Early experience with targeted therapy and dendritic cell vaccine in metastatic renal cell carcinoma after nephrectomy

PURPOSE: Metastatic renal cell carcinoma (RCC) is one of the most treatment-resistant malignancies and nephrectomy, isolated or combined with systemic chemotherapy typically has limited or no effectiveness. We report our initial results in patients treated with the association of molecular targeted therapy, nephrectomy, and hybrid dendritic-tumor cell (DC) vaccine. MATERIALS AND METHODS: Two male patients diagnosed with metastatic RCC were selected for the study. They were treated with the triple strategy, in which sunitinib (50 mg per day) was given for 4 weeks, followed by radical nephrectomy after two weeks. DC vaccine was initiated immediately after surgery and repeated monthly. Sunitinib was restarted daily after 2 to 3 weeks of surgery with a 7-day interval every 4 weeks. RESULTS: Both patients had complete adherence to the proposed treatment with DC vaccine therapy combined with sunitinib. Follow-up in these patients at 9 and 10 months demonstrated a stable disease in both, as shown by imaging and clinical findings, with no further treatment required. CONCLUSION: The immune response obtained with DC vaccine combined with the antiangiogenic effect of sunitinib and the potential benefits of cytoreductive nephrectomy in advanced disease could represent a new option in the treatment of metastatic RCC. Further prospective trials are needed not only to elucidate the ideal dosing and schedule, but also to better define the proof-of-concept proposed in this report and its role in clinical practice

Detecção de leucócitos em imagens de vídeo de microscopia intravital usando a técnica de congruência de fase

A quantificação do número de leucócitos rolantes e aderidos presentes na microcirculação de pequenos animais é uma tarefa importante para elucidar os mecanismos de inflamações e avaliar os efeitos terapêuticos de novas drogas. Em geral, a contagem de leucócitos é realizada de maneira visual por um observador (técnico laboratorial ou especialista) usando uma sequência de imagens de microscopia intravital (MI). Entretanto, tal tarefa é demorada e suscetível a erros, devido a fadiga visual do observador e a variabilidades inter e intra observadores. Neste trabalho uma nova técnica computacional é proposta para a detecção automática de leucócitos em vídeos de MI. A técnica usa uma medida de blobness, calculada a partir da análise dos autovalores de matrizes locais de momentos de segunda-ordem da medida de congruência de fase, para realçar os leucócitos nas imagens. A detecção dos leucócitos é alcançada pela busca de máximos locais no mapa de medidas de blobness. Usando um conjunto de quadros com os centroides dos leucócitos manualmente marcados, os resultados da técnica proposta foram avaliados usando os valores das métricas medida-F1 e áreas sob as curvas precisão-revocação (AUCPRs) calculadas para cada quadro do vídeo. Uma comparação com a técnica de casamento de padrões também foi realizada. Os resultados obtidos para a técnica proposta (medida-F1=0,791, AUCPR=0,776) foram superiores em comparação com a técnica de casamento de padrões (medida-F1=0,746, AUCPR=0,670)

Generating real-world evidence on the quality use, benefits and safety of medicines in australia: History, challenges and a roadmap for the future

Australia spends more than $20 billion annually on medicines, delivering significant health benefits for the population. However, inappropriate prescribing and medicine use also result in harm to individuals and populations, and waste of precious health resources. Medication data linked with other routine collections enable evidence generation in pharmacoepidemiology; the science of quantifying the use, effectiveness and safety of medicines in real-world clinical practice. This review details the history of medicines policy and data access in Australia, the strengths of existing data sources, and the infrastructure and governance enabling and impeding evidence generation in the field. Currently, substantial gaps persist with respect to cohesive, contemporary linked data sources supporting quality use of medicines, effectiveness and safety research; exemplified by Aus-tralia’s limited capacity to contribute to the global effort in real-world studies of vaccine and dis-ease-modifying treatments for COVID-19. We propose a roadmap to bolster the discipline, and population health more broadly, underpinned by a distinct capability governing and streamlining access to linked data assets for accredited researchers. Robust real-world evidence generation requires current data roadblocks to be remedied as a matter of urgency to deliver efficient and equitable health care and improve the health and well-being of all Australians

Integrative multi-kinase approach for the identification of potent antiplasmodial hits

Malaria is a tropical infectious disease that affects over 219 million people worldwide. Due to the constant emergence of parasitic resistance to the current antimalarial drugs, the discovery of new antimalarial drugs is a global health priority. Multi-target drug discovery is a promising and innovative strategy for drug discovery and it is currently regarded as one of the best strategies to face drug resistance. Aiming to identify new multi-target antimalarial drug candidates, we developed an integrative computational approach to select multi-kinase inhibitors for Plasmodium falciparum calcium-dependent protein kinases 1 and 4 (CDPK1 and CDPK4) and protein kinase 6 (PK6). For this purpose, we developed and validated shape-based and machine learning models to prioritize compounds for experimental evaluation. Then, we applied the best models for virtual screening of a large commercial database of drug-like molecules. Ten computational hits were experimentally evaluated against asexual blood stages of both sensitive and multi-drug resistant P. falciparum strains. Among them, LabMol-171, LabMol-172, and LabMol-181 showed potent antiplasmodial activity at nanomolar concentrations (EC50 15 folds. In addition, LabMol-171 and LabMol-181 showed good in vitro inhibition of P. berghei ookinete formation and therefore represent promising transmission-blocking scaffolds. Finally, docking studies with protein kinases CDPK1, CDPK4, and PK6 showed structural insights for further hit-to-lead optimization studies.7CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQCOORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPESFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP405996/2016-0; 400760/2014-2Sem informação2018/05926-2; 2017/02353-9; 2012/16525-2; 2017/18611-7; 2018/07007-4; 2013/13119-6; 2018/24878-9; 2015/20774-

MobiSaúde: Sistema de Informação para Visitas Domiciliares na Área de Saúde / MobiSaúde: Information System for Home Visits in the Health Area

Com a popularização de dispositivos móveis e o aumento das capacidades dos mesmos, houve a integração entre sistemas de informação da área de saúde e estes dispositivos, chamada de mHealth. Neste trabalho discutimos um SIS voltado para visitas domiciliares medicas, com foco na coleta de dados e nas dificuldades envolvendo a locomoção do agente realizador

A New Mouse Model for Marfan Syndrome Presents Phenotypic Variability Associated with the Genetic Background and Overall Levels of Fbn1 Expression

Marfan syndrome is an autosomal dominant disease of connective tissue caused by mutations in the fibrillin-1 encoding gene FBN1. Patients present cardiovascular, ocular and skeletal manifestations, and although being fully penetrant, MFS is characterized by a wide clinical variability both within and between families. Here we describe a new mouse model of MFS that recapitulates the clinical heterogeneity of the syndrome in humans. Heterozygotes for the mutant Fbn1 allele mgΔloxPneo, carrying the same internal deletion of exons 19–24 as the mgΔ mouse model, present defective microfibrillar deposition, emphysema, deterioration of aortic wall and kyphosis. However, the onset of a clinical phenotypes is earlier in the 129/Sv than in C57BL/6 background, indicating the existence of genetic modifiers of MFS between these two mouse strains. In addition, we characterized a wide clinical variability within the 129/Sv congenic heterozygotes, suggesting involvement of epigenetic factors in disease severity. Finally, we show a strong negative correlation between overall levels of Fbn1 expression and the severity of the phenotypes, corroborating the suggested protective role of normal fibrillin-1 in MFS pathogenesis, and supporting the development of therapies based on increasing Fbn1 expression

Bipolar versus unipolar energy in the surgical ablation of atrial fibrillation in patients with mitral valve surgery

Objective: To evaluate the presence of sinus rhythm or atrial fibrillation (AF) in patients who had mitral valve surgery with concomitant surgical ablation of AF, by unipolar or bipolar radiofrequency. Methods: Adults patients who had mitral valve replacement or mitral valvuloplasty with concomitant surgical ablation of AF, either by unipolar or bipolar radiofrequency, were consecutively included between the 2008 and 2012. Surgery was done by conventional median sternotomy. Results: A total of 99 patients were included; 20 (20.2%) had surgical ablation by unipolar energy and 79 (79.8%) by bipolar energy. There were 76 (76.8%) women, and mean age± SD was 51 ±11 years.  The median duration of AF before surgery was 41 months. Type of AF was paroxysmal in 21 (21%), persistent in 11 (11%), and long-standing persistent in 67 (67%). Mean left atrium size in the preoperative period was 5.54 ± 0.82 cm. Mean left ventricular ejection fraction was 58±12.4%. Types of mitral valve surgery were valvuloplasty (n=10), mechanical valve replacement in 30, and bioprosthesis replacement in 59. Concomitant tricuspid annuloplasty was performed in 39 patients. Thirty- day mortality was 8/99 (8%). Mean follow-up time was 1274 days (3.49 years). Survival was 92%. After 4 years no patient who had had unipolar ablation was in sinus rhythm, whilst 67% of those who had bipolar energy ablation were in sinus rhythm (p<0.001). Conclusion: The use of bipolar energy is superior to unipolar energy in the surgical ablation of atrial fibrillation in patients submitted to mitral valve surgery

Practical recommendations for the management of diabetes in patients with COVID-19

Diabetes is one of the most important comorbidities linked to the severity of all three known human pathogenic coronavirus infections, including severe acute respiratory syndrome coronavirus 2. Patients with diabetes have an increased risk of severe complications including Adult Respiratory Distress Syndrome and multi-organ failure. Depending on the global region, 20-50% of patients in the coronavirus disease 2019 (COVID-19) pandemic had diabetes. Given the importance of the link between COVID-19 and diabetes, we have formed an international panel of experts in the field of diabetes and endocrinology to provide some guidance and practical recommendations for the management of diabetes during the pandemic. We aim to briefly provide insight into potential mechanistic links between the novel coronavirus infection and diabetes, present practical management recommendations, and elaborate on the differential needs of several patient groups

Comment on "How green is blue hydrogen?"

This paper is written in response to the paper “How green is blue hydrogen?” by R. W. Howarth and M. Z. Jacobson. It aims at highlighting and discussing the method and assumptions of that paper, and thereby providing a more balanced perspective on blue hydrogen, which is in line with current best available practices and future plant specifications aiming at low CO2 emissions. More specifically, in this paper, we show that: (i) the simplified method that Howarth and Jacobson used to compute the energy balance of blue hydrogen plants leads to significant overestimation of CO2 emissions and natural gas (NG) consumption and (ii) the assumed methane leakage rate is at the high end of the estimated emissions from current NG production in the United States and cannot be considered representative of all-NG and blue hydrogen value chains globally. By starting from the detailed and rigorously calculated mass and energy balances of two blue hydrogen plants in the literature, we show the impact that methane leakage rate has on the equivalent CO2 emissions of blue hydrogen. On the basis of our analysis, we show that it is possible for blue hydrogen to have significantly lower equivalent CO2 emissions than the direct use of NG, provided that hydrogen production processes and CO2 capture technologies are implemented that ensure a high CO2 capture rate, preferably above 90%, and a low-emission NG supply chain