Clinical Outcomes of Anticoagulated Patients With Atrial Fibrillation After Falls or Head Injury: Insights From RE-LY.

BACKGROUND: Falls are always a concern regarding the balance of risk/benefit in patients with atrial fibrillation treated with anticoagulants. In this analysis, we aimed to evaluate the outcomes of patients that had a fall/head injury reported in the RE-LY clinical trial (Randomized Evaluation of Long-Term Anticoagulation Therapy) and to explore the safety of dabigatran (a nonvitamin K antagonist oral anticoagulant). METHODS: We performed a post hoc retrospective analysis of intracranial hemorrhage and major bleeding outcomes in the RE-LY trial with 18 113 individuals with atrial fibrillation, according to the status occurrence of falls (or head injury) reported as adverse events. Multivariate Cox regression models were used to provide adjusted hazard ratio (HR) and 95% CI. RESULTS: In the study, 974 falls or head injury events were reported among 716 patients (4%). These patients were older and had more frequently comorbidities such as diabetes, previous stroke, or coronary artery disease. Patients with fall had a higher risk of major bleeding (HR, 2.41 [95% CI, 1.90-3.05]), intracranial hemorrhage (HR, 1.69 [95% CI, 1.35-2.13]), and mortality (HR, 3.91 [95% CI, 2.51-6.10]) compared to those who did not have reported falls or head injury. Among patients who had falls, those allocated to dabigatran showed a lower intracranial hemorrhage risk (HR, 0.42 [95% CI, 0.18-0.98]) compared with warfarin. CONCLUSIONS: In this population, the risk of falls is important and confers a worse prognosis, increasing intracranial hemorrhage, and major bleeding. Patients who fell and were under dabigatran was associated with lower intracranial hemorrhage risk than those anticoagulated with warfarin, but the analysis was merely exploratory.

Myocardial infarction with non-obstructive coronary arteries: Etiology, diagnosis, treatment and prognosis.

Myocardial infarction with non-obstructive coronary arteries (MINOCA) is responsible for 10% of myocardial infarctions. Previously, patients were thought to have good prognosis, but evidence-based management and treatment strategies were scarce. Today, researchers and physicians recognize MINOCA as a condition with non-trivial mortality and morbidity. Therapeutic strategies are highly dependent on the underlying disease mechanism in each patient. However, to reach a diagnosis of MINOCA, a multimodal approach is required and, even with an optimal work-up, the cause remains unknown in 8-25% of patients. Research has been growing and position papers from the European Society of Cardiology (ESC) and the American Heart Association/American College of Cardiology have been published, and MINOCA has been included in the more recent ESC guidelines on myocardial infarction. Nonetheless, some clinicians still assume that the absence of coronary obstruction excludes the possibility of acute myocardial infarction. Therefore, in the present paper, we aim to compile and present the available data on the etiology, diagnosis, treatment, and prognosis of MINOCA.

MICA/B antibody induces macrophage-mediated immunity against acute myeloid leukemia.

Acute myeloid leukemia (AML) is a clonal hematopoietic stem and progenitor cell malignancy characterized by poor clinical outcomes. Major histocompatibility complex class I polypeptide-related sequence A and B (MICA/B) are stress proteins expressed by cancer cells, and antibody-mediated inhibition of MICA/B shedding represents a novel approach to stimulate immunity against cancers. We found that the MICA/B antibody 7C6 potently inhibits the outgrowth of AML in 2 models in immunocompetent mice. Macrophages were essential for therapeutic efficacy, and 7C6 triggered antibody-dependent phagocytosis of AML cells. Furthermore, we found that romidepsin, a selective histone deacetylase inhibitor, increased MICB messenger RNA in AML cells and enabled subsequent stabilization of the translated protein by 7C6. This drug combination substantially increased surface MICA/B expression in a human AML line, pluripotent stem cell-derived AML blasts and leukemia stem cells, as well as primary cells from 3 untreated patients with AML. Human macrophages phagocytosed AML cells following treatment with 7C6 and romidepsin, and the combination therapy lowered leukemia burden in a humanized model of AML. Therefore, inhibition of MICA/B shedding promotes macrophage-driven immunity against AML via Fc receptor signaling and synergizes with an epigenetic regulator. These results provide the rationale for the clinical testing of this innovative immunotherapeutic approach for the treatment of AML.

Digital home-based multidisciplinary cardiac rehabilitation: How to counteract physical inactivity during the COVID-19 pandemic.

Introduction and Objectives: Center-based cardiac rehabilitation (CR) programs have been forced to close due to COVID-19. Alternative delivery models to maintain access to CR programs and to avoid physical inactivity should be considered. The aim of this study was to assess physical activity (PA) levels after completing a home-based digital CR program. Methods: A total of 116 cardiovascular disease (CVD) patients (62.6±8.9 years, 95 male) who had been attending a face-to-face CR program were recruited and assessed (baseline and at three months) on the following parameters: PA, sedentary behavior, adherence, cardiovascular and non-cardiovascular symptoms, feelings toward the pandemic, dietary habits, risk factor control, safety and adverse events. The intervention consisted of a multidisciplinary digital CR program, including regular patient assessment, and exercise, educational and psychological group sessions. Results: Ninety-eight CVD patients successfully completed all the online assessments (15.5% drop-out rate). A favorable main effect of time was an increase in moderate to vigorous PA and a decrease in sedentary time at three months. Almost half of the participants completed at least one online exercise training session per week and attended at least one of the online educational sessions. No major adverse events were reported and only one minor event occurred. Conclusion: During the pandemic, levels of moderate to vigorous PA improved after three months of home-based CR in CVD patients with previous experience in a face-to-face CR model. Diversified CR programs with a greater variety of content tailored to individual preferences are needed to meet the motivational and clinical requirements of CVD patients.

Introdução e objetivos: Os programas convencionais de reabilitação cardíaca (RC) foram forçados a encerrar devido à Covid-19. Modelos alternativos para que os doentes tenham acesso a um programa de RC evitando a inatividade física devem ser considerados. O objetivo deste estudo foi avaliar os níveis de atividade física (AF) de um programa digital de RC em casa. Métodos: Foram recrutados e avaliados (inicialmente e aos três meses) 116 doentes cardiovasculares (CV) (62,6±8,9 anos, 95 homens) que frequentavam um programa presencial de RC, nos seguintes parâmetros: AF, comportamento sedentário, adesão, sintomas CV e não CV, sentimentos face à pandemia, hábitos alimentares, fatores de risco, segurança e eventos adversos. A intervenção consistiu num programa digital multidisciplinar de RC, inclusive acompanhamento regular, sessões de exercício, de ensino e de psicologia em grupo. Resultados: Completaram com sucesso todas as avaliações online (15,5% drop-out) 98 pessoas com doença CV. Houve um efeito favorável no aumento da AF moderada a vigorosa e diminuição do tempo sedentário aos três meses. Quase metade da amostra fez, pelo menos, mais de uma sessão de exercício físico online por semana e assistiu a pelo menos uma das sessões educacionais online. Não se verificaram eventos major e registou-se apenas um minor. Conclusão: Em tempo de pandemia, os níveis de AF moderada a vigorosa melhoraram após três meses em doentes CV que frequentavam previamente um modelo presencial de RC. São necessários mais programas de RC com maior variedade de conteúdos adaptados à preferência individual para dar resposta às necessidades motivacionais e clínicas dos doentes CV.

Prognostic Accuracy of the Modified CHA2DS2-VASc Score in COVID-19 Patients Admitted to the Emergency Department Due to Clinical Worsening.

INTRODUCTION: Risk factors comprising the CHA2DS2VASc score are recognized as risk factors for venous thromboembolism and mortality in COVID-19 patients. A modified CHA2DS2VASc score (M-CHA2D2VASc), developed by changing gender criteria from female to male, has been proposed to predict in-hospital mortality in COVID-19 patients. The aim of this study was to evaluate the prognostic accuracy of M-CHA2D2VASc for adverse clinical outcomes and short-term mortality in COVID-19 patients admitted to the Emergency Department. MATERIAL AND METHODS: Retrospective study of patients admitted to the ED who underwent computed tomography pulmonary angiography due to suspected pulmonary embolism or clinical worsening. Patients were stratified into three M-CHA2DS2-VASc risk-categories: low (0 - 1 points), intermediate (2 - 3 points) and high-risk (≥ 4 points). RESULTS: We included 300 patients (median age 71 years, 59% male). The overall mortality was 27%. The M-CHA2DS2-VASc score was higher in non-survivors compared to survivors [4 (IQR:3 - 5) vs 2 (IQR: 1 - 4), respectively, p < 0.001). The M-CHA2DS2-VASc score was identified as an independent predictor of mortality in a multivariable logistic regression model (OR 1.406, p = 0.007). The Kaplan-Meier survival curves showed that the M-CHA2DS2-VASc score was associated with short-term mortality (log-rank test < 0.001), regardless of hospitalization (log-rank test p < 0.001 and p = 0.007, respectively). The survival proportion was 92%, 80% and 63% in the lower, intermediate, and higher risk-groups. As for the risk-categories, no difference was found in pulmonary embolism, Intensive Care Unit admission, and invasive mechanical ventilation. DISCUSSION: This is the first study to validate M-CHA2DS2-VASc score as a predictor of short-term mortality in patients admitted to the Emergency Department. CONCLUSION: The M-CHA2DS2-VASC score might be useful for prompt risk-stratification in COVID-19 patients during admission to the Emergency Department.

Introdução: O score CHA2DS2VASc engloba variáveis reconhecidas como fatores de risco para tromboembolismo venoso e mortalidade nos doentes com COVID-19. O score CHA2DS2VASc modificado (M-CHA2DS2-VASc), criado pela alteração do critério de género de feminino para masculino, foi proposto como preditor da mortalidade intra-hospitalar nestes doentes. O objetivo deste trabalho foi avaliar o valor prognóstico do M-CHA2DS2-VASc como preditor de eventos adversos e mortalidade a curto-prazo nos doentes com COVID-19 admitidos no Serviço de Urgência. Material e Métodos: Análise retrospetiva de doentes admitidos no Serviço de Urgência que realizaram tomografia computorizada pulmonar com administração de contraste por agravamento clínico e/ou suspeita de embolia pulmonar. Definiram-se três categorias de risco M-CHA2DS2-VASc: baixo, intermédio e alto (0 - 1; 2 - 3 e ≥ 4 pontos, respectivamente). Resultados: Incluíram-se 300 doentes (idade mediana: 71 anos, 59% homens). A mortalidade global foi 27%. O M-CHA2DS2-VASc foi maior em não sobreviventes [4 (IQR: 3 - 5) vs 2 (IQR: 1 - 4), p < 0,001) e constituiu um preditor independente de mortalidade numa análise multiparamétrica (OR: 1.406, p = 0,007). As curvas de sobrevivência demonstraram a associação do M-CHA2DS2-VASc com a mortalidade a curto-prazo (log-rank test < 0,001), independentemente dos doentes serem hospitalizados ou não (log-rank test p < 0,001 e p = 0,007, respetivamente). A taxa de sobrevida foi de 92%, 80% e 63% nos grupos de baixo, intermédio e alto risco. De acordo com as categorias de risco, não foram encontradas diferenças na incidência de embolia pulmonar, admissão em Cuidados Intensivos e ventilação mecânica invasiva. Discussão: Este é o primeiro estudo a validar o M-CHA2DS2-VASc como preditor de mortalidade a curto prazo na admissão no Serviço de Urgência. Conclusão: O M-CHA2DS2-VASc pode ser útil para estratificação de risco nos doentes com COVID-19 admitidos no Serviço de Urgência.

Inhibition of MICA and MICB Shedding Elicits NK-Cell-Mediated Immunity against Tumors Resistant to Cytotoxic T Cells.

Resistance to cytotoxic T cells is frequently mediated by loss of MHC class I expression or IFNγ signaling in tumor cells, such as mutations of B2M or JAK1 genes. Natural killer (NK) cells could potentially target such resistant tumors, but suitable NK-cell-based strategies remain to be developed. We hypothesized that such tumors could be targeted by NK cells if sufficient activating signals were provided. Human tumors frequently express the MICA and MICB ligands of the activating NKG2D receptor, but proteolytic shedding of MICA/B represents an important immune evasion mechanism in many human cancers. We showed that B2M- and JAK1-deficient metastases were targeted by NK cells following treatment with a mAb that blocks MICA/B shedding. We also demonstrated that the FDA-approved HDAC inhibitor panobinostat and a MICA/B antibody acted synergistically to enhance MICA/B surface expression on tumor cells. The HDAC inhibitor enhanced MICA/B gene expression, whereas the MICA/B antibody stabilized the synthesized protein on the cell surface. The combination of panobinostat and the MICA/B antibody reduced the number of pulmonary metastases formed by a human melanoma cell line in NOD/SCID gamma mice reconstituted with human NK cells. NK-cell-mediated immunity induced by a mAb specific for MICA/B, therefore, provides an opportunity to target tumors with mutations that render them resistant to cytotoxic T cells.