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Leprosy is a chronic infectious disease caused by the bacilli Mycobacterium leprae and Mycobacterium lepromatosis. In addition to humans, animals such as nine-banded armadillos and red squirrels are species naturally infected. The objective of this study was to investigate the presence of M. leprae and M. lepromatosis in non-volant small mammals of the order Didelphimorphia and Rodentia through Polymerase Chain Reaction (PCR) assay. During 2015 and 2018, field expeditions were carried out in three municipalities, covering biotic elements of the Amazon and Cerrado biomes, in the Mato Grosso State, Midwest of Brazil. A specific primer for repetitive sequences of the genomic DNA of M. leprae and M. lepromatosis targeting the RLEP and RLPM gene, respectively, was used to screen for these agents. The molecular detection of M. leprae DNA in the samples was 13.8%. M. lepromatosis was not detected. The present study reports a description of M. leprae in small non-volant mammals in Brazil.

The trypsin inhibitor isolated from tamarind seeds (TTI) is being investigated for potential applications in the treatment of noncommunicable diseases (NCD), such as hypertension, obesity, and diabetes. This study aimed to assess TTI embryotoxicity and acute toxicity in adult zebrafish (Danio rerio). TTI was extracted and isolated from tamarind seeds. Embryonic and adult zebrafish were exposed for 96 hours to three concentrations of TTI (12.5, 25, and 50 mg/L). Zebrafish embryos (n=60 per group) were evaluated for survival, hatching, malformations, and potential developmental marker alterations, in addition to cardiotoxicity and neurotoxicity tests. For acute toxicity assessment in adults (n=20 per group), survival and locomotor and anxiety-like behaviors were assessed, along with genotoxicity (micronucleus) evaluation. Embryos exposed to TTI showed no significant adverse effects, presented normal heart rates and positive reflex response in the neurotoxicity tests. In adult fish, TTI did not cause mortality or significant behavioral changes, suggesting no neurotoxicity and no genotoxicity. Histopathological analyses of the whole body showed only changes in the liver and spinal cord, similar to those observed in the control group not exposed to TTI. These findings indicate TTI's biosafety and therapeutic potential in complex organisms. Further research is required to evaluate its long-term effects and efficacy in treating non-communicable diseases.

IntroductionThe end of the coronavirus disease 2019 (COVID-19) pandemic has been declared by the World Health Organization on May 5, 2023. Several vaccines were developed, and new data is being published about their effectiveness. However, the clinical trials for the vaccines were performed before the Omicron variant appeared and there are population groups where vaccine effectiveness still needs to be tested. The overarching goal of the present study was to analyze the effects of COVID-19 vaccination before and after the Omicron variant in patients considering comorbidities in a population from Nuevo Leon, Mexico.MethodsEpidemiological COVID-19 data from the Mexican Social Security Institute were collected from 67 hospitals located in northeastern Mexico, from July 2020 to May 2023, and a total of 669,393 cases were compiled, 255,819 reported a SARS-CoV-2 positive reverse transcription quantitative polymerase chain reaction (RT-qPCR) test or a positive COVID-19 antigen rapid test.ResultsBefore Omicron (BO, 2020-2021), after 14 days of two doses of COVID-19 vaccine, BNT162b2 and ChAdOx1 vaccines were effective against infection in non-comorbid and all comorbid subgroups, whereas after Omicron (AO, 2022- 2023) there was no significant effectiveness against infection with none of the vaccines. Regarding hospitalization BO, BNT162b2, ChAdOx1, CoronaVac and mRNA-1273 significantly protected non-comorbid patients whereas BNT162b2, ChAdOx1, and mRNA-1273, protected all comorbid subgroups against hospitalization. AO, BNT162b2, ChAdOx1, CoronaVac and mRNA-1273 were effective against hospitalization in non-comorbid patients whereas for most comorbid subgroups BNT162b2, ChAdOx1 and CoronaVac were effective against hospitalization. Non-comorbid patients were protected against death as an outcome of COVID-19 during the BO period with most vaccines whereas a reduction in effectiveness was observed AO with mRNA-1273 vaccines in patients with hypertension, and diabetes mellitus.DiscussionBO, COVID-19 vaccines were effective against infection, hospitalization, and death whereas AO, COVID-19 vaccines failed to protect the population from COVID-19 infection. A varying effectiveness against hospitalization and death is observed AO.

Abstract In the search for alternatives to overcome the challenge imposed by drug resistance development in cancer treatment, the modulation of autophagy has emerged as a promising alternative that has achieved good results in clinical trials. Nevertheless, most of these studies have overlooked a novel and selective type of autophagy: chaperone-mediated autophagy (CMA). Following its discovery, research into CMA’s contribution to tumor progression has accelerated rapidly. Therefore, we now understand that stress conditions are the primary signal responsible for modulating CMA in cancer cells. In turn, the degradation of proteins by CMA can offer important advantages for tumorigenesis, since tumor suppressor proteins are CMA targets. Such mutual interaction between the tumor microenvironment and CMA also plays a crucial part in establishing therapy resistance, making this discussion the focus of the present review. Thus, we highlight how suppression of LAMP2A can enhance the sensitivity of cancer cells to several drugs, just as downregulation of CMA activity can lead to resistance in certain cases. Given this panorama, it is important to identify selective modulators of CMA to enhance the therapeutic response.

A aprendizagem autorregulada e as crenças de autoeficácia são conceitos essenciais na educação, influenciando a motivação e o desempenho dos alunos. Este trabalho objetivou analisar a produção científica de artigos publicados entre 2015 e 2020, sobre aprendizagem autorregulada e crenças de autoeficácia no Ensino Fundamental nas seguintes bases de dados: SciELO, PePSIC, Biblioteca Virtual em Saúde (BVS) e Google Acadêmico. Os resultados apresentaram indicadores de que a autoeficácia afeta o processo de autorregulação, pois favorece a percepção e promoção dos alunos como agentes do processo de aprendizagem, a aquisição de conhecimentos e habilidades, o vínculo dos alunos com os colegas, professores e com a escola, refletindo no comportamento, desempenho e motivação, porém nenhum deles apresentou uma correlação entre a autorregulação e a autoeficácia, o que indica a necessidade de mais estudos sobre essas temáticas.

In this study we aim to test the impact of applying translation error taxonomies oriented towards European Languages in the annotation of Asian Languages. We aim to demonstrate how an error typology adapted for the latter languages can not only result in more linguistically accurate annotations, but also how this can be applied to automating and scaling translation quality evaluation. As such, we propose a Translation Errors Typology that aims to cover the shortcomings of the Multidimensional Quality Metrics (Lommel et al. 2014) framework (MQM) in what concerns the annotation of the East Asian Languages of Mandarin, Japanese and Korean. The effectiveness of the typology here proposed was tested by analysing the Inter-annotator agreement (IAA) scores obtained, in contrast with the typology proposed by Ye and Toral (2020) and the Unbabel Error Typology1. Finally, we propose a way of automating Translation Quality Workflows through a Quality Estimation (QE) technology that is able to predict the MQM scores of machine translation outputs at scale with a fair correlation with the human judgement produced by applying the East Asian Languages MQM module proposed in this study.

BackgroundRobust data comparing long COVID in hospitalized and non-hospitalized patients in middle-income countries are limited.MethodsA retrospective cohort study was conducted in Brazil, including hospitalized and non-hospitalized patients. Long COVID was diagnosed at 90-day follow-up using WHO criteria. Demographic and clinical information, including the depression screening scale (PHQ-2) at day 30, was compared between the groups. If the PHQ-2 score is 3 or greater, major depressive disorder is likely. Logistic regression analysis identified predictors and protective factors for long COVID.ResultsA total of 291 hospitalized and 1,118 non-hospitalized patients with COVID-19 were included. The prevalence of long COVID was 47.1% and 49.5%, respectively. Multivariable logistic regression showed female sex (odds ratio [OR] = 4.50, 95% confidence interval (CI) 2.51–8.37), hypertension (OR = 2.90, 95% CI 1.52–5.69), PHQ-2 > 3 (OR = 6.50, 95% CI 1.68–33.4) and corticosteroid use during hospital stay (OR = 2.43, 95% CI 1.20–5.04) as predictors of long COVID in hospitalized patients, while female sex (OR = 2.52, 95% CI 1.95–3.27) and PHQ-2 > 3 (OR = 3.88, 95% CI 2.52–6.16) were predictors in non-hospitalized patients.ConclusionLong COVID was prevalent in both groups. Positive depression screening at day 30 post-infection can predict long COVID. Early screening of depression helps health staff to identify patients at a higher risk of long COVID, allowing an early diagnosis of the condition.

Abstract Background The generation of induced pluripotent stem cells has opened the field of study for stem cell research, disease modeling and drug development. However, the epigenetic signatures present in somatic cells make cell reprogramming still an inefficient process. This epigenetic memory constitutes an obstacle in cellular reprogramming. Here, we report the effect of hydralazine (HYD) and valproic acid (VPA), two small molecules with proven epigenetic activity, on the expression of pluripotency genes in adult (aHF) and neonatal (nbHF) human fibroblasts. Methods aHF and nbHF were treated with HYD and/or VPA, and viability and gene expression assays for OCT4, NANOG, c-MYC, KLF4, DNMT1, TET3, ARID1A and ARID2 by quantitative PCR were performed. aHF and nbHF were transfected with episomal plasmid bearing Yamanaka factors (OCT4, SOX2, KLF4 and c-MYC) and exposed to HYD and VPA to determine the reprogramming efficiency. Methylation sensitive restriction enzyme (MSRE) qPCR assays were performed on OCT4 and NANOG promoter regions. Immunofluorescence assays were carried out for pluripotency genes on iPSC derived from aHF and nbHF. Results HYD upregulated the expression of OCT4 (2.5-fold) and NANOG (fourfold) genes but not c-Myc or KLF4 in aHF and had no significant effect on the expression of all these genes in nbHF. VPA upregulated the expression of NANOG (twofold) in aHF and c-MYC in nbHF, while it downregulated the expression of NANOG in nbHF. The combination of HYD and VPA canceled the OCT4 and NANOG overexpression induced by HYD in aHF, while it reinforced the effects of VPA on c-Myc expression in nbHF. The HYD-induced overexpression of OCT4 and NANOG in aHDF was not dependent on demethylation of gene promoters, and no changes in the reprogramming efficiency were observed in both cell populations despite the downregulation of epigenetic genes DNMT1, ARID1A, and ARID2 in nbHF. Conclusions Our data provide evidence that HYD regulates the expression of OCT4 and NANOG pluripotency genes as well as ARID1A and ARID2 genes, two members of the SWI/SNF chromatin remodeling complex family, in normal human dermal fibroblasts.

Introdução: A hantavirose é uma doença viral aguda, e pode ser transmitida a partir da inalação de aerossóis de excretas de roedores e, raramente, por sua mordida. Pode causar síndromes clínicas como: Síndrome Cardiopulmonar por Hantavirose ou Febre Hemorrágica com Síndrome Renal (FHSR). O FHSR pode se manifestar de diferentes formas, podendo ser assintomática, ou com apresentação súbita de febre, cefaleia, lombalgia e dor abdominal, podendo evoluir para um quadro de choque, hemorragia e insuficiência renal. Esse tipo de Febre Hemorrágica tem taxa de mortalidade entre 6 e 15%, e com necessidade de notificação compulsória. Assim, por conta de seu quadro clínico possivelmente fatal, faz-se necessário compreender o perfil epidemiológico da condição. Objetivo: Traçar o perfil epidemiológico dos casos de hantavirose no Brasil no período de 2012 a 2022. Metodologia: Trata-se de um estudo quantitativo, ecológico, descritivo, baseado em dados notificados no Sistema de Informações de Agravos de Notificação (SINAN/SUS) do Ministério da Saúde por meio do DATASUS, entre Jan/2012 e Dez/2022. Foram analisadas as seguintes variáveis: raça, faixa etária, sexo e região. Resultados: No período analisado, houve 788 casos de hantavirose. Quanto ao sexo biológico, 76,52% dos casos registrados foram do sexo masculino e 23,48% do sexo feminino. Em relação à raça/cor, a maioria dos casos, 63,20%, ocorreram em pessoas brancas. Os indivíduos pardos ocuparam o segundo lugar, com 26,40%. Já os pretos, amarelos e indígenas representam 6,09% dos casos. Não se obteve informações da raça/cor em 4,31% dos casos. Tratando-se de faixa etária, a população de 20 a 39 anos foi a mais acometida, representando 48,48% dos casos. Ademais, a faixa etária entre 40 e 59 anos representou 34,14% dos casos, enquanto crianças e adolescentes representam 11,42% e idosos, 5,96%. Ao analisar as regiões, a região Sul possui o maior número de casos, 43,78%, seguida pelo Centro-Oeste e Sudeste, com 26,52% e 25,13%, respectivamente. Conclusão: Portanto, ao analisar os resultados obtidos nos últimos 10 anos, o perfil epidemiológico mais atingido é formado por indivíduos do sexo masculino, brancos, entre 20 e 39 anos e da região Sul. Assim, tendo em vista que a análise dos casos de hantavirose pode ajudar a entender os obstáculos e auxiliar na prevenção para reduzir casos futuros, faz-se fundamental que o poder público fique atento a esse perfil epidemiológico, objetivando a prevenção e controle de tal moléstia.

Introdução: A Tuberculose (TB) é uma patologia granulomatosa crônica, apresentando como principal agente etiológico o Mycobacterium tuberculosis. Ela é considerada como a principal doença infecciosa causadora de óbitos em todo o globo. Apesar de seu principal sítio de infecção ser o pulmão, o trato geniturinário (TGU) pode ser acometido pela infecção. Por conta de sua importância, faz-se necessário compreender as características dos pacientes que são acometidos pela patologia. Objetivos: Analisar as internações por TB do TGU, além de caracterizar o perfil epidemiológico dos afetados, no Brasil, entre 2004 e 2023. Metodologia: Um estudo descritivo, ecológico e quantitativo com dados do departamento de informática do SUS (DATASUS). As informações obtidas foram referentes às internações por TB do TGU, entre Jan/2004 e Mar/2023, no Brasil, a partir do Sistema de Informação de Agravos de Notificação (SINAN). Resultados: Houve um total de 6373 internações, onde o ano com maior e menor número foram 2004 (517) e 2023 (58), respectivamente. A região mais afetada foi a Sudeste (3515; 55,2%), seguida pelo Sul (1119; 17,6%) e Nordeste (1077; 16,9%). Destas, os principais representantes foram São Paulo (SP) (1922; 30,2%), Rio Grande do Sul (603; 9,5%) e Bahia (365; 5,7%). As faixas etárias mais acometidas foram entre 40 e 49 (1419; 22,27%), 30 e 39 (1297; 20,35%) e 50 e 59 anos (1249; 19,6%). Já o sexo, 3571 (56,03%) eram do sexo masculino, enquanto 2800 (43,94%) pacientes eram do feminino. Ademais, 229 (4%) eram tabagistas, 310 (5%) etilistas e 105 (2%) usuários de drogas ilícitas. Apesar disto, uma fração importante dos pacientes não preencheu os hábitos aqui apresentados (59%; 25%; e 59%, respectivamente). Conclusão: A partir dos dados aqui apresentados, fica explícito que as internações por TB do TGU apresentaram uma leve queda, com uma estabilização a partir do ano de 2011. Nota-se um maior acometimento pelo Sudeste, com destaque para SP, por paciente do sexo masculino, com faixa etária de 30 a 59 anos. Além disso, percebeu-se que a maior parte dos pacientes não apresentavam hábitos que pudessem piorar sua condição de base. Por fim, entretanto, observou-se que uma fração considerável dos pacientes não tinham a ficha preenchida de maneira adequada. Isto torna-se um desafio importante para o traçado adequado e preciso do perfil epidemiológico dos pacientes, bem como seus hábitos, o que traria informações preciosas para possíveis medidas de prevenção da condição.

Resumo Este artigo analisa quais fatores condicionam a disponibilidade dos dados educacionais. Com foco no ensino médio, o artigo demonstra que os municípios e as escolas que, em 2022, não tinham dados disponíveis para o Sistema de Avaliação da Educação Básica (Saeb) apresentaram, em sua maioria, baixos indicadores médios de proficiência em 2019, ou também não tinham dados disponíveis em 2019. Por meio de uma regressão logística, o artigo demonstra que a probabilidade de um município ter alcançado a taxa mínima de participação para o Saeb, em 2022, foi maior entre aqueles com alta proficiência média em 2019, maior quantidade de matrículas e respostas mais efetivas à pandemia de covid-19. Os resultados indicam uma reprodução das desigualdades educacionais na disponibilidade dos dados.

Abstract Topical instillation of drugs targeting the posterior ocular segment is an expanding area of research. Chitosan and hyaluronic acid have remarkable mucoadhesive properties and potentially enhance pre-corneal retention time after topical instillation. Bearing this in mind, we explored the possibility of delivering epoetin beta (EPOβ) to the posterior segment of the eye in a chitosan-hyaluronic acid (CS/HA-EPOβ) nanoparticulate system using the topical route of administration. Complete ophthalmological examinations, electroretinography and microhematocrit evaluations were performed in Wistar Hannover (WH) rats, before and after topical administration of nanoparticles. The right eye received CS/HA-EPOβ and the left eye received only empty nanocarriers (control). Animals were split into 6 groups and at designated timepoints, all animals from each group (n = 3) were euthanized and both eyes enucleated. Retinal morphology and EPOβ ocular distribution were assessed, respectively, through hematoxylin and eosin (HE) and immunofluorescence staining. After topical administration, no adverse ocular signs were noted and no significant changes either in microhematocrits nor in electroretinographies were detected. During the study, intraocular pressure (IOP) was always kept within physiological range bilaterally. No histological changes were detected in any of the ocular globes. Immunofluorescence enabled the identification of EPOβ in the retina 12 h after the administration, its presence still being detectable at day 21. In conclusion, CS/HA nanoparticles could efficiently deliver EPOβ to the retina of WH rats after topical instillation, being considered biologically safe. Topical administration of this nanoformulation could be a valuable tool for retinal neuroprotection, decreasing risks associated with more invasive routes of administration, being cost effective and also increasing long-term patients’ compliance.

Introduction and objectives: Although automatic artificial intelligence (AI) coronary angiography (CAG) segmentation is arguably the first step toward future clinical application, it is underexplored. We aimed to (1) develop AI models for CAG segmentation and (2) assess the results using similarity scores and a set of criteria defined by expert physicians. Methods: Patients undergoing CAG were randomly selected in a retrospective study at a single center. Per incidence, an ideal frame was segmented, forming a baseline human dataset (BH), used for training a baseline AI model (BAI). Enhanced human segmentation (EH) was created by combining the best of both. An enhanced AI model (EAI) was trained using the EH. Results were assessed by experts using 11 weighted criteria, combined into a Global Segmentation Score (GSS: 0–100 points). Generalized Dice Score (GDS) and Dice Similarity Coefficient (DSC) were also used for AI models assessment. Results: 1664 processed images were generated. GSS for BH, EH, BAI and EAI were 96.9+/-5.7; 98.9+/-3.1; 86.1+/-10.1 and 90+/-7.6, respectively (95% confidence interval, p

Introduction: Heart disease and cancer are the two leading causes of morbidity and mortality worldwide. Advances in cancer screening and management have led to longer survival and better quality of life. Despite this progress, many cancer patients experience cardiovascular complications during and after cancer treatment. This study describes the experience of a cardio-oncology program at tertiary academic hospital. Methods: In this retrospective observational study, cancer patients referred to the CHULN cardio-oncology consultation (COC) between January 2016 and December of 2019 were included. Data collected included: patient demographics, cancer type, reason for referral, cardiovascular risk factors, cardiac and oncologic treatments and clinical outcomes. Results: A total of 520 patients (mean age: 65 ± 14 years; 65% women) were referred to the COC. The main reasons for referral were suspected heart failure (26%), pre-high risk chemotherapy assessment (20%) and decreased LVEF (15%). Pre-existing cardiovascular risk factors were common (79%) and 309 (59%) were taking cardiac medications. The most common type of malignancy was breast cancer (216, 41%) followed by gastrointestinal (139, 27%). More than half received anthracycline-based regimens (303, 58%). Most patients (401; 77%) successfully completed cancer therapy. At the time of last data collection, the majority of patients were alive (430, 83%). Cardiac-related mortality was observed in 16%. Conclusions: The close collaboration between cardiology and oncology teams and timely cardiac monitoring was the key to the majority of patients to completing their prescribed cancer therapy. Resumo: Introdução: As doenças cardiovasculares e o cancro são as principais causas de morbilidade e mortalidade em todo o mundo. Avanços na triagem e tratamento do cancro têm permitido uma sobrevivência mais longa e uma melhor qualidade de vida. Apesar deste progresso, muitos pacientes com cancro apresentam complicações cardiovasculares durante e após o tratamento oncológico. Este estudo descreve a experiência de um programa de cardio-oncologia num hospital universitário terciário. Métodos: Neste estudo observacional retrospetivo, foram incluídos pacientes com cancro referenciados para consulta de cardio-oncologia (CCO) do CHULN entre janeiro de 2016 e dezembro de 2019. Os dados coletados foram: dados demográficos, tipo de cancro, motivo de referenciação, fatores de risco cardiovasculares (FRCV), terapêutica cardíaca e oncológica e desfechos clínicos. Resultados: Foram referenciados para a CCO, 520 pacientes (idade média: 65 ± 14 anos; 65% mulheres). Os principais motivos de referenciação foram: suspeita de insuficiência cardíaca (26%), avaliação pré-quimioterapia de alto risco (20%) e diminuição da FEVE (15%). CVRF pré-existentes foram frequentes (79%) e 309 (59%) estavam com terapêutica cardiovascular. O tipo de cancro mais frequente foi o cancro da mama (216; 41%), seguido pelo cancro gastrointestinal (139; 27%). Mais da metade dos pacientes tez terapêutica oncológica baseada em antraciclinas (303, 58%). A maioria dos pacientes (401; 77%) completou com sucesso a terapêutica oncológica. Na altura da última coleta de dados a maioria dos pacientes estava viva (430, 83%). A mortalidade relacionada com o coração foi observada em 16%. Conclusões: A estreita colaboração entre as equipas de cardiologia e oncologia e a monitorização cardíaca atempada foi decisiva para que a maioria dos pacientes concluísse o tratamento oncológico.

The main goal of this project consisted of the conceptualization and development of a product related to the olive tree chemical features to monetize the wastes of the olive fruit exploitation. The most abundant by-product of the olive fruit harvest is the olive leaves, used as the raw material in this project. By following the steps of Chemical Product Design, it was decided to pursue the idea of creating antibacterial cotton bed sheets impregnated with olive leaves extract, mainly composed of oleuropein. The production process includes a pre-treatment of the olive leaves, oleuropein extraction, and supercritical impregnation. The estimated amount of leaves required is 39 g/m2 of cotton, considering a cotton fabric with 115 GSM.

ObjectiveChronic ethanol consumption is known to cause alcohol-associated liver disease, which poses a global health concern as almost a quarter of heavy drinkers develop severe liver damage. Alcohol-induced liver disease ranges from a mild, reversible steatotic liver to alcoholic steatohepatitis and irreversible liver fibrosis and cirrhosis, ultimately requiring liver transplantation. While ethanol consumption is associated with dysregulated lipid metabolism and altered cholesterol homeostasis, the impact of dyslipidemia and pre-existing hypercholesterolemia on the development of alcohol-associated liver disease remains to be elucidated.DesignTo address the influence of systemic dyslipidemia on ethanol-induced liver disease, chronic-binge ethanol feeding was applied to female C57BL/6J (wild type) mice and mice deficient for the low-density lipoprotein receptor (Ldlr-/-), which display a human-like lipoprotein profile with elevated cholesterol and triglyceride levels in circulation. Respective control groups were pair-fed an isocaloric diet.ResultsChronic-binge ethanol feeding did not alter systemic lipid levels in wild type mice. While increased systemic cholesterol levels in Ldlr-/- mice were not affected by ethanol feeding, chronic-binge ethanol diet aggravated elevated plasma triglyceride levels in Ldlr-/- mice. Despite higher circulatory triglyceride levels in Ldlr-/- mice, hepatic lipid levels and the development of hepatic steatosis were not different from wild type mice after ethanol diet, while hepatic expression of genes related to lipid metabolism (Lpl) and transport (Cd36) showed minor changes. Immunohistochemical assessment indicated a lower induction of infiltrating neutrophils in the livers of ethanol-fed Ldlr-/- mice compared to wild type mice. In line, hepatic mRNA levels of the pro-inflammatory genes Ly6g, Cd11b, Ccr2, Cxcl1 and F4/80 were reduced, indicating less inflammation in the livers of Ldlr-/- mice which was associated with reduced Tlr9 induction. While systemic ALT and hepatic MDA levels were not different, Ldlr-deficient mice showed accelerated liver fibrosis development after chronic-binge ethanol diet than wild type mice, as indicated by increased levels of Sirius Red staining and higher expression of pro-fibrotic genes Tgfb, Col1a1 and Col3a1. Ldlr-/- and wild type mice had similar plasma ethanol levels and did not show differences in the hepatic mRNA levels of Adh1 and Cyp2e1, important for ethanol metabolism.ConclusionOur results highlight that chronic-binge ethanol feeding enhances systemic dyslipidemia in Ldlr-/- mice which might accelerate the development of hepatic fibrosis, independent of hepatic lipid levels.

Hepatocellular carcinoma (HCC) is among the main causes of death by cancer worldwide, representing about 80–90% of all liver cancers. Treatments available for advanced HCC include atezolizumab, bevacizumab, sorafenib, among others. Atezolizumab and bevacizumab are immunological options recently incorporated into first-line treatments, along with sorafenib, for which great treatment achievements have been reached. However, sorafenib resistance is developed in most patients, and therapeutical combinations targeting cancer hallmark mechanisms and intracellular signaling have been proposed. In this review, we compiled evidence of the mechanisms of cell death caused by sorafenib administered alone or in combination with valproic acid and metformin and discussed them from a molecular perspective.

Anacardium occidentale L. stem bark Traditional Herbal Preparations (AoBTHPs) are widely used in traditional medicine to treat inflammatory conditions, such as diabetes. The present study aims to evaluate the anti-inflammatory, antioxidant, and genotoxic potential of red and white Portuguese AoBTHPs. Using a carrageenan-induced rat paw edema model, a significant anti-edema effect was observed for all tested doses of white AoBTHP (40.2, 71.5, and 127.0 mg/kg) and the two highest doses of red AoB THP (71.5 and 127.0 mg/kg). The anti-edema effect of red AoBTHP’s highest dose was much more effective than indomethacin 10 mg/kg, Trolox 30 mg/kg, and Tempol 30 mg/kg. In DPPH, FRAP, and TAC using the phosphomolybdenum method, both types of AoBTHPs showed similar antioxidant activity and no genotoxicity up to 5000 µg/plate in the Ames test. The LC-UV/DAD-ESI/MS fingerprint allowed the identification of gallic and protocatechuic acids as the two main marker compounds and the presence of catechin, epicatechin, epigallocatechin gallate, and ellagic acid in both AoBTHPs. The obtained results support the validation of red and white AoB and their THPs as anti-inflammatory agents and contribute to the possible development of promising new therapeutic options to treat inflammatory conditions.

The aim of this study is to measure the invariance of the Multidimensional Jealousy Scale (MJS) and of the Quality of Relationships Inventory (Friend) (QRI-F) across gender, age, education, and being in a romantic relationship in a Portuguese sample (N = 662). A confirmatory factor analysis was performed to test the fit of different potential factor structures. The results pointed out that both MJS and QRI-F were most suitable if represented by three first-order factors correlated between them. Results from multi-group analyses suggested there was factorial invariance for these structures across groups, suggesting that the MJS and the QRI-F provide, respectively, an assessment of romantic jealousy and quality of relationship that are equivalent across gender, age, education, and being in a romantic relationship. The study established the strong psychometric properties of its instruments, validating reliability and convergent and discriminant validity, thereby bolstering the research’s overall credibility. Additionally, cognitive jealousy is primarily influenced by heightened conflict values, with education, relationship status, and gender moderating the associations between QRI-F dimensions and MJS behavioral and cognitive jealousy. The research offered in-depth perspectives on jealousy, underscoring its diverse manifestations across demographic variables and illuminating the complexities within the dynamics of friendships.

The study verified the influence of the teaching of financial education in saving decisions on the behavior of students of 5th-grade classes of the Ausônio Araújo Municipal School, based on the implementation of the extension project of the Federal University of Rio Grande do Norte, entitled “Education Financial in Schools”. The universe comprises 5th-grade classes, and the sample consisted of 180 students, with 45 participating in the project implemented in 2018 and 45 in 2019, and a control group with 45 not participating in the project in 2018 and 45 in 2019. For data analysis, a structured Likert scale questionnaire and Wilcoxon non-parametric mean difference test were used. The results suggest that the groups that participated in financial education classes in 2018 and 2019 had more knowledge regarding the answers to the propositions than the control group. The project is relevant and contributes to decision-making regarding the students' financial lives. However, concerning the domain of financial skills, the students had difficulties and limitations in decision making, highlighting the importance of further dialogue on the subject at home and in interpersonal relationships. In addition, there was a higher commitment and initiative from the Ministry of Education regarding the effective implementation of financial education in schools nationwide.

Juvenile systemic lupus erythematosus (JSLE) is diagnosed in children younger than 18 years of age. Depression and anxiety are common, but not well understood in JSLE. We investigated the clinical and psychological factors associated with the psychological manifestations of JSLE. Twenty-nine JSLE patients were recruited for the study. Patients completed surveys evaluating their psychological status and perceptions about their health. Medical records were used to obtain laboratory results. The JSLE patient population was compared with adult-onset SLE (ASLE) patients and unaffected controls. Kidney involvement was associated with depression in the JSLE patients. The BUN levels, BUN/creatinine ratio, and leukocyturia were all significantly associated with depressive symptoms. Multivariate analysis found that the BUN/creatinine ratio was the most predictive value for both depression and anxiety. Depressive symptoms in JSLE were less pronounced than in ASLE, although anxiety was not different. Age and education are likely to be protective against depression in the JSLE patients. These findings may indicate that symptomatology is an important indicator of whether the patient needs psychiatric care.

Bullying involves aggressive behaviors with the intention to harm others, including manifestations of systematic abuse of power. Two types of bullying can be considered: physical and psychological. Students may get involved in bullying dynamics as bullies, victims, or both - aggressive victims. The literature defines bullying as a global phenomenon, affecting both girls and boys. Therefore, Portuguese schools are no exception, with several studies from North to South of the country demonstrating the presence of bullying in schools, both in elementary and middle schools. The aim of this study is to elaborate the differences and experiences by both genders, boys and girls, in the current dynamics of school bullying. Thus, answering the question - how different are girls and boys as bullies and victims? In addition, it intends to impart the acquired knowledge and raise awareness of the implications of this social context in which Portuguese children are currently involved. The results obtained from a sample of 1147 students attending the 1st cycle of Portuguese education (elementary schools) were in line with previous studies. In order to enrich the literature, bullies, victims, and aggressive victims were characterized in detail. Finally, the importance of the adults’ intervention, especially teachers, was highlighted.

Fungal pigments, including melanin, are recognized as promising materials for biomedical, environmental, and technological applications. In previous studies, we have demonstrated that the DOPA-melanin produced by the MEL1 mutant of Aspergillus nidulans exhibits antioxidant, anti-inflammatory, and antimicrobial activities without any cytotoxic or mutagenic effects, suggesting its potential use in pharmaceuticals. In order to increase the yield of this pigment and reduce the costs of its large-scale production, the present study aimed to evaluate agro-industrial by-products, sugarcane molasses, vinasse, and corn steep liquor as inexpensive substrates for fungal growth using experimental design methodology. According to the results obtained, the optimal composition of the culture medium was 0.81% (v/v) vinasse and 1.62% (w/v) glucose, which promoted a greater production of melanin (225.39 ± 4.52 mg g−1 of biomass), representing a 2.25-fold increase compared with the condition before optimization (100.32 mg.g−1 of biomass). Considering the amount of biomass obtained in the optimized condition, it was possible to obtain a total melanin production of 1 g L−1. Therefore, this formulation of a less complex and low-cost culture medium composition makes the large-scale process economically viable for future biotechnological applications of melanin produced by A. nidulans.

Root tubers of Asphodelus bento-rainhae subsp. bento-rainhae (AbR), a vulnerable endemic species, and Asphodelus macrocarpus subsp. macrocarpus (AmR) have traditionally been used in Portugal to treat inflammatory and infectious skin disorders. The present study aims to evaluate the in vitro antimicrobial activity of crude 70% and 96% hydroethanolic extracts of both medicinal plants, specifically against multidrug-resistant skin-related pathogens, to identify the involved marker secondary metabolites and also to assess the pre-clinical toxicity of these medicinal plant extracts. Bioguided fractionation of the 70% hydroethanolic extracts of both species using solvents of increasing polarity, namely diethyl ether (DEE: AbR-1, AmR-1), ethyl acetate (AbR-2, AmR-2) and aqueous (AbR-3, AmR-3) fractions, enabled the identification of the DEE fractions as the most active against all the tested Gram-positive microorganisms (MIC: 16 to 1000 µg/mL). Furthermore, phytochemical analyses using TLC and LC-UV/DAD-ESI/MS techniques revealed the presence of anthracene derivatives as the main constituents of DEE fractions, and five known compounds, namely 7′-(chrysophanol-4-yl)-chrysophanol-10’-C-beta-D-xylopyranosyl-anthrone (p), 10,7′-bichrysophanol (q), chrysophanol (r), 10-(chrysophanol-7′-yl)-10-hydroxychrysophanol-9-anthrone (s) and asphodelin (t), were identified as the main marker compounds. All these compounds showed high antimicrobial activity, particularly against Staphylococcus epidermidis (MIC: 3.2 to 100 µg/mL). Importantly, no cytotoxicity against HepG2 and HaCaT cells (up to 125 µg/mL) for crude extracts of both species and genotoxicity (up to 5000 µg/mL, with and without metabolic activation) for AbR 96% hydroethanolic extract was detected using the MTT and Ames tests, respectively. Overall, the obtained results contribute to the concrete validation of the use of these medicinal plants as potential sources of antimicrobial agents in the treatment of skin diseases.

Ultrasound-assisted extraction and direct analysis were compared with total digestion for magnesium determination in beer samples by flame atomic absorption spectrometry. The method for total digestion used concentrated nitric acid under plate heating. In optimized instrumental conditions, validation of the analytical method was promoted, with good linear range (0.06 to 0.5 mg L–1), low limits of detection and quantification (0.04 and 0.12 µg g–1, respectively), good precision, relative standard deviation (RSD) 3.4%, and accuracy (recovery levels of 91.5 to 99.0%). The characteristic concentration (C0) was 9 µg L–1. The extraction procedure was performed in a 1:1 nitric acid solution for 55 min in an ultrasonic bath at 60 °C, while the direct analysis involved a dilution of the samples in a 2% v/v nitric acid solution. The different sample preparation methods were applied to 13 beer samples and at a 95% confidence level, no significant differences were observed. Thus, direct analysis proved to be more suitable for quality control routines of beer samples in the industry.

INTRODUÇÃO: Atividades complementares, como Ligas Acadêmicas, são essenciais à formação médica. O contexto pandêmico, todavia, impôs barreiras em suas dinâmicas e, para a Liga Acadêmica de Emergências Pré-Hospitalares não foi diferente. O alcance dos mesmos objetivos em meio a um cenário de virtualização abrupta das relações humanas requereu abordagens inovadoras que otimizassem o aprendizado teórico-prático e interpessoal. RELATO: O contexto pré-pandêmico baseava-se em sessões presenciais, em que o conhecimento era construído através de aulas e cursos ministrados pelos ligantes. O aspecto prático fundamentava-se na realização de simulações e capacitações práticas, experiências tais que estimulavam a integração entre os membros. A pandemia, contudo, estabeleceu a necessidade de adaptação das metodologias utilizadas. No âmbito teórico, são gravadas videoaulas a priori, cujos conteúdos são aprofundados telepresencialmente, quando ocorre resolução de provas de residência e realização de atendimentos narrados de casos clínicos. Por fim, para evitar perdas na integração entre membros, foram instituídas medidas como divisões aleatorizadas de subgrupos para diferentes projetos, manutenção das câmeras ligadas e incremento na prática de feedback acerca do desempenho dos ligantes. DISCUSSÃO: Os obstáculos enfrentados incluem o distanciamento das relações interpessoais e prejuízos à aquisição de competências relacionadas à docência e ao aprendizado prático, fundamentais à vivência médica. A despeito dessas perdas, a educação médica também obteve benefícios, que se revelam na maior flexibilidade de horários e aprofundamento através de métodos de revisão e discussão de artigos científicos, além da prática de feedback. Assim, têm sido discutidas maneiras de integrar esses recursos mesmo após o término da pandemia.

The leaves of Asphodelus bento-rainhae subsp. bento-rainhae, an endemic Portuguese species, and Asphodelus macrocarpus subsp. macrocarpus have been used as food, and traditionally as medicine, for treating ulcers, urinary tract, and inflammatory disorders. The present study aims to establish the phytochemical profile of the main secondary metabolites, together with the antimicrobial, antioxidant and toxicity assessments of both Asphodelus leaf 70% ethanol extracts. Phytochemical screenings were conducted by the TLC and LC-UV/DAD-ESI/MS chromatographic technique, and quantification of the leading chemical classes was performed by spectrophotometric methods. Liquid-liquid partitions of crude extracts were obtained using ethyl ether, ethyl acetate, and water. For in vitro evaluations of antimicrobial activity, the broth microdilution method, and for the antioxidant activity, the FRAP and DPPH methods were used. Genotoxicity and cytotoxicity were assessed by Ames and MTT tests, respectively. Twelve known compounds including neochlorogenic acid, chlorogenic acid, caffeic acid, isoorientin, p-coumaric acid, isovitexin, ferulic acid, luteolin, aloe-emodin, diosmetin, chrysophanol, and β-sitosterol were identified as the main marker compounds, and terpenoids and condensed tannins were found to be the major class of secondary metabolites of both medicinal plants. The ethyl ether fractions demonstrated the highest antibacterial activity against all the Gram-positive microorganisms, (MIC value of 62 to 1000 µg/mL), with aloe-emodin as one of the main marker compounds highly active against Staphylococcus epidermidis (MIC value of 0.8 to 1.6 µg/mL). Ethyl acetate fractions exhibited the highest antioxidant activity (IC50 of 800 to 1200 µg/mL, respectively). No cytotoxicity (up to 1000 µg/mL) or genotoxicity/mutagenicity (up to 5 mg/plate, with/without metabolic activation) were detected. The obtained results contribute to the knowledge of the value and safety of the studied species as herbal medicines.

Abstract Background Mortality due to tuberculosis (TB) has increased due to the development of drug resistance, the mechanisms of which have not been fully elucidated. Our research group identified a low expression of lipF gene in Mycobacterium tuberculosis clinical isolates with drug resistance. The aim of this work was to evaluate the effect of lipase F (LipF) expression on mycobacterial drug resistance. Results The effects of expressing lipF from Mycobacterium tuberculosis in Mycobacterium smegmatis on resistance to antituberculosis drugs were determined with resazurin microtiter assay plate and growth kinetics. Functionality of ectopic LipF was confirmed. LipF expression reduced the rifampicin (RIF) and streptomycin (STR) minimum inhibitory concentration (MIC) from 3.12 μg/mL to 1.6 μg/mL and 0.25 μg/mL to 0.06 μg/mL respectively, moreover a reduced M. smegmatis growth in presence of RIF and STR compared with that of a control strain without LipF expression (p

The present work investigates the effects of chitosan-hyaluronic acid-epoetin beta (CS/HA-EPOβ) nanoparticles after topical ocular administration in a rat glaucoma model. Wistar Hannover rats (n = 24) were submitted to a complete ophthalmological examination and electroretinography, followed by glaucoma induction in their right eye on day 1 of the study. Treatment group (T) received CS/HA-EPOβ nanocarriers (n = 12), while the control group (C) received only empty ones. Electroretinography was repeated on day 3 (n = 24) and before euthanasia on day 7 (n = 8), 14 (n = 8), and 21 (n = 8), followed by bilateral enucleation and histological assessment. The animals showed good tolerance to the nanoformulation. Maximum IOP values on the right eye occurred shortly after glaucoma induction (T = 62.6 ± 8.3 mmHg; C = 63.6 ± 7.9 mmHg). Animals from the treated group presented a tendency for faster recovery of retinal electrical activity (p > 0.05). EPOβ was detected on the retina of all treated eyes using immunofluorescence. Control animals presented with thinner retinas compared to the treated ones (p < 0.05). Therefore, topical ocular administration of CS/HA-EPOβ nanoparticles enabled EPOβ delivery to the retina of glaucomatous rats and promoted an earlier retinal recovery, confirming EPOβ’s neuroprotective effects. The encouraging results of this preclinical study pave the way for new strategies for topical ocular administration of neuroprotective compounds.

Dried leaves of Lannea velutina A. Rich. and Sorindeia juglandifolia (A. Rich.) Planch. ex Oliv. (family Anacardiaceae) are used in African traditional medicine. Although these medicinal plants have widespread use in the treatment of inflammatory diseases, there is no scientific data concerning their preclinical or clinical safety. This work aimed to investigate the phytochemical properties of the leaves of both species using HPLC-UV/DAD, as well as the in vivo oral repeated-dose toxicity of 70% hydroethanolic leaf extract of S. juglandifolia and the in vitro genotoxicity of 70% hydroethanolic leaf extracts of L. velutina and S. juglandifolia. Clinical signs of toxicity, body weight variations, and changes in food consumption, mortality, and blood biochemical parameters were monitored. Genotoxicity was assessed using the bacterial reverse mutation assay (Ames test) with and without metabolic activation, according to OECD guidelines. The obtained results showed the presence of gallic acid and anacardic acid as the main marker constituents in both species. No significant changes in general body weight or food intake were observed; small significant changes with no critical relevance were observed in the blood biochemistry of animals treated with S. juglandifolia hydroethanolic extract (50, 400, and 1000 mg/kg body weight) compared to those in the control group. No genotoxicity was observed in the bacterial reverse mutation assay with S. juglandifolia and L. velutina extracts (up to 5 mg/plate). The safety data obtained in vivo and lack of genotoxic potential in vitro points to the safe medicinal use of S. juglandifolia and L. velutina extracts.

The emergence of multidrug-resistant (MDR) Mycobacterium tuberculosis strains threaten the control of tuberculosis. New antitubercular dihydrosphingosine analogs, named UCIs, have been evaluated in preclinical studies but their cellular and molecular mechanisms of action against M. tuberculosis are still unknown. The aim of this study was to evaluate the effect of UCI exposure on gene expression of drug-sensitive H37Rv and MDR CIBIN:UMF:15:99 clones of M. tuberculosis which were isolated, phenotypically, and genetically characterized, cultured to log phase and treated with UCI compounds; followed by total RNA isolation, reverse transcription and hybridization assays on Affymetrix genomic microarrays. Data were validated with RT-qPCR assays. As results, UCI-05 and UCI-14 exposure increased gltA1 expression in drug-sensitive H37Rv clones. Furthermore, UCI-05 increased lprQ expression in MDR CIBIN:UMF:15:99 M. tuberculosis clones while UCI-14 reduced the expression of this gene in drug-sensitive H37Rv clones. In addition, UCI-05 reduced rpsO expression in drug-sensitive H37Rv clones. We found gene expression alterations that suggest these molecules may alter carbon and lipid metabolism as well as interfere in the protein-producing machinery in M. tuberculosis.

Root tubers of Asphodelus bento-rainhae subsp. bento-rainhae (AbR), an endemic species with relevant interest due to conservation concerns, and Asphodelus macrocarpus subsp. macrocarpus (AmR) have been traditionally used for culinary and medicinal purposes, mainly associated with skin infection and inflammation. The present study aims to establish the quality control criteria for the proper characterization of dried root tubers of both species as herbal substances, together with their preclinical safety assessments. Botanical identification using macroscopic and microscopic techniques and phytochemical evaluation/quantification of the main classes of marker secondary metabolites, including phenolic compounds (flavonoid, anthraquinone, condensed and hydrolysable tannin) and terpenoids were performed. Additionally, in vitro genotoxicity/mutagenicity was evaluated by Ames test. Evident morphological differences in the development of tubercles (3.5 × 1 cm in AbR and 8.7 × 1.4 cm in AmR) and microscopicly in the arrangements and characteristics of the vascular cylinder (metaxylem and protoxylems) were found. Anatomical similarities such as multiple-layered epidermis (velamen) and the cortex area with thin-walled idioblasts (134 ± 2.9 µm and 150 ± 27.6 µm) containing raphide crystals (37.2 ± 14.2 µm and 87.7 ± 15.3 µm) were observed between AbR and AmR, respectively. Terpenoids (173.88 ± 29.82 and 180.55 ± 10.57 mg OAE/g dried weight) and condensed tannins (128.64 ± 14.05 and 108.35 ± 20.37 mg CAE/g dried weight) were found to be the main class of marker secondary metabolites of AbR and AmR extracts, respectively. No genotoxicity (up to 5 mg/plate, without metabolic activation) was detected in these medicinal plants’ tested extracts. The obtained results will contribute to the knowledge of the value of the Portuguese flora and their future commercial cultivation utilization as raw materials for industrial and pharmaceutical use.

Histone deacetylases (HDAC) are epigenetic enzymes responsible for repressing gene expression through the deacetylation of histone lysine residues. Therefore, inhibition of HDACs has become an interesting approach for the treatment of several diseases, including cancer, hematology, neurodegenerative, immune diseases, bacterial infections, and more. Resveratrol (RVT) has pleiotropic effects, including pan-inhibition of HDAC isoforms; however, its ability to interfere with membranes requires additional optimization to eliminate nonspecific and off-target effects. Thus, to explore RVT as a scaffold, we designed a series of novel HDAC-1 and -2 inhibitors containing the 2-aminobenzamide subunit. Using molecular modeling, all compounds, except unsaturated compounds (4) and (7), exhibited a similar mode of interaction at the active sites of HDAC 1 and 2. The docking score values obtained from the study ranged from −12.780 to −10.967 Kcal/mol. All compounds were synthesized, with overall yields ranging from 33% to 67.3%. In an initial screening, compounds (4), (5), (7), and (20)–(26), showed enzymatic inhibitory effects ranging from 1 to 96% and 6 to 93% against HDAC-1 and HDAC-2, respectively. Compound (5), the most promising HDAC inhibitor in this series, was selected for IC50 assays, resulting in IC50 values of 0.44 µM and 0.37 µM against HDAC-1 and HDAC-2, respectively. In a panel of selectivity against HDACs 3–11, compound (5) presented selectivity towards Class I, mainly HDAC-1, 2, and 3. All compounds exhibited suitable physicochemical and ADMET properties as determined using in silico simulations. In conclusion, the optimization of the RVT structure allows the design of selective HDAC inhibitors, mainly targeting HDAC-1 and HDAC-2 isoforms.

Anacardium occidentale L. is used throughout the world to treat type 2 diabetes. In Portugal, a traditional herbal preparation made with stem bark of this species (AoBTHP) has been used for more than 30 years to treat this pathology. The AoBTHP was standardized on total phenolic content, and its hypoglycemic activity was assessed using db/db mice (n = 26) for 92 days. Three doses (40.2, 71.5, and 127.0 mg/kg/day, per os) were tested, and glibenclamide (5 mg/kg/day) was used as positive control. During the study, glycemia was measured under non-fasting or fasting states. In sequence, thin-layer chromatography bioautographic assays were used for the detection of possible alpha- and beta-glucosidase inhibitors. A significant hypoglycemic effect in fasting glycemia in days 31 and 57 was observed with the three tested doses. The 71.5 mg/kg and 127.0 mg/kg AoBTHPs significantly reduced non-fasting glycemia on day 24. The highest dose showed the most significant hypoglycemic effect. Gallic acid was identified as the major alpha- and beta-glucosidase inhibitor. The 127 mg/kg/day AoBTHP dose showed a greater glucose-lowering effect than glibenclamide. For the first time, a standardized AoBTHP was tested using an in vivo diabetes model, and its usage was preclinically validated for type 2 diabetes treatment. The hypoglycemic activity of an AoBTHP can be related to the presence of alpha- and beta-glucosidase inhibitors, such as gallic acid, but other mechanisms can also be involved.

Diabetes Mellitus is one of the World Health Organization's priority diseases under research by the first and second programmes of Innovative Medicines Initiative, with the acronyms IMI1 and IMI2, respectively. Up to October of 2019, 13 projects were funded by IMI for Diabetes & Metabolic disorders, namely SUMMIT, IMIDIA, DIRECT, StemBANCC, EMIF, EBiSC, INNODIA, RHAPSODY, BEAT-DKD, LITMUS, Hypo-RESOLVE, IM2PACT, and CARDIATEAM. In general, a total of €447 249 438 was spent by IMI in the area of Diabetes. In order to prompt a better integration of achievements between the different projects, we perform a literature review and used three data sources, namely the official project's websites, the contact with the project's coordinators and co-coordinator, and the CORDIS database. From the 662 citations identified, 185 were included. The data collected were integrated into the objectives proposed for the four IMI2 program research axes: (1) target and biomarker identification, (2) innovative clinical trials paradigms, (3) innovative medicines, and (4) patient-tailored adherence programmes. The IMI funded projects identified new biomarkers, medical and research tools, determinants of inter-individual variability, relevant pathways, clinical trial designs, clinical endpoints, therapeutic targets and concepts, pharmacologic agents, large-scale production strategies, and patient-centered predictive models for diabetes and its complications. Taking into account the scientific data produced, we provided a joint vision with strategies for integrating personalized medicine into healthcare practice. The major limitations of this article were the large gap of data in the libraries on the official project websites and even the Cordis database was not complete and up to date.

Organized by Flavia Batista da Silva. Edited and reviewed by Anna Paula Bennech and Giovanna Imbernon. "The current worldwide democracy crisis is not unexpected. In 2020, the Global Satisfaction with Democracy Report was published concerning news for democratic regimes (Centre for the Future of Democracy, 2020). Covering over 154 countries, Brazil included, it was the first time throughout the past 25 years that the world has spoken how unsatisfied it is with democracy. Since 1990, the share of individuals who are "dissatisfied" with democracy has risen by 10% points, from 47.9% to 57.5%. This raise represents the highest level of democratic discontent. Why are citizens so discontent with democracy? Why is Brazil at its highest-ever recorded level for democratic dissatisfaction?"

A Assembleia Nacional Constituinte de 1987 marcou o começo da redemocratização no Brasil. As disputas por um projeto de país tomaram diferentes formas e temas. E o mesmo não foi diferente com o sistema de controle interno. A trajetória deste fenômeno data o início do século XX e adentra o século XXI. Muito popular na literatura da Administração Pública, muitos estudos foram publicados sobre o controle interno, mas majoritariamente com uma perspectiva da gestão pública ou da contabilidade. Este artigo analisa quais foram as mudanças institucionais no sistema de controle interno do Poder Executivo Federal Brasileiro entre a Constituição de 1967 e 1988. À luz da teoria de mudanças institucionais este artigo pretende contribuir com a literatura das Ciências Sociais e da Ciência Política sobre os tipos de mudanças ocorridas, os tipos de agentes políticos envolvidos em tais mudanças, bem como interpretar a influência do contexto político na época sobre os resultados promulgados com a Constituição Federal Brasileira de 1988.

Embora defensores de doutrinas distintas, Confúcio e Mao Zedong partilham entre si a ideia de música como elemento fundamental na moldagem do ethosdo ser humano e, por conseguinte, influenciador da atividade política, defendendo o seu controlo por parte dos governantes. Esta ideia não só se refletiu na produção musical propriamente dita, como também na instituição de organizações e práticas musicais que consolidaram o poder dos governos sobre a arte musical ao longo de vários períodos da história chinesa, com o objetivo último de alcançar a harmonia social.

OBJETIVO: descrever, de acordo com a literatura, a importância da escuta qualificada realizada pelo enfermeiro no cuidado clínico com o paciente acometido pelo câncer. METODOLOGIA: revisão integrativa, com busca de estudos produzidos e devidamente publicados entre 2015 e 2020, nas bases de dados Biblioteca Virtual em Saúde (BVS), Literatura Latino-Americana em Ciências da Saúde (LILACS), Periódicos Capes e Scientific Eletronic Library Online (SCIELO), com os descritores controlados em português, em inglês e em espanhol. Também, foram acrescentados seis artigos a partir da busca manual no Google Achademics. A análise de conteúdo foi realizada a partir da identificação dos focos temáticos de onze artigos selecionados. RESULTADOS: identificaram-se três categorias: a busca por apoio e conforto no enfermeiro feita pela pessoa com câncer; capacitação e perfil profissional do enfermeiro que atua sobre as demandas clínicas oncológicas de seus pacientes; fatores capazes de dificultar e qualificar a escuta no cuidado clínico de enfermagem. CONCLUSÃO: a literatura evidenciou que a escuta é indispensável e deve ser adotada de forma qualificada na rotina de atuação do enfermeiro que atende pacientes oncológicos. Observou-se que a partir dessa adoção surge desse profissional um mediador redutor de incertezas e de angústias, deixando o cuidado clínico mais confortável e aceito.

Uma apresentação pessoal / A personal presentation

Non-Biological Complex Drugs (NBCDs) are complex non-biological drugs comprised of large high molecular weight molecules and, often, nanoparticular structures (including liposomes and block-copolymer micelles). In the case of NBCDs, the entire complex is the active pharmaceutical ingredient and its properties cannot be fully characterized by physicochemical analysis. Moreover, the manufacturing process is fundamental in creating the correct originator product. The same is true for generic versions of the product. A recent appraisal of approval procedures for NBCDs “follow-on products” approved in Europe shows a diversity of regulatory pathways. In fact, three different abridged application procedures, under European legislation, were used: the generic application procedure of Article 10(1), the hybrid application procedure of Article 10(3), and the biosimilar application procedure of Article 10(4). Three informed consent applications via Article 10(c) from innovator companies of glatiramer acetate and sevelamer carbonate were submitted shortly after the approval of the first follow-on products. Furthermore, a number of “well-established use” applications [via Article 10(a)] were approved for iron sucrose and iron dextran complexes. In order to protect patients from the increased risks of NBCD products and NBCD follow-on products, two complementary approaches should be considered: (i) improving the regulatory procedures and their guidance documents within the pre-registration phase, and (ii) not considering interchangeability whenever clinical data is not available. With regards to the latter, the need for adequate safety and efficacy data might also include risk management programmes within post-approval pharmacovigilance actions. This, however, would depend on a risk appraisal that must be considered for individual medicinal products, based on the nature of the submitted relevant set of safety/efficacy data.

Bullying's a phenomenon that carries great harm for those involved (bully or victim alike) in which academic achievement is harmed as well. However, the strength of such impact is yet to be clarified, existing many possibilities to explore. Or in other words, many variables that can justify such connection - classroom behavior being one example. The goal of the present investigation is to study the impact that bullying (while mediated by the classroom behavior) has on the academic achievement. The sample consisted of 288 children (from 1st year to 4th year’s students); and their teachers (whom reported their classroom behavior). Results showed that the bullying situation itself, didn’t significantly explain the academic achievement of those involved. However, from classroom behavior it was found an indirect effect between bullying and academic achievement. Within classroom behavior, the main contributive dimensions were - victim related, the excessive motor activity; and bully related, oppositional behaviors, excessive motor activity and ADHD index. This results alert to the importance of the educational agents’ attention given to the existing behavior in their classrooms. Not only because of the disruption created in each classroom’s environment, but also as a possible sign of an involvement in the existing bullying dynamics.

The Youth Quality of Life—Facial Differences (YQOL-FD), validated in the United States in 2005, was developed at the University of Washington by the Seattle Quality of Life Group (SeaQol), to evaluate quality of life of adolescents with facial deformities. Because no Portuguese version exists, the measure was not viable in Brazil. This study aimed to obtain linguistic and psychometric validation of a version of the YQOL-FD in Portuguese. Twenty-five patients with cleft lip and palate and five without facial deformity participated in Traumatology and Maxillofacial Prosthesis Surgery Clinic, School of Dentistry, University of São Paulo. The linguistic validation of the YQOL-FD was carried out by a team consisting of the researcher, as project manager, two native Portuguese-speaking consultants fluent in English, and one native English-speaking consultant fluent in Portuguese. After translation and back-translation, a Portuguese version was obtained, which was applied in a pilot test (n = 10); after the final adjustments the Seattle Quality of Life Group approved the official version of the YQOL-FD in Portuguese. To obtain the psychometric validation, we requested the participation of 20 patients with cleft lip and palate who answered the questionnaire twice in a range of 7 to 15 days. The Cronbach’s alpha test was applied in the 48-item block, showing a high degree of internal consistency (0.949). The Wilcoxon Signal Post Test was applied to verify if the test and retest values were similar; the general agreement was 4/5 = 80%, indicating high reproducibility. It was concluded that the Portuguese version of the YQOL-FD is adequate for evaluating Quality of Life of Brazilian adolescents with craniofacial deformities.

In recent years inhaled systems have shown momentum as patient-personalized therapies emerge. A significant improvement in terms of therapeutic efficacy and/or reduction adverse systemic effects is anticipated from their use owing these systems regional accumulation. Nevertheless, whatever safety and efficacy evidence required for inhaled formulations regulatory approval, it still poses an additional hurdle to gaining market access. In contrast with the formal intravenous medicines approval, the narrower adoption of pulmonary administration might rely on discrepancies in pre-clinical and clinical data provided by the marketing authorization holder to the regulatory authorities. Evidences of a diverse and inconsistent regulatory framework led to concerns over toxicity issues and respiratory safety. However, an overall trend to support general concepts of good practices exists. Current regulatory guidelines1 that supports PK/PD (pharmacokinetics/pharmacodynamic) assessment seeks attention threatening those inhaled formulations set to be approved in the coming years. A more complex scenario arises from the attempt of implementing nanomedicines for pulmonary administration. Cutting-edge image techniques could play a key role in supporting diverse stages of clinical development facilitating this pharmaceutics take off and speed to patients. The ongoing challenge in adapting conventional regulatory frameworks has proven to be tremendously difficult in an environment where market entry relies on multiple collections of evidence. This paper intention is to remind us that an acceptable pre-clinical toxicological program could emerge from, but not only, an accurate and robust data imaging collection. It is our conviction that if implemented, inhaled nanomedicines might have impact in multiple severe conditions, such as lung cancer, by fulfilling the opportunity for developing tailored treatments while solving dose-related toxicity issues; the most limiting threat in conventional lung cancer clinical management.

Neuroprotection in glaucoma using epoetin beta (EPOβ) has yielded promising results. Our team has developed chitosan-hyaluronic acid nanoparticles (CS/HA) designed to carry EPOβ into the ocular globe, improving the drug’s mucoadhesion and retention time on the ocular surface to increase its bioavailability. In the present in vivo study, we explored the possibility of delivering EPOβ to the eye through subconjunctival administration of chitosan-hyaluronic acid-EPOβ (CS/HA-EPOβ) nanoparticles. Healthy Wistar Hannover rats (n = 21) were split into 7 groups and underwent complete ophthalmological examinations, including electroretinography and microhematocrit evaluations before and after the subconjunctival administrations. CS/HA-EPOβ nanoparticles were administered to the right eye (OD), and the contralateral eye (OS) served as control. At selected timepoints, animals from each group (n = 3) were euthanized, and both eyes were enucleated for histological evaluation (immunofluorescence and HE). No adverse ocular signs, no changes in the microhematocrits (≈45%), and no deviations in the electroretinographies in both photopic and scotopic exams were observed after the administrations (p < 0.05). Intraocular pressure remained in the physiological range during the assays (11–22 mmHg). EPOβ was detected in the retina by immunofluorescence 12 h after the subconjunctival administration and remained detectable until day 21. We concluded that CS/HA nanoparticles could efficiently deliver EPOβ into the retina, and this alternative was considered biologically safe. This nanoformulation could be a promising tool for treating retinopathies, namely optic nerve degeneration associated with glaucoma.

Since the human genome decoding, understanding and identification of genetic disturbances behind many diseases, including cancer, are intensively increasing. Scientific and technological advances in this area trigger the search for therapeutic (curative) approaches targeting the correction of gene disturbances. Gene therapy medicinal products (GTMPs) emerge in this context, bringing new challenges for their characterization. Compared to small molecules, biodistribution is fundamental to identifying target organs and anticipating safety and efficacy, may be integrated into safety and pharmacology studies, and may eventually be anticipated based on specificities of vectors and constructs. This review describes and discusses the requirements for nonclinical development and evaluation of GTMPs versus conventional ones and the needs and challenges of constructing nonclinical packages that assure GTMPs’ human safety from early development, taking into consideration usefulness and/or limitations of many conventional, preclinical models. The experience gained in the European context is referenced.

Hepatocellular carcinoma (HCC) is the most common form of liver cancer. The number of cases is increasing and the trend for the next few years is not encouraging. HCC is usually detected in the advanced stages of the disease, and pharmacological therapies are not entirely effective. For this reason, it is necessary to search for new therapeutic options. The objective of this work was to evaluate the effect of the drugs isotretinoin and thalidomide on c-MYC expression and cancer-related proteins in an HCC cellular model. The expression of c-MYC was measured using RT-qPCR and western blot assays. In addition, luciferase activity assays were performed for the c-MYC promoters P1 and P2 using recombinant plasmids. Dose-response-time analyses were performed for isotretinoin or thalidomide in cells transfected with the c-MYC promoters. Finally, a proteome profile analysis of cells exposed to these two drugs was performed and the results were validated by western blot. We demonstrated that in HepG2 cells, isotretinoin and thalidomide reduced c-MYC mRNA expression levels, but this decrease in expression was linked to the regulation of P1 and P1-P2 c-MYC promoter activity in isotretinoin only. Thalidomide did not exert any effect on c-MYC promoters. Also, isotretinoin and thalidomide were capable of inducing and repressing proteins associated with cancer. In conclusion, isotretinoin and thalidomide down-regulate c-MYC mRNA expression and this is partially due to P1 or P2 promoter activity, suggesting that these drugs could be promising options for modulating the expression of oncogenes and tumor suppressor genes in HCC.