PCI. Twelve-month mortality was associated with older age, ACS presentation, preexisting renal disease, and cardiogenic shock preprocedure., (© 2022 Wiley Periodicals LLC.)

The lipid envelope of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an essential component of the virus; however, its molecular composition is undetermined. Addressing this knowledge gap could support the design of antiviral agents as well as further our understanding of viral-host protein interactions, infectivity, pathogenicity, and innate immune system clearance. Lipidomics revealed that the virus envelope comprised mainly phospholipids (PLs), with some cholesterol and sphingolipids, and with cholesterol/phospholipid ratio similar to lysosomes. Unlike cellular membranes, procoagulant amino-PLs were present on the external side of the viral envelope at levels exceeding those on activated platelets. Accordingly, virions directly promoted blood coagulation. To investigate whether these differences could enable selective targeting of the viral envelope in vivo, we tested whether oral rinses containing lipid-disrupting chemicals could reduce infectivity. Products containing PL-disrupting surfactants (such as cetylpyridinium chloride) met European virucidal standards in vitro; however, components that altered the critical micelle concentration reduced efficacy, and products containing essential oils, povidone-iodine, or chlorhexidine were ineffective. This result was recapitulated in vivo, where a 30-s oral rinse with cetylpyridinium chloride mouthwash eliminated live virus in the oral cavity of patients with coronavirus disease 19 for at least 1 h, whereas povidone-iodine and saline mouthwashes were ineffective. We conclude that the SARS-CoV-2 lipid envelope i) is distinct from the host plasma membrane, which may enable design of selective antiviral approaches; ii) contains exposed phosphatidylethanolamine and phosphatidylserine, which may influence thrombosis, pathogenicity, and inflammation; and iii) can be selectively targeted in vivo by specific oral rinses., Competing Interests: Conflict of interest Venture Life Group plc and Johnson & Johnson provided information on mouthwash formulations employed in the in vitro study. Venture Life Group partfunded the clinical study but had no input in study design, data analysis, or drafting of the article. The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Phospholipids (PLs) are found in all cell types and are required for structural support and cell activation signalling pathways. In resting cells, PLs are asymmetrically distributed throughout the plasma membrane with native procoagulant aminophospholipids (aPLs) being actively maintained in the inner leaflet of the membrane. Upon platelet activation, aPLs rapidly externalize to the outer leaflet and are essential for supporting the coagulation cascade by providing binding sites for factors in the cell-based model. More recent work has uncovered a role for enzymatically oxidized PLs (eoxPLs) in facilitating coagulation, working in concert with native aPLs. Despite this, the role of aPLs and eoxPLs in thrombo-inflammatory conditions, such as arterial and venous thrombosis, has not been fully elucidated. In this review, we describe the biochemical structures, distribution and regulation of aPL externalization and summarize the literature on eoxPL generation in circulating blood cells. We focus on the currently understood role of these lipids in mediating coagulation reactions in vitro , in vivo and in human thrombotic disease. Finally, we highlight gaps in our understanding in how these lipids vary in health and disease, which may place them as future therapeutic targets for the management of thrombo-inflammatory conditions.

Introduction: There is increasing evidence supporting the use of intracoronary imaging to optimize the outcomes of percutaneous coronary intervention (PCI). However, there are no studies examining the impact of imaging on PCI outcomes in cases utilising rotational atherectomy (RA-PCI). Our study examines the determinants and outcomes of using intracoronary imaging in RA-PCI cases including 12-month mortality., Methods: Using the British Cardiac Intervention Society database, data were analysed on all RA-PCI procedures in the UK between 2007 and 2014. Descriptive statistics and multivariate logistic regressions were used to examine baseline, procedural, and outcome associations with intravascular imaging., Results: Intracoronary imaging was used in 1,279 out of 8,417 RA-PCI cases (15.2%). Baseline covariates associated with significantly more imaging use were number of stents used, smoking history, previous CABG, pressure wire use, proximal LAD disease, laser use, glycoprotein inhibitor use, cutting balloons, number of restenosis attempted, off-site surgery, and unprotected left main stem (uLMS) PCI. Adjusted rates of in-hospital major adverse cardiac/cerebrovascular events (IH-MACCE), its individual components (death, peri-procedural MI, stroke, and major bleed), or 12-month mortality were not significantly altered by the use of imaging in RA-PCI. However, subgroup analysis demonstrated a signal towards reduction in 12-month mortality in uLMS RA-PCI cases utilising intracoronary imaging (OR 0.67, 95% CI 0.44-1.03)., Conclusions: Intracoronary imaging use during RA-PCI is associated with higher risk of baseline and procedural characteristics. There were no differences observed in IH-MACCE or 12-month mortality with intracoronary imaging in RA-PCI., Competing Interests: MM reports holding unrestricted educational grants from Boston Scientific, Terumo, and Abbott. All other authors report no conflicts of interest relevant to this work., (Copyright © 2022 Majd B. Protty et al.)

The prothrombotic state in atrial fibrillation (AF) occurs as a result of multifaceted interactions, known as Virchow's triad of hypercoagulability, structural abnormalities, and blood stasis. More recently, there is emerging evidence that lipoproteins are implicated in this process, beyond their traditional role in atherosclerosis. In this review, we provide an overview of the various lipoproteins and explore the association between lipoproteins and AF, the effects of lipoproteins on haemostasis, and the potential contribution of lipoproteins to thrombogenesis in AF. There are several types of lipoproteins based on size, lipid composition, and apolipoprotein category, namely: chylomicrons, very low-density lipoprotein, low-density lipoprotein (LDL), intermediate-density lipoprotein, and high-density lipoprotein. Each of these lipoproteins may contain numerous lipid species and proteins with a variety of different functions. Furthermore, the lipoprotein particles may be oxidized causing an alteration in their structure and content. Of note, there is a paradoxical inverse relationship between total cholesterol and LDL cholesterol (LDL-C) levels, and incident AF. The mechanism by which this occurs may be related to the stabilizing effect of cholesterol on myocardial membranes, along with its role in inflammation. Overall, specific lipoproteins may interact with haemostatic pathways to promote excess platelet activation and thrombin generation, as well as inhibiting fibrinolysis. In this regard, LDL-C has been shown to be an independent risk factor for thromboembolic events in AF. The complex relationship between lipoproteins, thrombosis and AF warrants further research with an aim to improve our knowledge base and contribute to our overall understanding of lipoprotein-mediated thrombosis., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Rotational atherectomy (RA) during PCI is linked to a higher likelihood coronary perforations (CP). However, the evidence base on incidence, predictors and outcomes of this complication in RA-PCI remains limited., Methods: Using the British Cardiac Intervention Society database, data were analysed on all RA-PCI procedures in UK 2007-2014. Descriptive statistics and multivariate logistic regressions were used to examine baseline, procedural and outcome associations., Results: During 10,980 RA-PCI procedures, 167 CPs were recorded (1.52%) with a stable annual incidence. Baseline and procedural covariates associated with higher rates of RA perforation were number of stents used, female gender, smoking, and left-main stenosis. CP was significantly associated with shock, DC cardioversion, heart block, transfusion, emergency surgery, periprocedural MI, in-hospital major bleed, acute kidney injury, dissection, side branch loss and in-hospital death. CP was also associated with higher rates of in-hospital MACCE (OR 12.22, 95% CI 7.67-19.47), 30-day mortality (OR 10.02, 95% CI 5.87-17.09) and 12-month mortality (OR 3.90, 95% CI 2.53-6.02)., Conclusions: CP is more frequent in RA-PCI than all-comer PCI and is associated with a significant burden of morbidity and mortality. There are a limited number of baseline and procedural co-variates associated with CP in RA-PCI, making it difficult to predict., Competing Interests: Declaration of competing interest There are no conflicts of interest for any authors relevant to this work., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: Combining rotational (RA) and excimer laser coronary atherectomy (ELCA)-RASER atherectomy-is technique utilized in the percutaneous management of calcific coronary disease. The evidence base examining its safety and utility is sparse and limited to small case-series. This study examines the patterns and outcomes of RASER atherectomy use in the largest cohort to date., Methods: Using the British Cardiac Intervention Society database, data were analyzed on all PCI procedures in the UK between 2006 and 2016. Descriptive statistics and multivariate logistic regressions were used to examine baseline, procedural, and outcome associations with RASER., Results: We identified 153 (0.02%) RASER atherectomy cases out of 686,358 PCI procedures. Baseline covariates associated with RASER use were age, BMI, diabetes, stable coronary disease, and previous CABG. Procedural co-variates associated with RASER were CTO-PCI, the use of more/longer stents, intravascular imaging, cutting balloons, and microcatheters. Adjusted rates of in-hospital major adverse cardiac/cerebrovascular events (MACCE) were not significantly different with RASER. However, there were higher odds of arterial complications (OR 3.23, 95% CI: 1.58-6.61), slow flow (OR 3.50, 95% CI: 1.29-9.55), and shock induction (OR 9.66, 95% CI: 3.44-27.06)., Conclusions: RASER atherectomy use in complex PCI is associated with higher risk baseline and procedural characteristics. Although increased rates of shock induction, slow flow, and arterial complications were observed, RASER does not increase the likelihood of in-hospital MACCE, major bleeding, or death., (© 2020 Wiley Periodicals LLC.)

Introduction: Excimer laser coronary atherectomy (ELCA) is a recognized adjunctive therapy utilized in the percutaneous management of complex coronary lesions. Studies examining its safety and utility have been limited by small sample sizes. Our study examines the determinants and outcomes of ELCA., Methods: Using the British Cardiac Intervention Society database, data were analyzed on all PCI procedures in the UK between 2006-2016. Descriptive statistics and multivariate logistic regressions were used to examine baseline, procedural and outcome associations with ELCA., Results: We identified 1,471 (0.21%) ELCA cases out of 686,358 PCI procedures. Baseline covariates associated with ELCA use were age, BMI, number of lesions, CTO or restenosis attempted and history of prior MI, CABG or PCI. Procedural co-variates associated with ELCA were the use of glycoprotein inhibitors, intravascular imaging, rotational atherectomy, cutting balloons, microcatheters and intra-aortic balloon pumps. Adjusted rates of in-hospital major adverse cardiac/cerebrovascular events (MACCE) or its individual components (death, peri-procedural MI, stroke and major bleed) were not significantly altered by the use of ELCA. However, there were higher odds of dissection (OR 1.52, 95% CI 1.17-1.98), perforation (OR 2.18, 95% CI 1.44-3.30), slow flow (OR: 1.67, 95% CI 1.18-2.36), reintervention (OR: 2.12, 95% CI 1.14-3.93) and arterial complications (OR: 1.63, 95% CI 1.21-2.21)., Conclusions: ELCA use during complex PCI is associated with higher risk baseline and procedural characteristics. Although increased rates of acute procedural complications were observed, ELCA does not increase likelihood of in-hospital MACCE or its individual components., (© 2021 Wiley Periodicals LLC.)

Background: Percutaneous coronary intervention (PCI) is increasingly utilized for treatment of coronary disease involving the unprotected left main stem (ULMS). However, no studies to date have examined the outcomes of such interventions when complicated by coronary perforation (CP)., Methods: Using the British Cardiovascular Intervention society (BCIS) database, data were analyzed on all ULMS-PCI procedures complicated by CP in England and Wales between 2007 and 2014. Multivariate logistic regressions were used to identify predictors of ULMS CP and to evaluate the association between this complication and outcomes., Results: During 10,373 ULMS-PCI procedures, CP occurred more frequently than in non-ULMS-PCI (0.9 vs. 0.4%, p < .001) with a stable annual incidence. Covariates associated with CP included number of stents used, female gender, use of rotational atherectomy and chronic total occlusion (CTO) intervention. Adjusted odds of adverse outcomes for ULMS-PCI complicated by CP were higher for peri-procedural complications including cardiogenic shock, tamponade, side-branch loss, DC cardioversion, in-hospital major bleeding, transfusion requirement, and peri-procedural myocardial infarction. There were also significantly increased odds for in-hospital major adverse cardiac events (MACCE, OR 8.961, 95% CI [4.902-16.383]) and 30-day mortality (OR 5.301, 95% CI [2.741-10.251])., Conclusions: CP is an infrequent event during ULMS-PCI and is predicted by female gender, rotational atherectomy, CTO interventions or number of stents used. CP was associated with significantly higher odds of mortality and morbidity, but at rates similar to previously published all-comer PCI complicated by CP., (© 2020 Wiley Periodicals, Inc.)

WW domain binding protein 1-like (WBP1L), also known as outcome predictor of acute leukaemia 1 (OPAL1), is a transmembrane adaptor protein, expression of which correlates with ETV6-RUNX1 (t(12;21)(p13;q22)) translocation and favourable prognosis in childhood leukaemia. It has a broad expression pattern in haematopoietic and in non-haematopoietic cells. However, its physiological function has been unknown. Here, we show that WBP1L negatively regulates signalling through a critical chemokine receptor CXCR4 in multiple leucocyte subsets and cell lines. We also show that WBP1L interacts with NEDD4-family ubiquitin ligases and regulates CXCR4 ubiquitination and expression. Moreover, analysis of Wbp1l-deficient mice revealed alterations in B cell development and enhanced efficiency of bone marrow cell transplantation. Collectively, our data show that WBP1L is a novel regulator of CXCR4 signalling and haematopoiesis., (© 2019 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Objectives: We sought to evaluate whether socioeconomic status influences outcome after first-time transcatheter aortic valve implantation (TAVI)., Method: This is a single-centre study carried out in Swansea, South West Wales, UK between 5 November 2009 and 10 June 2018. Data included age, gender, domiciliary postal code, comorbidities, complications post-TAVI, length of stay, follow-up time and survival status. The Welsh Index of Multiple Deprivation, 2014 was used to stratify cases by level of social deprivation according to domiciliary postal codes., Results: Study population was 387 patients of whom 213 (54.8%) were men with mean age ±SD of 82.8±8.3 years. Patients, who were less deprived (296 (76.4%)), were more likely to be older (83.5±7.9 vs 80.4±9.3, p<0.05) and to be married (83.2% vs 69.7%, p<0.05). Conversely, 'more deprived' patients (91 (23.6%)) were more likely to have a longer stay in hospital as compared with patients in the 'less deprived group' (29.6±32.7 days vs 21.3±21.1 days, p<0.05). However, 30-day, 1-year and 3-year survival/mortality rates were similar across all socioeconomic levels., Conclusions: This is the first study in which social deprivation has been investigated as a risk factor for mortality in a high-risk group of patients with severe aortic stenosis undergoing TAVI. Residing in a 'more deprived' area in South West Wales is not associated with adverse outcome following TAVI but patients who are 'more deprived' tend to stay longer in hospital compared with patients who are 'less deprived'., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aim: Antiplatelets have been used for decades to prevent atherothrombotic disease, but there is limited 'real-life' prescribing data. We hereby report the prescribing patterns for oral antiplatelets in Wales, UK., Methods/results: Retrospective analysis of anonymized data in Wales from 2005 to 2016 revealed differences in prescribing patterns of oral antiplatelets. Aspirin and dipyridamole use declined with a corresponding increase in clopidogrel prescription. Costs declined with a sharp decrease coinciding with clopidogrel coming off patent. Prasugrel and ticagrelor have shown significant cost contribution (29% of total) despite only forming 1% of total items prescribed in 2016., Conclusion: This first-look analysis of real-life antiplatelet data demonstrates a decrease in the overall prescribing costs with varying patterns. This may aid policy-makers in reviewing funding strategies.

Background: Application to cardiology specialty training is competitive with uncertainty among candidates as to what the secret recipe for a successful appointment is. We aimed to investigate objective variables, which were demonstrated by successful appointees to cardiology training schemes in the UK., Methods: Data from successful cardiology applicants for the years 2014 to 2016 were obtained from the Joint Royal Colleges of Physicians Training Board under the Freedom of Information Act. These data included basic demographics as well as objective scores awarded for selection categories such as qualifications, academic, teaching and other achievements., Results: There were a total of 976 applicants during the study period, of whom 423 were successfully appointed, generating a competition ratio of 2.3 applicants for each position. There was an increasing proportion of successful female applicants (22% in 2014, 28% in 2015 and 32% in 2016). Median scores for postgraduate exams (14/14), presentations (6/6) and quality improvement (10/10) scores corresponded to maximum possible scores, whereas median scores for additional undergraduate and postgraduate degrees were 0. Median scores for prizes, publications and teaching experience were 6/10, 4/8 and 9/10, respectively., Conclusion: The secret to a successful cardiology training appointment is associated with completion of all postgraduate clinical exams, completion and presentation of quality improvement projects, national presentations and substantial teaching achievements. At least half of the successful candidates had no additional undergraduate or postgraduate degrees but had evidence of some prizes and publications. The ratio of successful female candidates is rising, but remains less than males in cardiology training., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Psychiatric and cardiac comorbidities form the top two budget categories for health systems in high-income countries with evidence that psychiatric pre-morbidities lead to worse outcomes in patients with acute coronary syndrome (ACS). There are no studies examining this relationship in a national multicentre population level study in the UK, and no studies examining their impact on length of in-hospital stay (LoS) in ACS. Recognizing at-risk populations and reducing LoS in ACS is an essential part of improving patient care and cost-effectiveness., Methods: We investigated the impact of psychiatric diagnoses on morbidity, all-cause mortality and LoS amongst 57,668 ACS patients between Jan-2004 and Dec-2014 using the Secure-Anonymized-Information-Linkage (SAIL) databank. Demographics, admissions, cardiac and psychiatric comorbidities were identified using coded data., Results: There were a total of 3857 out of 57,668 patients who had a pre-morbid psychiatric diagnosis. The mean LoS in patients without psychiatric comorbidities was 9.78days (95% CI: 9.66-9.91). This was higher (p<0.01) in the presence of any psychiatric diagnosis (14.72), dementia (20.87), schizophrenia (15.67), and mood disorders (13.41). Patients with psychiatric comorbidities had worse net adverse cardiac events (HR 1.18, 95% CI: 1.16-1.21) and mortality rates (HR 1.26, 95% CI: 1.23-1.30)., Conclusions: Our results demonstrate that psychiatric comorbidities have a significant and clinically important impact on morbidity, mortality and LoS in ACS patients in Wales, UK. Clinicians' awareness and active management of psychiatric conditions amongst ACS patients is needed to reduce poor outcomes and LoS and ultimately the risk for patients and financial burden for the health-service., (Copyright © 2016. Published by Elsevier B.V.)

What Is Known and Objective: Oral anticoagulants (OACs) have been used for decades for the long-term prevention of arterial and venous thromboembolic disease. These include warfarin and the newer direct-acting OACs (DOACs). Data on 'real-life' prescribing patterns for DOACs are limited. In this commentary, we report the prescribing patterns for OACs in Wales, as a representative country within the UK., Comment: A retrospective analysis of anonymized OAC prescribing data in Wales from June 2009 to December 2015. Results reveal that the number of OAC prescription items increased from 40·48 to 65·26 per 1000 prescribing unit (PU). Average cost increased from £87·41 to £529·31 per 1000 PU. The share of warfarin prescribing declined from 100% to 68%, with the a rising share for the DOACs, made up of rivaroxaban (19%), apixaban (9%) and dabigatran (3%) WHAT IS NEW AND CONCLUSION: Analysis of real-life data demonstrates that there has been an increase in the overall numbers and costs of OAC prescriptions, with a rising proportion of DOACs to warfarin prescribing., (© 2016 John Wiley & Sons Ltd.)

Aim: Statins have a proven role for the secondary prevention of cardiovascular disease. Despite this, typical patient use in real life is variable. Our aim was to investigate the typical clinical use, including adherence, for statins in a sample population in South Wales (UK)., Methods: We identified 2248 patients admitted to hospitals in South Wales with acute coronary syndrome using a retrospective 3-year-long longitudinal study. We performed data linkage using the Secure Anonymized Information Linkage databank., Results & Conclusion: In total, 1806 (80.3%) of patients were initiated on statins at discharge, with simvastatin being most common. Only 38% of patients were on high-intensity dosage. There was minimal change in cholesterol levels, with discontinuation rates of 53.7 and 84.3% at 1- and 3-year follow-up, respectively.

Background: Friday the 13th is described as an "unlucky" day that brings misfortune. There are few studies on the question, and none on its effect in cardiovascular patients. The recently misreported "weekend effect" has led to changes in the junior doctor contract in England, providing greater staffing levels on weekends. Should we make similar provisions for Friday the 13th?, Methods: A retrospective analysis of a large database for patients admitted to hospitals in South Wales with an acute coronary syndrome (ACS) during 1999-2014. Mortality rates for 217 admission day number/name combinations and for Friday the 13th were compared in a Cox proportional hazards regression model., Results: 56 062 ACS patients were identified. There were no significant differences in 13-year mortality between most admission dates (211 of 216) and Friday the 13th. However, a statistically significant reduction in mortality was identified for five dates: Thursday the 15th (HR, 0.77; 95% CI, 0.59-0.999), Wednesday the 18th (HR, 0.76; 95% CI, 0.58-0.99), Monday the 28th (HR, 0.76; 95% CI, 0.57-0.99), Monday the 30th (HR, 0.75; 95% CI, 0.57-0.99) and Tuesday the 31st (HR, 0.71; 95% CI, 0.51-0.99)., Conclusion: On most days, there was no difference in the 13-year mortality rate for patients admitted with their first ACS from that for "unlucky" Friday the 13th. However, patients admitted on five day/number combinations were 20-30% more likely to survive at 13 years. These findings could be explained by subgroup analysis inflation of the type I error, although supernatural causes merit further investigation. Our findings should be taken into account in future junior doctor contract negotiations, and may provide a case for reduced staffing levels on these lucky days.

Objectives: Determine the real-world difference between 2 groups of patients with severe aortic stenosis and similar baseline comorbidities: surgical turn down (STD) patients, who were managed medically prior to the availability of transcatheter aortic valve implantation (TAVI) following formal surgical outpatient assessment, and patients managed with a TAVI implant., Design: Retrospective cohort study from real-world data., Setting: Electronic patient letters were searched for patients with a diagnosis of severe aortic stenosis and a formal outpatient STD prior to the availability of TAVI (1999-2009). The second group comprised the first 90 cases of TAVI in South Wales (2009 onwards). 2 years prior to and 5 years following TAVI/STD were assessed. Patient data were pseudoanonymised, using the Secure Anonymized Information Linkage (SAIL) databank, and extracted from Office National Statistics (ONS), Patient-Episode Database for Wales (PEDW) and general practitioner databases., Population: 90 patients who had undergone TAVI in South Wales, and 65 STD patients who were medically managed., Main Outcome Measures: Survival, hospital admission frequency and length of stay, primary care visits, and cost-effectiveness., Results: TAVI patients were significantly older (81.8 vs 79.2), more likely to be male (59.1% vs 49.3%), baseline comorbidities were balanced. Mortality in TAVI versus STD was 28% vs 70% at 1000 days follow-up. There were significantly more hospital admissions per year in the TAVI group prior to TAVI/STD (1.5 (IQR 1.0-2.4) vs 1.0 IQR (0.5-1.5)). Post TAVI/STD, the TAVI group had significantly lower hospital admissions (0.3 (IQR 0.0-1.0) vs 1.2 (IQR 0.7-3.0)) and lengths of stay (0.4 (IQR 0.0-13.8) vs 11.0 (IQR 2.5-28.5), p<0.05). The incremental cost-effectiveness ratio (ICER) for TAVI was £10 533 per quality-adjusted life year (QALY)., Conclusions: TAVI patients were more likely to survive and avoid hospital admissions compared with the medically managed STD group. The ICER for TAVI was £10 533 per QALY, making it a cost-effective procedure.

Graduated compression stockings carry a potential risk of pressure, vascular and other complications. Current understanding of deep vein thrombosis (DVT) risk leaves it uncertain whether patients with hip fracture should wear stockings on both legs., Objectives: To determine the association between the side of the hip fracture and the subsequent occurrence of symptomatic lower limb DVT., Setting: Single tertiary trauma centre, Wales., Participants: All 3657 patients presenting with hip fracture between 2007 and 2013 were identified from our unit's National Hip Fracture Database. We excluded 404 patients (11.0%) resident outside our catchment area, leaving a total of 3253. Median age was 83 years (±12.4)., Primary/secondary Outcome Measures: We cross-linked patient details with Medical Physics records, to identify 634 (19.5%) who had undergone one or more lower-limb Doppler-ultrasound scans at some point during the study period. The distribution rates of DVT were calculated from this resulting data set., Results: Many of the total 634 scans were unrelated to the hip fracture, including 225 (35.5%) performed prior to the fracture. We calculated a baseline rate of DVT of 3.7/1000 patients per year, for the 3-month period immediately before the hip fracture. Scans performed following hip fracture showed DVT risk to be highest in the 3-month period after fracture (35.7/1000 patients per year). This resulted from a six-fold increase in DVTs on the side of the fracture (29.5/1000 patients per year, p<0.01). We found only a very small non-significant increase in DVT on the contralateral leg (6.1/1000 patients per year), Conclusions: The additional risk of DVT after hip fracture is essentially confined to the fractured limb-the leg to which it is most painful to apply stockings. There appears little justification for the cost and potential risk of using stockings on the contralateral leg., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

We investigated the cause of mild mucocutaneous bleeding in a 14-year-old male patient (P1). Platelet aggregation and ATP secretion induced by arachidonic acid and the thromboxane A(2) receptor (TxA(2)R) agonist U46619 were reduced in P1 compared with controls, whereas the responses to other platelet agonists were retained. P1 was heterozygous for a transversion within the TBXA2R gene predictive of a D304N substitution in the TxA(2)R. In Chinese hamster ovary-K1 cells expressing the variant D304N TxA(2)R, U46619 did not increase cytosolic free Ca(2+) concentration, indicating loss of receptor function. The TxA(2)R antagonist [(3)H]-SQ29548 showed an approximate 50% decrease in binding to platelets from P1 but absent binding to Chinese hamster ovary-K1 cells expressing variant D304N TxA(2)R. This is the second naturally occurring TxA(2)R variant to be associated with platelet dysfunction and the first in which loss of receptor function is associated with reduced ligand binding. D304 lies within a conserved NPXXY motif in transmembrane domain 7 of the TxA(2)R that is a key structural element in family A G protein-coupled receptors. Our demonstration that the D304N substitution causes clinically significant platelet dysfunction by reducing ligand binding establishes the importance of the NPXXY motif for TxA(2)R function in vivo.

Platelets are essential for wound healing and inflammatory processes, but can also play a deleterious role by causing heart attack and stroke. Normal platelet activation is dependent on tetraspanins, a superfamily of glycoproteins that function as 'organisers' of cell membranes by recruiting other receptors and signalling proteins into tetraspanin-enriched microdomains. However, our understanding of how tetraspanin microdomains regulate platelets is hindered by the fact that only four of the 33 mammalian tetraspanins have been identified in platelets. This is because of a lack of antibodies to most tetraspanins and difficulties in measuring mRNA, due to low levels in this anucleate cell. To identify potentially platelet-expressed tetraspanins, mRNA was measured in their nucleated progenitor cell, the megakaryocyte, using serial analysis of gene expression and DNA microarrays. Amongst 19 tetraspanins identified in megakaryocytes, Tspan9, a previously uncharacterized tetraspanin, was relatively specific to these cells. Through generating the first Tspan9 antibodies, Tspan9 expression was found to be tightly regulated in platelets. The relative levels of CD9, CD151, Tspan9 and CD63 were 100, 14, 6 and 2 respectively. Since CD9 was expressed at 49000 cell surface copies per platelet, this suggested a copy number of 2800 Tspan9 molecules. Finally, Tspan9 was shown to be a component of tetraspanin microdomains that included the collagen receptor GPVI (glycoprotein VI) and integrin alpha6beta1, but not the von Willebrand receptor GPIbalpha or the integrins alphaIIbbeta3 or alpha2beta1. These findings suggest a role for Tspan9 in regulating platelet function in concert with other platelet tetraspanins and their associated proteins.

Background: Increasing evidence suggests that individual isoforms of protein kinase C (PKC) play distinct roles in regulating platelet activation., Methodology/principal Findings: In this study, we focus on the role of two novel PKC isoforms, PKCdelta and PKCepsilon, in both mouse and human platelets. PKCdelta is robustly expressed in human platelets and undergoes transient tyrosine phosphorylation upon stimulation by thrombin or the collagen receptor, GPVI, which becomes sustained in the presence of the pan-PKC inhibitor, Ro 31-8220. In mouse platelets, however, PKCdelta undergoes sustained tyrosine phosphorylation upon activation. In contrast the related isoform, PKCepsilon, is expressed at high levels in mouse but not human platelets. There is a marked inhibition in aggregation and dense granule secretion to low concentrations of GPVI agonists in mouse platelets lacking PKCepsilon in contrast to a minor inhibition in response to G protein-coupled receptor agonists. This reduction is mediated by inhibition of tyrosine phosphorylation of the FcRgamma-chain and downstream proteins, an effect also observed in wild-type mouse platelets in the presence of a PKC inhibitor., Conclusions: These results demonstrate a reciprocal relationship in levels of the novel PKC isoforms delta and epsilon in human and mouse platelets and a selective role for PKCepsilon in signalling through GPVI.

During thrombopoiesis, maturing megakaryocytes (MKs) migrate within the complex bone marrow stromal microenvironment from the proliferative osteoblastic niche to the capillary-rich vascular niche where proplatelet formation and platelet release occurs. This physiologic process involves proliferation, differentiation, migration, and maturation of MKs before platelet production occurs. In this study, we report a role for the glycoprotein PECAM-1 in thrombopoiesis. We show that following induced thrombocytopenia, recovery of the peripheral platelet count is impaired in PECAM-1-deficient mice. Whereas MK maturation, proplatelet formation, and platelet production under in vitro conditions were unaffected, we identified a migration defect in PECAM-1-deficient MKs in response to a gradient of stromal cell-derived factor 1 (SDF1), a major chemokine regulating MK migration within the bone marrow. This defect could be explained by defective PECAM-1(-/-) MK polarization of the SDF1 receptor CXCR4 and an increase in adhesion to immobilized bone marrow matrix proteins that can be explained by an increase in integrin activation. The defect of migration and polarization was confirmed in vivo with demonstration of altered spatial localization of MKs within the bone marrow in PECAM-1-deficient mice, following immune-induced thrombocytopenia. This study identifies a novel role for PECAM-1 in regulating MK migration and thrombopoiesis.