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INTRODUCTION A massive increase of soluble thrombomodulin (sTM) due to variants in the thrombomodulin gene (THBD) has recently been identified as a novel bleeding disorder. AIM To investigate sTM levels and underlying genetic variants as a cause for haemostatic impairment and bleeding in a large number of patients with a mild to moderate bleeding disorder (MBD), including patients with bleeding of unknown cause (BUC). PATIENTS AND METHODS In 507 MBD patients, sTM levels, thrombin generation and plasma clot formation were measured and compared to 90 age- and sex-matched healthy controls. In patients, genetic analysis of the THBD gene was performed. RESULTS No difference in sTM levels between patients and controls was found overall (median ([IQR] 5.0 [3.8-6.3] vs. 5.1 [3.7-6.4] ng/ml, p = .762), and according to specific diagnoses of MBD or BUC, and high sTM levels (≥95th percentile of healthy controls) were not overrepresented in patients. Soluble TM levels had no impact on bleeding severity or global tests of haemostasis, including thrombin generation or plasma clot formation. In the THBD gene, no known pathogenic or novel disease-causing variants affecting sTM plasma levels were identified in our patient cohort. CONCLUSION TM-associated coagulopathy appears to be rare, as it was not identified in our large cohort of patients with MBD. Soluble TM did not arise as a risk factor for bleeding or altered haemostasis in these patients.

Left ventricular (LV) aneurysm is a serious mechanical complication following acute myocardial infarction (MI). Approximately 85% of true LV aneurysms are located at the apical and anteroseptal wall. They are associated with increased morbidity and mortality due to complications that can potentially occur, including heart failure, thromboembolism and tachyarrhythmias. As the need for prompt treatment is vital, transthoracic echocardiography, contrast echocardiography, computed tomography (CT) and cardiac magnetic resonance (CMR) are the preferred noninvasive modalities used for the diagnosis. The incidence of LV aneurysm as a complication of acute myocardial infarction has declined, primarily thanks to the advances in percutaneous coronary intervention and early revascularization. We report the case of a large LV apical aneurysm in a patient with a delayed presentation after ST-elevation myocardial infarction during the COVID-19 pandemic. A 60-year-old female with history of previous anterior myocardial infarction with delayed revascularization presented to the emergency department with worsening shortness of breath, orthopnea and marked limitation of physical activity. The transthoracic echocardiogram that was conducted revealed a giant LV aneurysm located at the apex as well as a markedly reduced left ventricular ejection fraction. Contrast echo-cardiography and cardiac CT were used to confirm these findings while CMR also provided accurate measurements of left ventricular volumes and mass. In addition, the extent of myocardial scar tissue and viability of the other regions of left ventricle were identified. The patient underwent a successful left ventricular reconstructive surgery leading to a significant functional status improvement.

A targeted high-throughput sequencing (HTS) panel test for clinical diagnostics requires careful consideration of the inclusion of appropriate diagnostic-grade genes, the ability to detect multiple types of genomic variation with high levels of analytic sensitivity and reproducibility, and variant interpretation by a multidisciplinary team (MDT) in the context of the clinical phenotype. We have sequenced 2396 index patients using the ThromboGenomics HTS panel test of diagnostic-grade genes known to harbor variants associated with rare bleeding, thrombotic, or platelet disorders (BTPDs). The molecular diagnostic rate was determined by the clinical phenotype, with an overall rate of 49.2% for all thrombotic, coagulation, platelet count, and function disorder patients and a rate of 3.2% for patients with unexplained bleeding disorders characterized by normal hemostasis test results. The MDT classified 745 unique variants, including copy number variants (CNVs) and intronic variants, as pathogenic, likely pathogenic, or variants of uncertain significance. Half of these variants (50.9%) are novel and 41 unique variants were identified in 7 genes recently found to be implicated in BTPDs. Inspection of canonical hemostasis pathways identified 29 patients with evidence of oligogenic inheritance. A molecular diagnosis has been reported for 894 index patients providing evidence that introducing an HTS genetic test is a valuable addition to laboratory diagnostics in patients with a high likelihood of having an inherited BTPD. ispartof: BLOOD vol:134 issue:23 pages:2082-2091 ispartof: location:United States status: published

Cytotoxicity of oxaliplatin-containing solutions (OCS), sampled during patient treatment with hyperthermic intraperitoneal chemotherapy (HIPEC), was assessed by well-established continuous impedance-based real-time cell analysis (RTCA)ex vivo. HIPEC treatment was replicated by exposing OAW-42 cancer cells to OCS for 30 or 60 minutes at 42 °C. In contrast to previous observations with continuous exposure, where cytotoxicity was proven, identical OCS obtained during HIPEC did not induce cell death reproducibly and showed strongly attenuated effects after only 30 minutes of application. Based on these unexpected findings, spike-ins of oxaliplatin (OX) into peritoneal dialysis solution (PDS) or dextrose 5 % in water (D5W) were used to replicate HIPEC conditions, as used in either our own protocols or the recently presented randomized controlled PRODIGE 7 trial, where OX HIPEC for 30 minutes failed to produce survival benefits in colorectal carcinoma patients. With OX-spiked into D5W or PDS at identical concentrations as used for PRODIGE 7 or conforming with own HIPEC protocols, we did not observe the expectable cytotoxic effects in RTCA, after replicating OX HIPEC for 30 minutes. These results were corroborated for both solvents at relevant drug concentrations by classical end-point assays for cytotoxicity in two cancer cell lines. Further results suggest that penetration depth, drug dosage, exposure time and drug solvents may constitute critical factors for HIPEC effectiveness. Accordingly, we witnessed substantial cell shrinkage with both PDS and D5W, potentially contributing to reduced drug effects. Based on these results, intensified pharmacological research seems warranted to establish effective HIPEC protocols.Key PointsOxaliplatin (OX)-containing solutions obtained during patient treatment with Hyperthermic intraperitoneal chemotherapy (HIPEC) unexpectedly showed low cytotoxicity in an impedance-basedex vivocytotoxicity cell assay.OX cytotoxicity under HIPEC conditions could be enhanced by extending drug exposure to one hour by an impedance-basedex vivocytotoxicity cell assay.HIPEC failed to show survival benefits in the randomized controlled PRODIGE 7 trial and was questioned in the aftermath.Clinically relevant OX concentrations applied in conjunction with hyperthermia (42 °C) for 30 minutes, as used either at our own medical center or according to the PRODIGE 7 trial, proved predominantly ineffective, when used according to HIPEC routines in an impedance-basedin vitrocytotoxicity cell assay.Respective findings were corroborated in two different cell lines and by two established end-point assays, showing that 50 % cell death could not be reached by the same HIPEC treatment with OX, in contrast to continuous drug exposure.As potentially relevant factor, the thickness of the exposed cell layer was identified, requiring at least ~100 µm penetration depth for our model to indicate effectiveness.Additionally, we show relevant cell shrinkage by two drug diluents used either at our own medical center or according to the PRODIGE 7 trial, potentially associated with fluid shifts out of the cell and impaired drug effects.Our own as well as recent findings by Ubinket al.(Br J Surg. 2019. doi: 10.1002/bjs.11206) support the notion that lacking effectiveness of OX HIPEC may explain the negative PRODIGE 7 trial results.

Transcatheter aortic valve implantation (TAVI) has become the mainstay for high-risk or inoperable patients with symptomatic aortic valve stenosis, and research regarding the use of transcatheter valves in intermediate or low-risk patients is currently ongoing. The aim of this article is to provide comprehensive insight into the anesthetic management of patients undergoing TAVI and to highlight possible gaps in the current knowledge. One important procedural characteristic that is imperative to consider is the type of anesthesia being used and its possible complications. Increasingly, experienced centers have changed from general anesthesia with endotracheal intubation to local anesthesia with sedation, especially when the transfemoral access route is used for TAVI. There is still debate regarding what type of anesthesia should be used in the procedure, and the lack of randomized data makes it even more challenging for the operators.

Introduction Cardiac perforation of the right ventricle associated with pacemaker or implantable cardioverter defibrillator (ICD) leads' implantation is uncommon, albeit potentially life-threatening, complication. The aim of this study is to further identify the optimal therapeutic strategy, especially when lead dislocation has occurred outside the pericardial sac. Methods and results The study population included 10 consecutive patients (six female, mean age: 66.5 years old) diagnosed with early ventricular lead perforation following a pacemaker or ICD implantation, with significant protrusion inside the pericardial sac (n = 2) or migration of the lead at the pleural space ( n = 3), the diaphragm ( n = 1), or the abdominal cavity ( n = 4), during the period 2013-2017. All patients were symptomatic; however, individuals presenting with hemodynamic instability were excluded. The outcome of the percutaneous therapeutic approach was retrospectively assessed. All patients underwent a successful removal of the perforating lead percutaneously at the electrophysiology lab, by direct traction, and repositioning in another location of the right ventricle. The operation was performed by a multidisciplinary team, under continuous hemodynamic and transesophageal echocardiographic monitoring and cardiac surgical backup. The periprocedural period was uneventful. Subjects were followed up for at least 1 year. Interestingly, all patients developed a type of postcardiac injury syndrome, successfully treated with a 3-month regimen of ibuprofen and colchicine. Conclusion Percutaneous traction and repositioning of the perforating ventricular lead are effective, safe, and less invasive compared with the thoracotomy method in hemodynamically stable patients when dislocation has occurred outside the pericardial sac provided that there is no visceral organs injury.

Background High platelet reactivity (HPR) under treatment with clopidogrel or aspirin is associated with adverse outcome. We aimed to investigate whether high platelet reactivity (HPR) to both aspirin and clopidogrel is a stronger predictor of adverse events compared to isolated HPR to clopidogrel or aspirin. Methods In this prospective cohort study platelet reactivity to adenosine diphosphate (ADP) and arachidonic acid (AA) was assessed by Multiple Electrode Aggregometry (MEA) in 403 patients undergoing percutaneous coronary intervention. The rates of the composite of cardiac adverse events (acute coronary syndrome, stent thrombosis, stroke, death and revascularization) were recorded during 12-month follow-up. Results The composite endpoint of cardiovascular adverse events occurred more often in patients with high platelet reactivity (HPR) to both agonists ADP and AA (37.5%) than in those with isolated HPR to ADP (33.3%), AA (25.6%) or without any HPR (18.6%; p=0.003). Classification tree analysis indicated that any HPR emerged as an independent predictor influencing outcome, which was associated with a 1.75 higher risk of cardiac adverse events (OR=1.75: 95%CI=1.1–2.9). Interestingly, the predictive value of HPR tended to be greater among patients with diabetes mellitus (OR=2.18; 95%CI=1.20–3.95). C-reactive protein and diabetes mellitus were independent predictors of high platelet reactivity to both agonists. Conclusions Dual low responsiveness to clopidogrel and aspirin is a strong predictor of cardiac adverse events, especially in patients with diabetes mellitus, which underlines the need for personalized antiplatelet treatment.

Diabetes is one of the fastest growing diseases in Canada. It is estimated that 2 million Canadians have type 2 diabetes and that there are more than 60,000 new cases of this disease diagnosed each year. The cost of diabetes in Canada is projected to be up to $9 billion annually.1 One-third of those affected with type 2 diabetes are unaware that they have the disease.1 Managing diabetes is a challenging endeavour for those diagnosed and involves routine monitoring and regular testing in order for patients to maintain reasonable glycemic control. The DICE study in 2005 found that 1 in 2 Canadians with type 2 diabetes do not have their blood sugar under control and that control is worse the longer patients have had diabetes.2 As a measure of glycemic control, the Canadian Diabetes Association (CDA) recommends glycated hemoglobin (HbA1c [%]) levels ≤7.0.3 However, according to one study, only 29% of patients with diabetes actually had an HbA1c test in the previous year, and among those tested, only 43% had an HbA1c less than 7%.4 Additionally, 18% of those tested had an HbA1c of 9.5% or more, meaning that their blood glucose levels were uncontrolled.4 Given the complexity of diabetes control, evidence suggests that diabetes can be best managed through an interdisciplinary team that includes a pharmacist.5 The relative accessibility of the community pharmacist allows patients the opportunity to discuss their health care concerns, typically without the need for a referral or appointment (though making an appointment so that the pharmacist is able to set aside an appropriate amount of time is becoming more common). This unique position allows pharmacists to readily monitor patients and assist them in attaining adequate glucose control. HbA1c testing is an important outcome measure in patients with diabetes. Unlike a point-in-time blood glucose measure, the HbA1c provides an estimate of glycemic control over a 3-month period. It allows the health care provider to monitor patients with diabetes and estimate how well their disease is controlled and whether they require additional interventions to maintain target levels. The United Kingdom Prospective Diabetes Study (UKPDS) has shown that lower HbA1c levels have been correlated with fewer complications.6 For instance, in epidemiologic analyses, HbA1c levels >7.0% are associated with a significantly increased risk of both microvascular and macrovascular complications, regardless of underlying treatment.3 John Papastergiou Pharmacy Limited operates at 3 locations as Shoppers Drug Mart in Toronto, Ontario. All 3 pharmacies are located in an urban setting with a diverse, multi-ethnic patient population. The Pharmacy team, including pharmacists, pharmacy technicians, interns and pharmacy students from all 3 locations, is working to improve the management of patients with diabetes through the use of HbA1c testing. Historically, the testing of HbA1c required a visit to the physician and was limited to a laboratory blood test. With the introduction of the Bayer A1C Now meters, patients can be tested by their community pharmacist without a laboratory requisition and HbA1c results can be made available within 5 minutes. The HbA1c meter has demonstrated an accuracy of 99% in 3 independent evaluation studies.7 The Pharmacy team decided that the level of accuracy, in combination with the ease and speed of testing, made this new innovation the perfect tool for testing and monitoring their patients with diabetes. The meters provide an efficient and reliable method for HbA1c monitoring. The HbA1c result provides the pharmacist with more information regarding the patient's glycemic control and allows for additional consultation and recommendations in an attempt to improve outcomes.

We report two cases of successful treatment of Brucella endocarditis. Both of them were treated with antibiotics and aortic valve replacement after Brucellosis was diagnosed. In one of these cases emergency operation was required. Our observations suggest that a combined surgical and medical treatment is the best option for the management of this disease. B. endocarditis should be operated after improvement of clinical status but emergency cardiac surgery may be required if heart failure develops.