Clinical outcomes and progression rate of tricuspid regurgitation in patients with rheumatic mitral valve disease.

OBJECTIVE: A substantial proportion of patients with rheumatic heart disease (RHD) have tricuspid regurgitation (TR). This study aimed to identify the impact of functional TR on clinical outcomes and predictors of progression in a large population of patients with RHD. METHODS: A total of 645 patients with RHD were enrolled, mean age of 47±12 years, 85% female. Functional TR was graded as absent, mild, moderate or severe. TR progression was defined either as worsening of TR degree from baseline to the last follow-up echocardiogram or severe TR at baseline that required surgery or died. Incidence of TR progression was estimated accounting for competing risks. RESULTS: Functional TR was absent in 3.4%, mild in 83.7%, moderate in 8.5% and severe in 4.3%. Moderate and severe functional TR was associated with adverse outcome (HR 1.91 (95% CI 1.15 to 3.2) for moderate, and 2.30 (95% CI 1.28 to 4.13) for severe TR, after adjustment for other prognostic variables. Event-free survival rate at 3-year follow-up was 91%, 72% and 62% in patients with no or mild, moderate and severe TR, respectively. During mean follow-up of 4.1 years, TR progression occurred in 83 patients (13%) with an overall incidence of 3.7 events (95% CI 2.9 to 4.5) per 100 patient-years. In the Cox model, age (HR 1.71, 95% CI 1.34 to 2.17), New York Heart Association functional class III/IV (HR 2.57, 95% CI 1.54 to 4.30), right atrial area (HR 1.52, 95% CI 1.10 to 2.10) and right ventricular (RV) dysfunction (HR 2.02, 95% CI 1.07 to 3.84) were predictors of TR progression. By considering competing risk, the effect of RV dysfunction on TR progression risk was attenuated. CONCLUSIONS: In patients with RHD, functional TR was frequent and associated with adverse outcomes. TR may progress over time, mainly related to right-sided cardiac chambers remodelling.

Targeting C5aR1 signaling reduced neutrophil extracellular traps and ameliorates COVID-19 pathology

Patients with severe COVID-19 develop acute respiratory distress syndrome (ARDS) that may progress to cytokine storm syndrome, organ dysfunction, and death. Considering that complement component 5a (C5a), through its cellular receptor C5aR1, has potent proinflammatory actions, and plays immunopathological roles in inflammatory diseases, we investigated whether C5a/C5aR1 pathway could be involved in COVID-19 pathophysiology. C5a/C5aR1 signaling increased locally in the lung, especially in neutrophils of critically ill COVID-19 patients compared to patients with influenza infection, as well as in the lung tissue of K18-hACE2 Tg mice (Tg mice) infected with SARS-CoV-2. Genetic and pharmacological inhibition of C5aR1 signaling ameliorated lung immunopathology in Tg-infected mice. Mechanistically, we found that C5aR1 signaling drives neutrophil extracellular trap (NET)s-dependent immunopathology. These data confirm the immunopathological role of C5a/C5aR1 signaling in COVID-19 and indicate that antagonist of C5aR1 could be useful for COVID-19 treatment.

CASP4/11 contributes to pulmonary inflammation and disease exacerbation in COVID-19

Infection with SARS-CoV-2 induces COVID-19, an inflammatory disease that is usually self-limited, but depending on patient conditions may culminate with critical illness and patient death. The virus triggers activation of intracellular sensors, such as the NLRP3 inflammasome, which promotes inflammation and aggravates the disease. Thus, identification of host components associated with NLRP3 inflammasome is key for understanding the physiopathology of the disease. Here, we reported that SARS-CoV-2 induces upregulation and activation of human Caspase-4/CASP4 (mouse Caspase-11/CASP11) and this process contributes to inflammasome activation in response to SARS-CoV-2. CASP4 was expressed in lung autopsy of lethal cases of COVID-19 and CASP4 expression correlates with expression of inflammasome components and inflammatory mediators such as CASP1, IL1B, IL18 and IL6. In vivo infections performed in transgenic hACE2 humanized mouse, deficient or sufficient for Casp11, indicate that hACE2 Casp11-/- mice were protected from disease development, with reduced body weight loss, reduced temperature variation, increased pulmonary parenchymal area, reduced clinical score of the disease and reduced mortality. Collectively, our data establishes that CASP4/11 contributes to disease pathology and contributes for future immunomodulatory therapeutic interventions to COVID-19.

Vandetanib Reduces Inflammatory Cytokines and Ameliorates COVID-19 in Infected Mice

The portfolio of SARS-CoV-2 small molecule drugs is currently limited to a handful that are either approved (remdesivir), emergency approved (dexamethasone, baricitinib) or in advanced clinical trials. We have tested 45 FDA-approved kinase inhibitors in vitro against murine hepatitis virus (MHV) as a model of SARS-CoV-2 replication and identified 12 showing inhibition in the delayed brain tumor (DBT) cell line. Vandetanib, which targets the vascular endothelial growth factor receptor (VEGFR), the epidermal growth factor receptor (EGFR), and the RET-tyrosine kinase showed the most promising results on inhibition versus toxic effect on SARS-CoV-2-infected Caco-2 and A549-hACE2 cells (IC50 0.79 M) while also showing a reduction of > 3 log TCID50/mL for HCoV-229E. The in vivo efficacy of vandetanib was assessed in a mouse model of SARS-CoV-2 infection and statistically significantly reduced the levels of IL-6, IL-10, TNF-, and mitigated inflammatory cell infiltrates in the lungs of infected animals but did not reduce viral load. Vandetanib rescued the decreased IFN-1{beta} caused by SARS-CoV-2 infection in mice to levels similar to that in uninfected animals. Our results indicate that the FDA-approved vandetanib is a potential therapeutic candidate for COVID-19 positioned for follow up in clinical trials either alone or in combination with other drugs to address the cytokine storm associated with this viral infection.

COVID-19 Bimodal Clinical and Pathological Phenotypes

BackgroundPatients with coronavirus disease-2019 (COVID-19) present varying clinical complications. Different viral load and host response related to genetic and immune background are probably the reasons for these differences. We aimed to sought clinical and pathological correlation that justifies the different clinical outcomes among COVID-19 autopsies cases. MethodsMinimally invasive autopsy was performed on forty-seven confirmed COVID-19 patients from May-July, 2020. Electronic medical record of all patients was collected and a comprehensive histopathological evaluation was performed. Immunohistochemistry, immunofluorescence, special stain, western blotting and post-mortem real-time reverse transcriptase polymerase chain reaction on fresh lung tissue were performed. ResultsWe show that 5/47 (10,6%) patients present a progressive decline in oxygenation index for acute respiratory distress syndrome (PaO2/FiO2 ratio), low compliance levels, interstitial fibrosis, high -SMA+ cells/protein expression, high collagens I/III deposition and NETs(P<0.05), named as fibrotic phenotype (N=5). Conversely, 10/47 (21,2%) patients demonstrated progressive increase in PaO2/FiO2 ratio, high pulmonary compliance levels, preserved elastic framework, increase thrombus formation and high platelets and D-dimer levels at admission (P<0.05), named as thrombotic phenotype. While 32/47 (68,1%) had a mixed phenotypes between both ones. ConclusionsWe believe that categorization of patients based on these two phenotypes can be used to develop prognostic tools and potential therapies since the PaO2/FiO2 ratio variation and D-dimer levels correlate with the underlying fibrotic or thrombotic pathologic process, respectively; which may indicate possible clinical outcome of the patient.

Pyronaridine Protects Against SARS-CoV-2 in Mouse

There are currently relatively few small-molecule antiviral drugs that are either approved or emergency approved for use against SARS-CoV-2. One of these is remdesivir, which was originally repurposed from its use against Ebola and functions by causing early RNA chain termination. We used this as justification to evaluate three molecules we had previously identified computationally with antiviral activity against Ebola and Marburg. Out of these we previously identified pyronaridine, which inhibited the SARS-CoV-2 replication in A549-ACE2 cells. Herein, the in vivo efficacy of pyronaridine has now been assessed in a K18-hACE transgenic mouse model of COVID-19. Pyronaridine treatment demonstrated a statistically significant reduction of viral load in the lungs of SARS CoV-2 infected mice. Furthermore, the pyronaridine treated group reduced lung pathology, which was also associated with significant reduction in the levels of pro-inflammatory cytokines/chemokine and cell infiltration. Notably, pyronaridine inhibited the viral PLpro activity in vitro (IC50 of 1.8 {micro}M) without any effect on Mpro, indicating a possible molecular mechanism involved in its ability to inhibit SARS-CoV-2 replication. Interestingly, pyronaridine also selectively inhibits the host kinase CAMK1 (IC50 of 2.4 {micro}M). We have also generated several pyronaridine analogs to assist in understanding the structure activity relationship for PLpro inhibition. Our results indicate that pyronaridine is a potential therapeutic candidate for COVID-19. One sentence summaryThere is currently intense interest in discovering small molecules with direct antiviral activity against the severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2). Pyronaridine, an antiviral drug with in vitro activity against Ebola, Marburg and SARS-CoV-2 has now statistically significantly reduced the viral load in mice along with IL-6, TNF-, and IFN-{beta} ultimately demonstrating a protective effect against lung damage by infection to provide a new potential treatment for testing clinically.

Evaluation of craft beers through the direct determination of amino acids by capillary electrophoresis and principal component analysis.

The composition of beer wort in terms of amino acid (AA) content affects the final product quality, once it is related to the vitality of yeast during the initial exponential growth phase and throughout fermentation. The objective of this work was the use of a capillary zone electrophoresis method with UV-vis detection in association with Principal Component (Data) Analysis for craft beer classification. Cysteine, histidine, phenylalanine, lysine, tryptophan and arginine were the monitored AAs in wort and finished beer, which were extracted through cation exchange resin. Good differentiation among samples according to their production was obtained, showing a profile of AAs (

SARS-CoV-2 triggered neutrophil extracellular traps (NETs) mediate COVID-19 pathology

Severe COVID-19 patients develop acute respiratory distress syndrome that may progress to respiratory failure. These patients also develop cytokine storm syndrome, and organ dysfunctions, which is a clinical picture that resembles sepsis. Considering that neutrophil extracellular traps (NETs) have been described as an important factors of tissue damage in sepsis, we investigated whether NETs would be produced in COVID-19 patients and participate in the lung tissue damage. A cohort of 32 hospitalized patients with a confirmed diagnosis of COVID-19 and respective healthy controls were enrolled. NETs concentration was assessed by MPO-DNA PicoGreen assay or by confocal immunofluorescence. The cytotoxic effect of SARS-CoV-2-induced NETs was analyzed in human epithelial lung cells (A549 cells). The concentration of NETs was augmented in plasma and tracheal aspirate from COVID-19 patients and their neutrophils spontaneously released higher levels of NETs. NETs were also found in the lung tissue specimens from autopsies of COVID-19 patients. Notably, viable SARS-CoV-2 can directly induce in vitro release of NETs by healthy neutrophils in a PAD-4-dependent manner. Finally, NETs released by SARS-CoV-2-activated neutrophils promote lung epithelial cell death in vitro. These results unravel a possible detrimental role of NETs in the pathophysiology of COVID-19. Therefore, the inhibition of NETs represent a potential therapeutic target for COVID-19.

Prevalence of nutritional deficiencies and morbidity by infectious diseases in children 0-5 years of age in Iñapari in the Peruvian Amazon

Introduction: Iñapari is a town located in Peru, on the border of Brazil, between the Amazonian states of Acre and Amazonas. The local Peruvian children under five years of age present moderate anemia while the percentage of chronic child malnutrition is a major public health problem in the country as a whole. Goals: The purpose of this study was to identify the prevalence of major childhood morbidities caused by anemia, malnutrition, intestinal parasites, toxocariasis, and hepatitis A, and identify connections with the socioeconomic and environmental conditions found in Iñapari. Methods: Interviews with questionnaires; anthropometric measurements, collection of feces and venous blood samples. Results: A 20% prevalence of anemia and 8.5% prevalence of chronic malnutrition (height for age deficiency) was found. A pathogenic intestinal parasite was noted in 24.5% of the samples, where Giardia intestinalis (14.7%) was the most frequent. The seroprevalence of toxocariasis was 33.8% and hepatitis A was 21.2%. Conclusion: There is a connection between the results found and the poor living and sanitary conditions of the population. The low income noted is also linked to the malnutrition and anemia detected

Conhecimento de acadêmicos de Odontologia sobre os aspectos clínicos, éticos e legais da prescrição medicamentosa / Dentistry students´knowledge about the clinical, ethical and legal drug prescription

Objetivo: avaliar o conhecimento de acadêmicos de Odontologia sobre a prescrição medicamentosa, implicações legais, bem como dados sobre o protocolo utilizado na confecção de receitas farmacológicas. Metodologia: participaram 103 alunos de graduação, cursando o terceiro e quarto anos do curso de Odontologia. Os participantes da pesquisa responderam a um questionário com 15 questões objetivas. Resultados: os dicionários de especialidades farmacêuticas (DEF) são a primeira opção da maioria dos alunos para obtenção dos conhecimentos sobre farmacologia (73,78%). Em relação à conduta de prescrição, 91,26% escrevem e/ou imprimem cópia com assinatura do paciente na segunda via ao receitar algum tipo de medicamento. Cerca de 46,60% têm conhecimento da lei no 5.081/1966; entretanto, apenas 35,92% responderam que esta habilita o cirurgião-dentista a prescrever medicamentos de uso odontológico. Conclusão: os alunos de graduação apresentam deficiências nos conhecimentos sobre os aspectos clínicos, éticos e legais que envolvem a prescrição medicamentosa.

Aplicação sobre dados da política nacional de cirurgias eletivas do Ministério da Saúde em bases relacionais no contexto das ontologias e web semântica / Application data on the national policy of elective surgeries in the Ministry of Health in relational databases in the context of ontologies and semantic web

Empresas e instituições que produzem sistemas de informações precisam estar sempre em busca de metodologias e estratégias tecnológicas que aumentem seu poder de organizar e disponibilizar seus dados. Precisam estabelecer mecanismos de interoperabilidade dos seus sistemas próprios e com outros externos, principalmente nesses tempos em que a Internet se impõe como tecnologia predominante. Isto implica em transmitir e receber conhecimentos de domínios de conhecimentos de várias fontes. A Web semântica foi concebida com esse intuito. A construção de ontologias através de uma linguagem própria, a Ontology Web Language, disponibiliza formatos estruturados e organizados que podem ser associados às páginas da Internet. Essas tecnologias estão permitindo a construção de softwares para buscase interpretações automáticas de conteúdos. Neste trabalho é proposto estudo dessas tecnologias seguindo o percurso do conhecimento nas suas várias fases e apoiadas pela larga discussão na comunidade científica.Através de um estudo de caso, percorre os caminhos necessários para construção de uma aplicação sobre os dados da Política Nacional de Cirurgias Eletivas do Ministério da Saúde em bases relacionais, utilizando o contexto da Web semântica. Almeja, dessa forma,introduzir o tema Ontologias e Web semântica ao corpo dirigente e técnico do Departamento de Informática do Sistema Único de Saúde do Ministério da Saúde na perspectiva de sua adoção em futuros trabalhos da instituição, produtora de sistemas e disseminação deinformações de interesse público.

Insuficiência istmo-cervical: antecedentes obstétricos e resultados do tratamento de 31 pacientes pela circlagem cervical / Isthmus-cervical incompetence: obstretical antecedents and treatment results of 31 patients by cervical cerclage

Um grupo de 31 pacientes portadoras de IIC foi estudado, considerando-se a idade, paridade e antecedentes obstétricos. Concluiu-se que a idade média das pacientes foi de 27,6 anos, 71% eram multíparas, com maior incidência de abortamentos (28%) e de prematuros (53,3%), quando comparado com a populaçäo em geral. As perdas conceptuais foram elevadas, alcançando taxa de 69,3%. Após o tratamento pela circlagem, considerou-se a época de realizaçäo das circlagens, a época dos partos, a evoluçäo dos recém-nascidos pós-circlagens e o índice de salvamento fetal. Concluiu-se que a circlagem após 18 semanas pode permitir boa evoluçäo, devendo ser praticada. Após as circlagens, um número significante de pacientes alcançou o termo (60,5%, com aumento, também significativo, da sobrevida fetal (81,6%). A freqüência de recém-nascidos com peso superior a 2.500 g foi de 75,7%. O índice de salvamento fetal foi de 2,66 e o parto cesárea ocorreu em 48,5% dos casos