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BACKGROUND: Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF) is a prospective registry of outcomes from patients with newly diagnosed AF at risk of stroke. In the propensity score (PS)-matched global population of phase 3 GLORIA-AF, at 3 years, dabigatran-treated patients experienced reduced risk for major bleeding, and similar risk for stroke and myocardial infarction, compared with vitamin K antagonist (VKA)-treated patients. STUDY QUESTION: Do patients in Eastern Europe benefit from treatment with dabigatran versus VKA? STUDY DESIGN: Descriptive analysis, without PS matching. To contextualize the Eastern Europe results of GLORIA-AF phase 3, we also descriptively analyzed the global population without PS matching. Consecutive patients with newly diagnosed AF and CHA2DS2-VASc-score ≥1 were enrolled until December 2016 in 38 countries (9 in Eastern Europe). MEASURES AND OUTCOMES: Three-year outcomes with dabigatran and VKA. RESULTS: In Eastern Europe, 1341 patients were eligible (6% of patients globally), and incidence rates (per 100 patient-years) for the following outcomes were numerically lower with dabigatran (N = 498) versus VKA (N = 466): major bleeding (0.26 vs. 0.90), all-cause death (2.04 vs. 3.50), and a composite of stroke, systemic embolism, myocardial infarction, life-threatening bleeding, and vascular death (1.37 vs. 1.92); stroke was comparable (0.51 vs. 0.50). All incidence rates were numerically lower in Eastern Europe versus the global population for both treatments. Chronic concomitant use of high bleeding risk medications (eg, nonsteroidal anti-inflammatories) was lower in Eastern Europe (dabigatran 3.8%, VKA 9.3%) than globally (dabigatran 14.8%, VKA 20.6%) and persistence with dabigatran was higher in Eastern Europe (76%) than globally (64%). CONCLUSIONS: Dabigatran was associated with numerically reduced major bleeding, all-cause death, and cardiovascular (CV) composite, with comparable risk of stroke versus VKA, in Eastern Europe. Limitations of this descriptive analysis include few CV events (n = 11 for stroke, in the dabigatran and VKA groups combined) and a lack of statistical analysis and PS matching, which precludes definitive conclusions; however, the CV outcomes in Eastern Europe were consistent with the beneficial impact of dabigatran versus VKA in the statistically analyzed global population with PS matching.
Assuntos
Fibrilação Atrial , Infarto do Miocárdio , Acidente Vascular Cerebral , Humanos , Fibrilação Atrial/complicações , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/epidemiologia , Dabigatrana/efeitos adversos , Fibrinolíticos/efeitos adversos , Anticoagulantes/efeitos adversos , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/prevenção & controle , Europa Oriental/epidemiologia , Infarto do Miocárdio/epidemiologia , Hemorragia/induzido quimicamente , Hemorragia/epidemiologia , Vitamina KRESUMO
Chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment of hematological malignancies. The importance of the receptor costimulatory domain for long-term CAR-T cell engraftment and therapeutic efficacy was demonstrated with second-generation CAR-T cells. Fifth generation CAR-T cells are currently in preclinical trials. At the same time, the processes that orchestrate the activation and differentiation of CAR-T cells into a specific phenotype that predisposes them to long-term persistence are not fully understood. This review highlights ongoing research aimed at elucidating the role of CAR domains and T-cell signaling molecules involved in these processes.
Assuntos
Neoplasias Hematológicas , Receptores de Antígenos Quiméricos , Humanos , Linfócitos T , Imunoterapia Adotiva , Neoplasias Hematológicas/tratamento farmacológico , Transdução de SinaisRESUMO
Recent studies have demonstrated the relationship between vitamin D deficiency, infection severity and mortality from COVID-19. This study aimed to analyze the vitamin D metabolites and cytokine expression levels of COVID-19 patients who were hospitalized with bolus cholecalciferol supplementation. MATERIALS AND METHODS: This study represents the next stage of the open-label randomized pilot conducted by the Almazov National Medical Research Centre. A total of 44 hospitalized patients, comparable in demographic, clinical, laboratory and instrumental baseline characteristics, with moderate/severe COVID-19 were included. All patients had similar doses of concomitant corticosteroid therapy. Twenty-two patients received 50,000 IU cholecalciferol on the first and eighth days of hospitalization. The serum 25(OH)D, 1,25(OH)2D and 28 plasma cytokines were estimated for each group initially and on the ninth day of hospitalization. RESULTS: Initially, there were no differences in the 1,25(OH)2D and cytokine levels in patients with vitamin D deficiency and normal 25(OH)D. Bolus cholecalciferol therapy at a total dose of 100,000 IU led to an increase in 25(OH)D levels in hospitalized patients with COVID-19, while the levels of the active metabolite (1,25(OH)2D) did not show significant differences between the groups or in its increased level over time, regardless of cholecalciferol supplementation. Furthermore, cholecalciferol supplementation at a total dose of 100,000 IU did not affect the majority of the cytokines estimated on the ninth day of hospitalization, except for the pro-inflammatory marker IL-1b, the concentration of which was lower in the group of patients without vitamin D supplementation. CONCLUSIONS: The 25(OH)D level was positively associated with an anti-inflammatory immune response, but cholecalciferol supplementation at a total dose of 100,000 IU did not affect the active-form vitamin D or cytokine expression levels. This fact may be explained by the impact of corticosteroid therapy, and it requires further investigation in a post-COVID-19 context.
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The NOTCH-signaling pathway is responsible for intercellular interactions and cell fate commitment. Recently, NOTCH pathway genes were demonstrated to play an important role in aortic valve development, leading to an increased calcified aortic valve disease (CAVD) later in life. Here, we further investigate the association between genetic variants in the NOTCH pathway genes and aortic stenosis in a case-control study of 90 CAVD cases and 4723 controls using target panel sequencing of full-length 20 genes from a NOTCH-related pathway (DVL2, DTX2, MFNG, NUMBL, LFNG, DVL1, DTX4, APH1A, DTX1, APH1B, NOTCH1, ADAM17, DVL3, NCSTN, DTX3L, ILK, RFNG, DTX3, NOTCH4, PSENEN). We identified a common intronic variant in NOTCH1, protecting against CAVD development (rs3812603), as well as several rare and unique new variants in NOTCH-pathway genes (DTX4, NOTCH1, DTX1, DVL2, NOTCH1, DTX3L, DVL3), with a prominent effect of the protein structure and function.
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Molecular chaperones, especially 70 kDa heat shock protein, in addition to their intracellular localization in cancer cells, can be exposed on the surface of the plasma membrane. We report that the membrane-associated chaperone mHsp70 of malignant brain tumors is required for high migratory and invasive activity of cancer cells. Live-cell inverted confocal microscopy of tumor samples from adult (n = 23) and pediatric (n = 9) neurooncologic patients showed pronounced protein expression on the membrane, especially in the perifocal zone. Mass spectrometry analysis of lipid rafts isolated from tumor cells confirmed the presence of the protein in the chaperone cluster (including representatives of other families, such as Hsp70, Hsc70, Hsp105, and Hsp90), which in turn, during interactome analysis, was associated with proteins involved in cell migration (e.g., Rac1, RhoC, and myosin-9). The use of small-molecule inhibitors of HSP70 (PES and JG98) led to a substantial decrease in the invasive potential of cells isolated from a tumor sample of patients, which indicates the role of the chaperone in invasion. Moreover, the use of HSP70 inhibitors in animal models of orthotopic brain tumors significantly delayed tumor progression, which was accompanied by an increase in overall survival. Data demonstrate that chaperone inhibitors, particularly JG98, disrupt the function of mHsp70, thereby providing an opportunity to better understand the diverse functions of this protein and offer aid in the development of novel cancer therapies. SIGNIFICANCE: Membrane-bound mHsp70 is required for brain tumor cell migration and invasion and therefore could be employed as a target for anticancer therapies.
Assuntos
Neoplasias Encefálicas , Movimento Celular , Proteínas de Choque Térmico HSP70 , Invasividade Neoplásica , Humanos , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/metabolismo , Movimento Celular/efeitos dos fármacos , Animais , Proteínas de Choque Térmico HSP70/metabolismo , Camundongos , Linhagem Celular Tumoral , Feminino , Membrana Celular/metabolismo , Masculino , Adulto , Microdomínios da Membrana/metabolismoRESUMO
The population of Russia consists of more than 150 local ethnicities. The ethnic diversity and geographic origins, which extend from eastern Europe to Asia, make the population uniquely positioned to investigate the shared properties of inherited disease risks between European and Asian ancestries. We present the analysis of genetic and phenotypic data from a cohort of 4,145 individuals collected in three metro areas in western Russia. We show the presence of multiple admixed genetic ancestry clusters spanning from primarily European to Asian and high identity-by-descent sharing with the Finnish population. As a result, there was notable enrichment of Finnish-specific variants in Russia. We illustrate the utility of Russian-descent cohorts for discovery of novel population-specific genetic associations, as well as replication of previously identified associations that were thought to be population-specific in other cohorts. Finally, we provide access to a database of allele frequencies and GWAS results for 464 phenotypes.
Assuntos
Frequência do Gene , Estudo de Associação Genômica Ampla , Humanos , Federação Russa/epidemiologia , Masculino , Polimorfismo de Nucleotídeo Único , Feminino , Predisposição Genética para Doença , Genética Populacional , Fenótipo , População Branca/genética , Finlândia , Povo Asiático/genética , Variação Genética , Estudos de Coortes , Herança Multifatorial/genética , Etnicidade/genética , População do Leste EuropeuRESUMO
Resumen: La Red de Editores de la Sociedad Europea de Cardiología (ESC, por su sigla en inglés) constituye un foro dinámico dedicado a discusiones editoriales y respalda las recomendaciones del Comité Internacional de Editores de Revistas Médicas (ICMJE, por su sigla en inglés) destinadas a mejorar la calidad científica de las revistas biomédicas. La paternidad literaria confiere crédito, además de importantes recompensas académicas. Recientemente, sin embargo, el ICMJE ha destacado que la autoría también exige que los autores sean responsables y se hagan cargo de lo que publican. Estas cuestiones ahora están cubiertas por el nuevo (cuarto) criterio para la autoría. Los autores deben aceptar hacerse responsables de lo que escriben y garantizar un adecuado enfoque de las cuestiones concernientes a la precisión e integridad de todo el trabajo. Esta revisión analiza las implicancias de este cambio de paradigma en los requisitos de autoría con el objetivo de aumentar la conciencia sobre las buenas prácticas científicas y editoriales.
Summary: The Editors´ Network of the European Society of Cardiology provides a dynamic forum for editorial discussions and endorses the recommendations of the International Committee of Medical Journal Editors to improve the scientific quality of biomedical journals. Authorship confers credit and important academic rewards. Recently, however, the International Committee of Medical Journal Editors emphasized that authorship also requires responsibility and accountability. These issues are now covered by the new (fourth) criterion for authorship. Authors should agree to be accountable and ensure that questions regarding the accuracy and integrity of the entire work will be appropriately addressed. This review discusses the implications of this paradigm shift on authorship requirements with the aim of increasing awareness on good scientific and editorial practices.
Resumo: A Rede de Editores da Sociedade Europeia de Cardiologia é um fórum dinâmico para discussões editoriais e apoia as recomendações do Comitê Internacional de Editores de Revistas Médicas, visando melhorar a qualidade científica das revistas biomédicas. A autoria confere crédito, além de importantes recompensas acadêmicas. Recentemente, no entanto, o Comitê Internacional de Editores de Revistas Médicas enfatizou que a autoria também requer que os autores sejam responsáveis do que escrevem e se encarreguem do que publicam. Essas questões agora estão cobertas pelo novo (quarto) critério de autoria. Os autores devem concordar em ser responsáveis e garantir que as questões relativas à precisão e integridade de todo o trabalho sejam abordadas de maneira apropriada. Esta revisão discute as implicações dessa mudança de paradigma nos requisitos de autoria, com o objetivo de aumentar a conscientização sobre as boas práticas científicas e editoriais.
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Humanos , Autoria , Responsabilidade Social , Turquia , Cardiologia , Políticas Editoriais , Europa (Continente)RESUMO
Abstract The Editors Network of the European Society of Cardiology (ESC) provides a dynamic forum for editorial discussions and endorses the recommendations of the International Committee of Medical Journal Editors (ICMJE) to improve the scientific quality of biomedical journals. Authorship confers credit and important academic rewards. Recently, however, the ICMJE emphasized that authorship also requires responsibility and accountability. These issues are now covered by the new (fourth) criterion for authorship. Authors should agree to be accountable and ensure that questions regarding the accuracy and integrity of the entire work will be appropriately addressed. This review discusses the implications of this paradigm shift on authorship requirements with the aim of increasing awareness on good scientific and editorial practices.
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Editoração/ética , Autoria , Responsabilidade Social , Políticas EditoriaisRESUMO
Abstract The International Committee of Medical Journal Editors (ICMJE) provides recommendations to improve the editorial standards and scientific quality of biomedical journals. These recommendations range from uniform technical requirements to more complex and elusive editorial issues including ethical aspects of the scientific process. Recently, registration of clinical trials, conflicts of interest disclosure, and new criteria for authorship - emphasizing the importance of responsibility and accountability-, have been proposed. Last year, a new editorial initiative to foster sharing of clinical trial data was launched. This review discusses this novel initiative with the aim of increasing awareness among readers, investigators, authors and editors belonging to the Editors´ Network of the European Society of Cardiology.
Resumo O Comitê Internacional de Editores de Revistas Médicas (ICMJE) fornece recomendações para aprimorar o padrão editorial e a qualidade científica das revistas biomédicas. Tais recomendações variam desde requisitos técnicos de uniformização até assuntos editoriais mais complexos e elusivos, como os aspectos éticos do processo científico. Recentemente, foram propostos registro de ensaios clínicos, divulgação de conflitos de interesse e novos critérios de autoria, enfatizando a importância da responsabilidade e da responsabilização. No último ano, lançou-se uma nova iniciativa editorial para fomentar o compartilhamento dos dados de ensaios clínicos. Esta revisão discute essa nova iniciativa visando a aumentar a conscientização de leitores, investigadores, autores e editores filiados à Rede de Editores da Sociedade Europeia de Cardiologia.
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Humanos , Publicações Periódicas como Assunto/normas , Ensaios Clínicos como Assunto/organização & administração , Disseminação de Informação , Políticas Editoriais , Conjuntos de Dados como Assunto/normas , Sociedades Médicas , Ensaios Clínicos como Assunto/normas , Cooperação InternacionalRESUMO
Abstract: The International Committee of Medical Journal Editors (ICMJE) provides recommendations to improve the editorial standards and scientific quality of biomedical journals. These recommendations range from uniform technical requirements to more complex and elusive editorial issues including ethical aspects of the scientific process. Recently, registration of clinical trials, conflicts of interest disclosure, and new criteria for authorship - emphasizing the importance of responsibility and accountability -, have been proposed. Last year, a new editorial initiative to foster sharing of clinical trial data was launched. This review discusses this novel initiative with the aim of increasing awareness among readers, investigators, authors and editors belonging to the Editors' Network of the European Society of Cardiology.
Resumen: El Comite internacional de editores de revistas medicas (CIERM) propone recomendaciones para mejorar los standares editoriales y la calidad científica de las revistas biomédicas. Estas recomendaciones abarcan desde requerimeintos ténicos uniformados a temas editoriales mas complejos y evasivos, como los aspectos bioéticos relacionados con el proceso científico. Recientemente se han propuesto algunas iniciativas editoriales, como el registro de los ensayos clinicos, la declaración de los conflictos de interés y los nuevos criterios para autoría (que destacan la responsabilidad de los autores sobre el estudio). El año pasado se presentó una nueva iniciativa editorial para resaltar la importancia de compartir los datos generados en los estudios clinicos. En este artículo se discute esta nueva iniciativa editorial, con la idea de difundir su conocimiento entre los lectores, investigadores, autores y editores de la red de editores de revistas cardiovasculares nacionales de la Sociedad Europea de Cardiología.
Assuntos
Publicações Periódicas como Assunto , Editoração , Cardiologia , Disseminação de Informação , Políticas Editoriais , Cooperação InternacionalRESUMO
В течение десятилетия, в рамках федеральной программы борьбы с сердечно-сосудистыми заболеваниями в России, услуги по лечению острого коронарного синдрома (ОКС) в Санкт-Петербурге были полностью трансформированы. Это было обусловлено относительно высокой смертностью от сердечно-сосудистых заболеваний, высокой госпитальной летальностью от ОКС, малодоступностью современных технологий, недостаточным соблюдением руководств, неадекватным качеством медицинского обслуживания и недостаточным финансированием. Комплексная регионализация услуг способствовала обеспечению высокой доступности медицинского обслуживания, эффективности маршрутизации скорой медицинской помощи, высокой степени применения модели оказания медицинских услуг, расширению доступа к технологиям реперфузионной терапии, улучшению соблюдения руководств, а также улучшению качества оказываемой медицинской помощи. Это способствовало снижению госпитальной летальности от ОКС и смертности от сердечно-сосудистых заболеваний.
Assuntos
Síndrome Coronariana Aguda , Isquemia Miocárdica , Doenças Cardiovasculares , Regionalização da Saúde , Reperfusão Miocárdica , Ambulâncias , Federação RussaRESUMO
Within the framework of the Federal Cardiovascular Programme, services for acute coronary syndrome (ACS) were transformed over a decade in St Petersburg. It was motivated by a relatively high cardiovascular mortality, high in-hospital mortality from ACS, low availability of modern technologies, low adherence to guidelines, insufficient quality of care and insufficient funding. A comprehensive regionalization of services led to high availability of care, efficacy in ambulance routing, a high degree of implementation of the model of care, increased access to reperfusion technologies, improved adherence to guidelines and improved quality of care. It was associated with a decrease of in-hospital mortality from ACS and a decrease in cardiovascular mortality.