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Linking non-coding genetic variants associated with the risk of diseases or disease relevant traits to target genes is a crucial step to realize GWAS potential in the introduction of precision medicine. Here we set out to determine the mechanisms underpinning variant association with platelet quantitative traits using cell type matched epigenomic data and promoter long-range interactions. We identified potential regulatory functions for 423 of 565 (75%) non-coding platelet variants and highlighted, including ex vivo and genome editing proof of principle validation, the role of associated variants in super enhancers in controlling archetypical platelet functions. ; The work was funded by a grant from the European Commission 7th Framework Program (FP7/2007-2013, grant 282510, BLUEPRINT). F.A.C. is a Medical Research Council (MRC) clinical fellow (MR/K024043/1); K.D. is funded by NHS Health Education England; M.F. is supported by the British Heart Foundation (BHF) Cambridge Centre of Excellence (RE/13/6/30180); research in the W.H.O. laboratory is also supported by grants from Bristol Myers-Squibb, BHF, European Commission, MRC, NIHR (W.H.O. is NIHR Senior Investigator) and NHS Blood and Transplant (NHSBT). RP is supported by the European Union's Horizon 2020 research and innovation program under grant agreement No. 692041 (TrainMALTA, H2020-TWINN-2015). L.V. is funded by the ERC grant Relieve IMDs (ERC-2011-StG). P.M. and A-S.L. are funded by the NIHR Cambridge Biomedical Research Centre (BRC) hIPSCs core facility. B.M.J., P.Fr. and M.S. are supported by the MRC (MR/L007150/1) and Biotechnology and Biological Sciences Research Council (BB/J004480/1). K.F. is funded by FWO-Vlaanderen (G.0B17.13N) and BOF KULeuven (OT/14/098). Work at EMBL-EBI received additional support from the Wellcome Trust (WT095908) to P.Fl and from the European Molecular Biology Laboratory to L.C., M.K., P.Fl. and O.S. The MRC/BHF Cardiovascular Epidemiology receives core support from the MRC (G0800270), the BHF (SP/09/002), the NIHR and NIHR Cambridge BRC, as well as grants from the European Research Council (268834), the European Commission FP7 (HEALTH-F2-2012-279233), Merck and Pfizer. J.D. is a BHF Professor, European Research Council Senior Investigator, and NIHR Senior Investigator. The NIHR Blood and Transplant Research Unit in Donor Health and Genomics at the University of Cambridge is funded by NIHR and NHSBT.

IntroductionIn randomised controlled trials (RCTs), bleeding outcomes are often assessed using definitions provided by the International Society on Thrombosis and Haemostasis (ISTH). Information relating to bleeding events in real-world evidence (RWE) sources are not identified using these definitions. To assist with accurate comparisons between clinical trials and real-world studies, algorithms are required for the identification of ISTH-defined bleeding events in RWE sources.
ObjectivesTo present a novel algorithm to identify ISTH-defined major and clinically-relevant non-major (CRNM) bleeding events in a US Electronic Health Record (EHR) database.
MethodsThe ISTH definition for major bleeding was divided into three subclauses: fatal bleeds, critical organ bleeds and symptomatic bleeds associated with haemoglobin reductions. Data elements from EHRs required to identify patients fulfilling these subclauses (algorithm components) were defined according to International Classification of Diseases, 9th and 10th Revisions, Clinical Modification disease codes that describe key bleeding events. Other data providing context to bleeding severity included in the algorithm were: `interaction type' (diagnosis in the inpatient or outpatient setting), `position' (primary/discharge or secondary diagnosis), haemoglobin values from laboratory tests, blood transfusion codes and mortality data.
ResultsIn the final algorithm, the components were combined to align with the subclauses of ISTH definitions for major and CRNM bleeds. A matrix was proposed to guide identification of ISTH bleeding events in the EHR database. The matrix categorises bleeding events by combining data from algorithm components, including: diagnosis codes, 'interaction type', 'position', decreases in haemoglobin concentrations (≥2 g/dL over 48 hours) and mortality.
ConclusionsThe novel algorithm proposed here identifies ISTH major and CRNM bleeding events that are commonly investigated in RCTs in a real-world EHR data source. This algorithm could facilitate comparison between the frequency of bleeding outcomes recorded in clinical trials and RWE. Validation of algorithm performance is in progress.

Deep vein thrombosis (DVT) occurs when thrombosis (blood clots) forms in veins far below the skin's surface due to veins or sluggish blood flow injuries. An obstruction in blood flow through a vein could be partially or completely caused by blood clots. DVTs typically occur in the thigh, lower leg, or pelvis, yet can also occur in other body parts, such as the brain, liver, intestines, arm, or kidney. This research proposes a novel Deep Vein Net, integrating deep learning-based dilated CNN and Sooty Tern optimization to detect DVT from CT and MRI images efficiently. The input CT and MRI images are pre-processed to eliminate noise artifacts using the Discrete Wavelet Transform (DWT). Furthermore, the pre-processed images are fed into a Dilated convolutional neural network (Dilated CNN) for feature extraction to extract the most pertinent features. Lastly, the STO algorithm uses the fuzzy Extreme Learning Machine of thrombosis stages normal and DVT to select the best features for additional classification. Metrics like rec, spe, acc, pre, and F1 scores were used to assess the Deep Vein Net's performance. The suggested method achieves a classification accuracy of 99.25 % when identifying DVT cases.

The total clinical neurologic and neurophysiological and neuropsychological checkup was hold for raising of capacity for work of 93 military personnel. The fundamental factors of risk of precerebral thrombosis diseases (vegeto-vascular dystonia and vertebral reasons) were discovered. This fact allows to realize the differential method of attack in treatment and prophylaxis of precerebral thrombosis diseases. ; С целью продления работоспособности военнослужащих (n=93) выполнялось полное клинико-неврологическое, нейрофизиологическое, нейропсихологическое обследование, позволяющее своевременно выявлять основные факторы риска доинсультных заболеваний (ВСД и вертеброгенная патология) и осуществлять дифференцированный подход в их лечении и профилактике.

Abstract Dabigatran is an emerging oral anticoagulant which is a direct inhibitor of thrombin activity. It has been approved in the European Union and the United States of America for the prevention of thrombosis after major orthopedic surgery. It has also been approved by the American Food and Drug Administration and the European Medicines Agency for the prevention of stroke in chronic atrial fibrillation. Dabigatran provides a stable anticoagulation effect without any need to perform periodical laboratory controls. Of note, there is a growing amount of clinical evidence which shows its safety and efficacy. For these reasons, dabigatran may suppose a revolution in oral anticoagulation. However, two important limitations remain. First, it is contraindicated in patients with end-stage renal disease. Second, there is no evidence of the prevention of thrombosis in mechanical heart valves.

Background: Chronic Aorta Iliac Occlusive Disease (CAIOD) is a significant cause of lower limb ischemia and is often found in various age group with varied etiology. Objective: To review recent results achieved treating CAIOD patients with open surgery and endovascular surgery. Methods: From January 2017 to December 2018, 39 patients , who were admitted in Tamilnadu Government Multi Super Specialty Hospital, affiliated to The Tamilnadu Dr.M.G.R Medical University. Tamilnadu, Chennai. were operated with diagnosis of aorta iliac occlusion. Demographic data, co morbidities, clinical presentation and surgical results were analyzed. Results: Thirty six men and 3 women were treated with aortic reconstruction. procedures included aortic bi femoral bypass (ABF; n=18), Ilio- Femoral Bypass ( IFB; n=3), Aorta Iliac Plasty (AIP, n=1 ). Mean age was 53.7 ? 7.3 years (range: 43-79 years) and 30 patients were smokers. Thirty patients (%) had critical limb ischemia. Six of the patients treated with ABF (%) also required additional revascularization ( femoropopliteal procedures). Perioperative mortality was two. Four patients (%) suffered transitory renal dysfunction, but only one patient (%) required hemodialysis. Median follow-up time was 17 months (range: 2-29 months) and there was just one late death, from ischemic heart disease, 7 months after the surgery on the abdominal aorta. Conclusions: Aortic reconstruction with both open and endo- vascular methods is a safe for treating patients with Aorta iliac occlusions, with low perioperative morbidity and mortality rates.

The formation of a thrombus in a vein leads to a narrowing of its lumen and a reduction in blood flow, which results in the development of venous thromboembolism (VTE). It manifests itself in most cases, including pain, swelling and redness of the affected limb. Data published in 2007 indicate that in 6 European Union countries as many as 370,000 deaths per year are a consequence of deep vein thrombosis (DVT), which is 75% a consequence of hospitalization. [2] [11] The causes of blood clots are found in the factors of the so-called Virchow triad. The main risk factors for venous thromboembolism as well as its complications of pulmonary embolism include thrombophilia, advanced age, previous VTE, immobilization of trauma or surgery. In the diagnosis of VTE, the determination of D-dimer level plays a key role.

The formation of a thrombus in a vein leads to a narrowing of its lumen and a reduction in blood flow, which results in the development of venous thromboembolism (VTE). It manifests itself in most cases, including pain, swelling and redness of the affected limb. Data published in 2007 indicate that in 6 European Union countries as many as 370,000 deaths per year are a consequence of deep vein thrombosis (DVT), which is 75% a consequence of hospitalization. [2] [11] The causes of blood clots are found in the factors of the so-called Virchow triad. The main risk factors for venous thromboembolism as well as its complications of pulmonary embolism include thrombophilia, advanced age, previous VTE, immobilization of trauma or surgery. In the diagnosis of VTE, the determination of D-dimer level plays a key role.

The formation of a thrombus in a vein leads to a narrowing of its lumen and a reduction in blood flow, which results in the development of venous thromboembolism (VTE). It manifests itself in most cases, including pain, swelling and redness of the affected limb. Data published in 2007 indicate that in 6 European Union countries as many as 370,000 deaths per year are a consequence of deep vein thrombosis (DVT), which is 75% a consequence of hospitalization. [2] [11] The causes of blood clots are found in the factors of the so-called Virchow triad. The main risk factors for venous thromboembolism as well as its complications of pulmonary embolism include thrombophilia, advanced age, previous VTE, immobilization of trauma or surgery. In the diagnosis of VTE, the determination of D-dimer level plays a key role.

Combat firearm trauma is one of the factors that initiate the imbalance in the hemostasis system. The presence of thrombophilia in the wounded persons increases the possibility of pathological thrombosis and the risk of pulmonary embolism.Objective – to study the effect of polymorphism in the genes of components of the hemostasis system on the development of venous thrombosis in the victims with combat gunshot trauma.Materials and methods. The features of the allelic polymorphism of 10 genes encoding the various components of the hemostasis system were studied in 46 patients with a gunshot injury. They were treated in the Main Clinical Hospital of the Ministry of Internal Affairs of Russian Federation and in the Main Military Clinical Hospital of National Guard Troops of Russian Federation in 2013-2015. The allelic polymorphism of the genes associating with the process of thrombus formation was studied on the basis of polymerase chain reaction (PCR) technology and polymorphism analysis of the length of the restriction fragments of the PCR product.Results. The analysis of the conducted study established the presence of prothrombotic genetic variants in 42 (91.3 %) patients. It was found that the most significant risk factors of venous thromboembolic complications (VTEC) in this category of individuals are FII G20210A mutation, the carriage of the GpIbα 434C allele, and the genotype FI-B -455AA.Conclusion. This study is the first work in Russia to study the occurrence of allelic variants of the genes of the components of the hemostasis system in patients with combat gunshot trauma. The presence of the thrombosis predisposition markers in participants of war conflicts can form the basis for identifying the risk groups and development of recommendations for prevention and treatment of VTEC in carriers of prothrombotic genotypes. ; Боевая огнестрельная травма является одним из факторов, инициирующих нарушение равновесия в системе гемостаза. Наличие тромбофилий у раненых увеличивает вероятность развития патологического тромбообразования и повышает риск эмболии легочных артерий.Цель – изучение влияния полиморфизма генов компонентов системы гемостаза на развитие венозного тромбоза у раненых с боевой огнестрельной травмой.Материал и методы. Изучены особенности аллельного полиморфизма 10 генов, кодирующих различные компоненты системы гемостаза, у 46 раненых с боевой огнестрельной травмой, находившихся на лечении в Главном клиническом госпитале МВД России и в Главном военном клиническом госпитале войск национальной гвардии Российской Федерации в период с 2013 по 2015 год. Изучение аллельного полиморфизма генов, связанных с процессом образования тромбов, осуществлялось на основе технологии полимеразной цепной реакции (ПЦР) и анализа полиморфизма длин рестрикционных фрагментов ПЦР-продукта.Результаты. Анализ проведенного исследования установил наличие протромботических генетических вариантов у 42 (91,3 %) раненых. Было установлено, что наиболее значимыми факторами риска венозных тромбоэмболических осложнений (ВТЭО) у данной категории лиц являются мутация FII G20210A, носительство аллеля GpIbα 434C, а также генотип FI-B -455AA.Заключение. Проведенное исследование является первой работой в России по изучению встречаемости аллельных вариантов генов компонентов системы гемостаза у раненых с боевой огнестрельной травмой. Данные о наличии в генотипе лиц, принимающих участие в боевых действиях, маркеров предрасположенности к тромбозу могут служить основой для определения «групп риска» и выработки рекомендаций по профилактике и лечению ВТЭО у раненых – носителей протромботических генотипов.

Covid positive pregnant women were increasingly getting delivery in the health institution. Most of them were asymptomatic and had positive report after their obstetric event was over because of emergency nature of care. Lack of autopsy is the lacunae in determining tissue pathology. One case of sudden intrauterine fetal death in Covid positive patient had induced delivery in the hospital and the placental histopathology examination showed widespread villous infarction, decidual arteriopathy with thrombosis and chorioamnionitis.Keywords: Covid positive; fetal death; placenta; thrombosis

In recent months, vaccination policies against COVID-19 have evolved worldwide as pharmacovigilance provides new evidence on efficacy, and adverse events of all vaccines available. The first alerts that prompted changes in vaccination policies in several countries were related to rare severe thrombosis occurring mainly in women under 55 years old, happening several days after the first dose of the ChAdOx1 nCoV-19 (AZD1222, AstraZeneca) vaccine (1), and the single dose of Ad.26.COV2.S (Johnson & Johnson, J&J/Janssen) vaccine (2).The European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) recommended to continue the use of these vaccines, considering that benefits outweighed the risks. However, some high-income countries mandated that the AZD1222 vaccine be given only to people over 60 years old, while other countries paused its use indefinitely. On the other hand, many governments of low-middle income countries continue using the AZD1222 vaccine in people under 60 years of age, as they vaccinate their population with the options they have available.In the case of the BNT162b2 (BNT, Pfizer) and mRNA-1273 (Moderna) vaccines, there are some reports of rare cases of non-severe acute myocarditis and pericarditis in young people older than 16 years, especially men, and typically a few days after the second dose (3). The mechanism for this adverse event of these two mRNA vaccines is still under study, and it is unknown whether a second booster of these vaccines could lead to more cases of acute myocarditis in the susceptible population. The recommendation to actively monitor and study the aforementioned adverse events to determine a cause-effect relation, seems to be under looked in many low-middle income countries where pharmacovigilance or post marketing studies are not being conducted.Another issue forcing policy changes is the vaccine delay in production and delivery. Recently, there was a warning about the insufficient production of the Gam-COVID-Vac (Sputnik V) second dose, leaving several million people awaiting indefinitely to complete the immunization schedule. A few preliminary studies about mixing and matching vaccines in case of shortage, are being used to justify the administration of a different vaccine for second dose. This has raised debates about which vaccines could be used to complete immunization in these cases. However, despite the race against time to end the pandemic, it is imperative to carry out more clinical trials and pharmacological surveillance to evaluate the effectiveness of those combinations before they become part of emergency public health policies.Post-vaccination pharmacovigilance should be systematic worldwide, and should run parallel to genomic surveillance of SARS-CoV-2 and its variants. This will allow to revisit the effectiveness and the safety profile of COVID-19 vaccines, and to provide evidence-based vaccination policies . ; En los últimos meses, las políticas de vacunación para prevenir el COVID-19 han evolucionado a nivel global a medida que la vigilancia farmacológica ha demostrado nuevas evidencias tanto de la eficacia como de los eventos adversos de todas las vacunas disponibles. Las primeras alertas que promovieron cambios en las políticas de vacunación en diferentes países estuvieron relacionadas a casos raros de trombosis severa, que ocurrieron principalmente en mujeres menores de 55 años, usualmente días después de la primera dosis de la vacuna ChAdOx1 nCoV-19 (AZD1222, AstraZeneca) y de la dosis única de la vacuna Ad.26.COV2.S (Johnson & Johnson, J&J/Janssen) (2). La Agencia Europea de Medicamentos (EMA) y la Administración de Medicamentos y Alimentos de Estados Unidos (FDA) recomendaron continuar con el uso de estas vacunas, teniendo en cuenta que los beneficios eran superiores a los riesgos. Sin embargo, algunos países de altos ingresos ordenaron que la vacuna AZD1222 se suministrara solo a personas mayores de 60 años, mientras que otros países pausaron su aplicación indefinidamente. Por otra parte, varios gobiernos de países de bajos y medianos ingresos, siguieron aplicando la vacuna AZD1222 a personas menores de 60 años, ya que realizan la vacunación de sus habitantes con las opciones disponibles.En el caso de las vacunas BNT162b2 (BNT, Pfizer) y mRNA-1273 (Moderna) existen algunos reportes de casos aislados de miocarditis aguda y pericarditis no severas en jóvenes mayores de 16 años, especialmente en varones, típicamente algunos días después de la segunda dosis. Los mecanismos de este evento adverso se encuentran aún en estudio y se desconoce si un segundo refuerzo de estas dos vacunas rRNA podría ocasionar más casos de miocarditis aguda en población susceptible. La recomendación de monitorear y estudiar activamente dichos eventos adversos no parece ser una prioridad en muchos países de bajos y medianos recursos, donde no se han llevado a cabo estudios de farmacovigilancia ni de poscomercialización. Otro problema que obliga a realizar cambios en las políticas es el retraso en la producción como en la distribución de las vacunas. Recientemente, hubo una alerta debido a la insuficiente producción de la segunda dosis de la vacuna Gam-COVID-Vac (Sputnik V), lo cual dejó a varios millones de personas esperando indefinidamente para completar su esquema de inmunización. Unos pocos estudios preliminares sobre la combinación de vacunas en condiciones de escasez están siendo usados para justificar la administración de una vacuna diferente para la segunda dosis. Este hecho ha suscitado debates sobre cuál vacuna debería usarse para completar la inmunización en estos casos. Sin embargo, pese a la carrera contra el tiempo para acabar con la pandemia, es imperativo llevar a cabo más ensayos clínicos y de farmacovigilancia para evaluar la efectividad de estas combinaciones antes de formar parte de políticas públicas de salud en situación de emergencia. La farmacovigilancia posvacuna debe ser sistemática a nivel mundial y también debe llevarse a cabo paralelamente con la vigilancia genómica del SARS-CoV-2 y de sus variantes. Esto permitirá revisar la efectividad y el perfil de seguridad de las vacunas contra el COVID-19 y por ende, formular políticas de vacunación basadas en la evidencia.

Potts: There are differences in the risks associated with hormonal contraception in relation to smoking, obesity and previous patterns of thromboembolic disease. In a study carried out in Bangkok and Oxford (Chumnijarakij & Poshyachinda, 1975) comparing the incidence of thrombosis, as measured by 125I-labelled fibrinogen, after hysterectomy or cancer surgery, there was a higher incidence of postoperative thrombosis, measured by objective criteria, in Oxford (12–35%) than in Bangkok (1·7–3·8%). The argument could be made by inference that Asian women have less risks with the pill, although there are no data to prove it either way.