Comparative analysis of sediment quality indices using different reference values in an environmental protection area in Southeastern Brazil.

Contamination of aquatic ecosystems by potentially toxic elements (PTEs) is a concerning environmental issue, given their persistence, toxicity potential, and ability to accumulate in living organisms. Several studies have been conducted to assess the contamination of aquatic ecosystems by PTEs, using pollution and ecological risk indices that rely on the concentration of these elements in aquatic sediments. However, many of these studies use global reference values for calculating the indices, which can lead to misleading interpretations due to substantial variations in PTEs concentrations influenced by the geological characteristics of each region. Therefore, the use of regional reference values is more appropriate when available. This study aimed to investigate variations in the results of five indices, employing global, regional, and quality reference values, based on sediment samples collected from rivers in the Ipanema National Forest, a protected area in Brazil exposed to various anthropogenic pressures. The results revealed that elements such as Al, Fe, and Mn exceeded the limits allowed by legislation in water samples, while As and Cr surpassed the limits in sediment samples. Comparative analysis highlighted significant discrepancies in the results of the indices when global reference values were used compared to regional and quality reference values, especially for As and Ba. Thus, this study underscores the importance of establishing specific regional values for an accurate assessment of sediment quality and the risks associated with contamination by PTEs in different regions worldwide.

The utilisation of primary health care system concepts positively impacts the assistance of patients with rare diseases despite limited knowledge and experience by health care professionals: A qualitative synopsis of the evidence including approximately 78 000 individuals.

Background: Individuals with rare diseases (RD) have been historically understudied. Previous publications reported that existing primary health care (PHC) workforces and associated infrastructure had been shown to improve their access and health-related outcomes in low- and middle-income countries (LMICs). As current evidence about the impact of PHC on patients diagnosed with RD is yet highly dispersed, this scoping review aimed to collate available evidence of the impact of PHC on patients with RD and summarize published information from multiple stakeholders about the perceived usefulness and barriers to effective use of the PHC system. Methods: We searched Embase, Health System Evidence, PubMed, LILACS / BVS, and The Cochrane Library, from inception to September 1, 2022, for publications providing clear expert- or experience-based insights or data from patients living with RD at the PHC level of care. We included publications highlighting barriers to integrated care of patients with RD, reported by multiple social actors involved in caring for patients with RD. Two investigators screened publications, extracted data, and clustered information among records deemed eligible for inclusion. Data synthesis was performed using narrative and thematic-based analysis. Major findings identified and coded through a semantic-driven analysis were processed in vosViewer software and reported using descriptive statistics. Findings: Eighty publications were included in this review. Quali-quantitative analyses evidenced that the PHC level is essential for approaching patients with RD, mainly due to its longitudinal, multidisciplinary, and coordinated care delivery. In addition, several publications highlighted that the medical curriculum is inappropriate for preparing health care providers to deal with patients presenting unusual signs and symptoms and being diagnosed with RD. PHC teams are essential in orienting patients and families on emergency events. Technology-related concepts were reported in 19 publications, emphasizing their effectiveness on early diagnosis, optimal treatment definition, improvement of quality of life, and long-lasting follow-up. Conclusions: We provided valuable information on the effectiveness of the PHC in fostering a creative, integrative, and supportive environment for patients living with RD. Our results can be helpful to several stakeholders in deciding what actions are still pending to achieve a solid and positive experience for patients with RD in the PHC. Registration: PROSPERO (CRD42022332347).

Anti-Citrullinated Protein Antibody Reactivity towards Neutrophil-Derived Antigens: Clonal Diversity and Inter-Individual Variation.

BACKGROUND: Why the adaptive immune system turns against citrullinated antigens in rheumatoid arthritis (RA) and whether anti-citrullinated protein antibodies (ACPAs) contribute to pathogenesis are questions that have triggered intense research, but still are not fully answered. Neutrophils may be crucial in this context, both as sources of citrullinated antigens and also as targets of ACPAs. To better understand how ACPAs and neutrophils contribute to RA, we studied the reactivity of a broad spectrum of RA patient-derived ACPA clones to activated or resting neutrophils, and we also compared neutrophil binding using polyclonal ACPAs from different patients. METHODS: Neutrophils were activated by Ca2+ ionophore, PMA, nigericin, zymosan or IL-8, and ACPA binding was studied using flow cytometry and confocal microscopy. The roles of PAD2 and PAD4 were studied using PAD-deficient mice or the PAD4 inhibitor BMS-P5. RESULTS: ACPAs broadly targeted NET-like structures, but did not bind to intact cells or influence NETosis. We observed high clonal diversity in ACPA binding to neutrophil-derived antigens. PAD2 was dispensable, but most ACPA clones required PAD4 for neutrophil binding. Using ACPA preparations from different patients, we observed high patient-to-patient variability in targeting neutrophil-derived antigens and similarly in another cellular effect of ACPAs, the stimulation of osteoclast differentiation. CONCLUSIONS: Neutrophils can be important sources of citrullinated antigens under conditions that lead to PAD4 activation, NETosis and the extrusion of intracellular material. A substantial clonal diversity in targeting neutrophils and a high variability among individuals in neutrophil binding and osteoclast stimulation suggest that ACPAs may influence RA-related symptoms with high patient-to-patient variability.

Identification of proteinase 3 autoreactive CD4+T cells and their T-cell receptor repertoires in antineutrophil cytoplasmic antibody-associated vasculitis.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is an autoimmune disease involving autoreactivity to proteinase 3 (PR3) as demonstrated by presence of ANCAs. While autoantibodies are screened for diagnosis, autoreactive T cells and their features are less well-studied. Here, we investigated PR3-specific CD4+T cell responses and features of autoreactive T cells in patients with PR3-AAV, using a cohort of 72 patients with either active or inactive disease. Autoreactive PR3-specific CD4+T cells producing interferon γ in response to protein stimulation were found to express the G-protein coupled receptor 56 (GPR56), a cell surface marker that distinguishes T cells with cytotoxic capacity. GPR56+CD4+T cells were significantly more prominent in the blood of patients with inactive as compared to active disease, suggesting that these cells were affected by immunosuppression and/or that they migrated from the circulation to sites of organ involvement. Indeed, GPR56+CD4+T cells were identified in T-cell infiltrates of affected kidneys and an association with immunosuppressive therapy was found. Moreover, distinct TCR gene segment usage and shared (public) T cell clones were found for the PR3-reactive TCRs. Shared T cell clones were found in different patients with AAV carrying the disease-associated HLA-DP allele, demonstrating convergence of the autoreactive T cell repertoire. Thus, we identified a CD4+T cell signature in blood and in affected kidneys that display PR3 autoreactivity and associates with T cell cytotoxicity. Our data provide a basis for novel rationales for both immune monitoring and future therapeutic intervention in PR3-AAV.

Naview: A d3.js Based JavaScript Library for Drawing and Annotating Voltage-Gated Sodium Channels Membrane Diagrams.

Voltage-gated sodium channels (Nav) are membrane proteins essential to initiating and propagating action potential in neurons and other excitable cells. For a given organism there are often multiple, specialized sodium channels found in different tissues, whose mutations can cause deleterious effects observed in numerous diseases. Consequently, there is high medical and pharmacological interest in these proteins. Scientific literature often uses membrane diagrams to depict important patterns in these channels including the six transmembrane segments (S1-S6) present in four different homologous domains (D1-D4), the S4 voltage sensors, the pore-lining residue segments and the ion selectivity filter residues, glycosylation and phosphorylation residues, toxin binding sites and the inactivation loop, among others. Most of these diagrams are illustrated either digitally or by hand and programs specifically dedicated to the interactive and data-friendly generation of such visualizations are scarce or non-existing. This paper describes Naview, an open-source javascript visualization compatible with modern web browsers for the dynamic drawing and annotation of voltage-gated sodium channels membrane diagrams based on the D3.js library. By using a graphical user interface and combining user-defined annotations with optional UniProt code as inputs, Naview allows the creation and customization of membrane diagrams. In this interface, a user can also map and display important sodium channel properties, residues, regions and their relationships through symbols, colors, and edge connections. Such features can facilitate data exploration and provide fast, high-quality publication-ready graphics for this highly active area of research.

PDBe and PDBe-KB: Providing high-quality, up-to-date and integrated resources of macromolecular structures to support basic and applied research and education.

The archiving and dissemination of protein and nucleic acid structures as well as their structural, functional and biophysical annotations is an essential task that enables the broader scientific community to conduct impactful research in multiple fields of the life sciences. The Protein Data Bank in Europe (PDBe; pdbe.org) team develops and maintains several databases and web services to address this fundamental need. From data archiving as a member of the Worldwide PDB consortium (wwPDB; wwpdb.org), to the PDBe Knowledge Base (PDBe-KB; pdbekb.org), we provide data, data-access mechanisms, and visualizations that facilitate basic and applied research and education across the life sciences. Here, we provide an overview of the structural data and annotations that we integrate and make freely available. We describe the web services and data visualization tools we offer, and provide information on how to effectively use or even further develop them. Finally, we discuss the direction of our data services, and how we aim to tackle new challenges that arise from the recent, unprecedented advances in the field of structure determination and protein structure modeling.

Dense optical flow software to quantify cellular contractility.

Cell membrane deformation is an important feature that occurs during many physiological processes, and its study has been put to good use to investigate cardiomyocyte function. Several methods have been developed to extract information on cardiomyocyte contractility. However, no existing computational framework has provided, in a single platform, a straightforward approach to acquire, process, and quantify this type of cellular dynamics. For this reason, we develop CONTRACTIONWAVE, high-performance software written in Python programming language that allows the user to process large data image files and obtain contractility parameters by analyzing optical flow from images obtained with videomicroscopy. The software was validated by using neonatal, adult-, and human-induced pluripotent stem-cell-derived cardiomyocytes, treated or not with drugs known to affect contractility. Results presented indicate that CONTRACTIONWAVE is an excellent tool for examining changes to cardiac cellular contractility in animal models of disease and for pharmacological and toxicology screening during drug discovery.

O impacto da pandemia pela COVID-19 na saúde mental: qual é o papel da Atenção Primária à Saúde? / The impact of COVID-19 pandemic on mental health: what is the role of Primary Health Care? / El impacto de la pandemia de la COVID-19 en la salud mental: ¿cuál es el rol de la Atención Primaria de Salud?

Introdução: Em momentos como a pandemia causada pela COVID-19, há evidências de que a morbimortalidade relacionada à saúde mental tende a superar a relacionada diretamente à infecção, sendo resultado da própria pandemia e também das medidas de distanciamento social. Objetivo:Apresentar uma proposta para a atuação das equipes de Atenção Primária no enfrentamento ao adoecimento mental relacionado à pandemia. Métodos: Revisando os fatores de risco e estressores, e resgatando os atributos e potencialidades da atenção primária à saúde, foi escrito um ensaio científico apresentando propostas do papel da APS. Resultados e Discussão: Os principais fatores de risco para adoecimento mental identificados incluem: vulnerabilidade social, contrair a doença ou conviver com alguém infectado, existência de transtorno mental prévio, ser idoso e ser profissional de saúde. O isolamento físico e o excesso de informações nem sempre confiáveis somam estressores à crise. As especificidades do luto durante a pandemia também aumentam o risco de lutos complicados. No contexto brasileiro, há ainda a crise político-institucional aumentando a ansiedade e insegurança da população. Propõe-se que a Atenção Primária à Saúde, com suas características e atributos, deve: identificar as famílias com risco aumentado para adoecimento mental; articular intersetorialmente para que as demandas dos mais vulneráveis sejam atendidas; orientar a população sobre como minimizar os fatores geradores de ansiedade; apoiar as famílias para possibilitar o processo de luto. Conclusões: Este ensaio pretende qualificar a discussão sobre o papel da APS na saúde mental da população e, portanto, subsidiar ações que potencializem o cuidado prestado pelas equipes durante a pandemia de COVID-19.

Introduction: At times like the COVID-19 pandemic, there is evidence that mental health-related morbidity and mortality tends to overcome that directly related to infection, resulting from the pandemic itself and also from measures of social distance. Objective: To present a proposal for primary care teams in dealing with the population's mental health issues related to the pandemic. Methods: Reviewing the risk factors and stressors and recovering the attributes and potential of primary health care, an essay was written with proposals for the role of primary care. Results and Discussion: The main risk factors for mental distress include social vulnerability, contracting the disease or living with someone infected, existence of a previous mental disorder, being elderly or being a health professional. Social isolation and excessive and unreliable information are adding stressors to the crisis. The specifics of bereavement during the pandemic also increase the risk of complicated bereavement. In the Brazilian context, there is still the institutional political crisis increasing the population's anxiety. It is recommended that primary health care, with its characteristics and attributes, should: identify families at increased risk for mental illness; articulate intersectorally so that the demands of the most vulnerable are met; guide the population on how to minimize the factors that generate anxiety; support families to enable the grieving process. Conclusions: This essay intends to qualify the discussion about the role of PHC in attending to the population's mental health needs and, therefore, to subsidize actions that enhance the care provided by the teams during the COVID-19 pandemic.

Introducción: En momentos como la pandemia de la COVID-19, hay evidencias de que la morbilidad y mortalidad relacionada con la salud mental tienden a superar las relacionadas directamente con la infección, como resultado de la pandemia en sí y también de las medidas de aislamiento social. Objetivo: Presentar una propuesta para el desempeño de los equipos de atención primaria en la administración de enfermedades mentales relacionadas con la pandemia. Método: Revisando los factores de riesgo y factores estresantes, y rescatando los atributos y la potencialidad de la atención primaria de salud (APS), se desarrolló un ensayo científico presentando propuestas para el rol de las APS. Resultados y Discusión: Los principales factores de riesgo para la enfermedad mental identificados incluyen: vulnerabilidad social, contraer la enfermedad o vivir con alguien infectado, existencia de un trastorno mental previo, ser mayor y ser un profesional de la salud. El aislamiento físico y la información excesiva no siempre confiables agregan estresores a la crisis. Las especificidades del duelo durante la pandemia también aumentan el riesgo de estados de lutos complicados. En el contexto brasileño, aún hay la crisis política e institucional que aumenta la ansiedad y la inseguridad de la población. Se propone que la atención primaria de salud, con sus características y atributos, debe: identificar a las familias con mayor riesgo de aumento de la enfermedad mental; articularse intersectorialmente para que se cumplan las demandas de los más vulnerables; guiar a la población sobre cómo minimizar los factores que generan ansiedad; apoyar a las familias para permitir el proceso de duelo. Conclusión: Este ensayo tiene la intención de calificar la discusión sobre el rol de la APS en la salud mental de la población y, por lo tanto, subvencionar acciones que mejoren el cuidado prestado por los equipos de la salud durante la pandemia de la COVID-19.

Recomendações para a qualidade dos Programas de Residência de Medicina de Família e Comunidade no Brasil / Recomendaciones para la calidad de los programas de residencia en medicina familiar y comunitaria en Brasil / Recommendations for the quality of Family Medicine Residency Programs in Brazil

Diante de mudanças recentes no panorama nacional de programas de incentivos para provimento e formação médica em Atenção Primária à Saúde (APS), o Grupo de Trabalho de Ensinagem da SBMFC organizou um Encontro Nacional entre os dias 29 de novembro e 1º de dezembro de 2019, na cidade do Rio de Janeiro/RJ. O evento reuniu professores, supervisores, preceptores e residentes de Medicina de Família e Comunidade de diferentes regiões do país, e teve como objetivos discutir o atual cenário, além de elencar recomendações para qualidade dos PRMFC e caminhos para o fortalecimento da formação de médicas e médicos de família e comunidade via Residência Médica. Essas recomendações buscaram considerar a diversidade dos PRMFC em um país tão vasto quanto o Brasil e, principalmente, a necessidade de se estabelecer parâmetros mínimos de organização para os programas das mais variadas configurações, como PRMFC vinculados a Instituições de Ensino Superior (IES), secretarias estaduais ou municipais de saúde. As recomendações foram então organizadas em três eixos: 1) recomendações para supervisores e coordenadores de PRMFC e modelos possíveis de preceptoria; 2) recomendações para formuladores e executores de políticas públicas; e 3) recomendações para lideranças da medicina de família e comunidade.

Facing recent changes in the national panorama of incentive programs for provision and medical training in Primary Health Care, the Education Work Group of the SBMFC organized a National Meeting between November 29th and December 1st, 2019, in the city of Rio de Janeiro-RJ. The event brought together professors, supervisors, tutors and residents of Family and Community Medicine from different regions of the country, to discuss the current scenario, in addition to listing both benchmark recommendations for the quality of Residency Programs in Family and Community Medicine (RPFCM) and paths for strengthening the training of family and community doctors through Medical Residency. These recommendations sought to consider the diversity of RPFCM in a country as vast as Brazil and, mainly, the urge to establish the minimum organizational parameters for programs of the most varied configurations, such as: RPFCMs linked to higher education institutions (HEIs), state or municipal health departments. The recommendations were then organized into three axes: 1) recommendations for supervisors and coordinators and possible models of preceptorship; 2) recommendations for public policy makers and executors; and 3) recommendations for family medicine community leaders.

Primaria de Salud, el Grupo de Trabajo Docente de la SBMFC organizó una Reunión Nacional entre el 29 de noviembre y el 1 de diciembre de 2019, en la ciudad de Río de Janeiro - RJ. El evento reunió a profesores, supervisores, preceptores y residentes de medicina familiar y comunitaria de diferentes regiones del país, y tuvo como objetivo discutir el escenario actual, además de enumerar recomendaciones para la calidad de los programas de residencia médica en medicina familiar y comunitaria (PRMFC) y formas de fortalecer la formación de médicas y médicos de familia y comunidad través de residencia médica. Estas recomendaciones buscaron considerar la diversidad de PRMFC en un país tan vasto como Brasil y, principalmente, la necesidad de establecer parámetros organizacionales mínimos para programas de las más variadas configuraciones, tales como PRMFC vinculados a instituciones de educación superior (IES), departamentos de salud estatales o municipales. Las recomendaciones se organizaron en tres ejes: 1) recomendaciones para supervisores y coordinadores de PRMFC y posibles modelos de preceptoría; 2) recomendaciones para encargados de la formulación de políticas públicas y ejecutores; y 3) recomendaciones para los líderes de la medicina familiar y comunitaria.

Coevolved Positions Represent Key Functional Properties in the Trypsin-Like Serine Proteases Protein Family.

Trypsin-like serine proteases are a group of homologous enzymes which exert multiple roles in both vertebrate and invertebrate organisms. Key properties of these enzymes include their activation from an inactive zymogen form to their active form by cleavage of residues in their N-terminus, the presence of a conserved catalytic triad of residues, and the existence of different patterns of substrate selectivity for residue cleavage between the various members of this protein family. In this article, we apply the decomposition of residue coevolution networks computational method to find sets of residues related to some of these key properties, especially to zymogen activation. Positive selection detection, normal modes analysis, and the calculation of thermal couplings between the bovine trypsinogen and bovine trypsin structures residues yielded further information for understanding the zymogen activation process and highlighted the importance of some of the coevolved set residues during these transitions.

Advancements and achievements in the Brazilian Federal District public health: an essential contribution by family and community medicine. / Avanços e conquistas na saúde pública do DF, Brasil: uma contribuição essencial da medicina de família e comunidade.

The history of Primary Health Care (PHC) in the Federal District (DF) is as old as the history of the Federative Unit. The history of Family and Community Medicine (MFC), however, is relatively recent, both locally and nationally. This paper proposes to focus on the fundamental contribution of MFC to advances in Public Health in the Federal District, especially in the last 10 years, after the founding of the Family and Community Medicine Association of Brasília (ABMFC). In order to do so, the most relevant historical events and contexts related to Health Care, Management, Social Control and Medical Education - including Undergraduate course and Residency - were documented, which support this position, in parallel with the evolution of the specialty in the Federal District. Therefore, its organization was divided into four historical stages: until 2008, from 2008 to 2011, from 2011 to 2016, and from 2016 to 2018.

A história da Atenção Primária à Saúde (APS) no Distrito Federal (DF) é tão antiga quanto a história da unidade federativa. A história da especialidade Medicina de Família e Comunidade (MFC), porém, é relativamente recente, tanto em âmbito local como nacional. O presente artigo se propõe a focar na fundamental contribuição da MFC para os avanços na Saúde Pública do DF, sobretudo nos últimos 10 anos, após a fundação da Associação Brasiliense de Medicina de Família e Comunidade (ABMFC). Para tanto, foram rememorados os eventos e os contextos históricos mais relevantes, relacionados às áreas de Assistência à Saúde, Gestão, Controle Social e Ensino Médico ­ incluindo Graduação e Residência ­, que embasam essa posição, paralelamente à evolução da própria especialidade no DF. Sua organização foi, portanto, dividida em quatro etapas históricas: até 2008, de 2008 a 2011, de 2011 a 2016, e de 2016 até 2018.

Avanços e conquistas na saúde pública do DF, Brasil: uma contribuição essencial da medicina de família e comunidade / Advancements and achievements in the Brazilian Federal District public health: an essential contribution by family and community medicine

Resumo A história da Atenção Primária à Saúde (APS) no Distrito Federal (DF) é tão antiga quanto a história da unidade federativa. A história da especialidade Medicina de Família e Comunidade (MFC), porém, é relativamente recente, tanto em âmbito local como nacional. O presente artigo se propõe a focar na fundamental contribuição da MFC para os avanços na Saúde Pública do DF, sobretudo nos últimos 10 anos, após a fundação da Associação Brasiliense de Medicina de Família e Comunidade (ABMFC). Para tanto, foram rememorados os eventos e os contextos históricos mais relevantes, relacionados às áreas de Assistência à Saúde, Gestão, Controle Social e Ensino Médico - incluindo Graduação e Residência -, que embasam essa posição, paralelamente à evolução da própria especialidade no DF. Sua organização foi, portanto, dividida em quatro etapas históricas: até 2008, de 2008 a 2011, de 2011 a 2016, e de 2016 até 2018.

Abstract The history of Primary Health Care (PHC) in the Federal District (DF) is as old as the history of the Federative Unit. The history of Family and Community Medicine (MFC), however, is relatively recent, both locally and nationally. This paper proposes to focus on the fundamental contribution of MFC to advances in Public Health in the Federal District, especially in the last 10 years, after the founding of the Family and Community Medicine Association of Brasília (ABMFC). In order to do so, the most relevant historical events and contexts related to Health Care, Management, Social Control and Medical Education - including Undergraduate course and Residency - were documented, which support this position, in parallel with the evolution of the specialty in the Federal District. Therefore, its organization was divided into four historical stages: until 2008, from 2008 to 2011, from 2011 to 2016, and from 2016 to 2018.

A new method bridging graph theory and residue co-evolutionary networks for specificity determinant positions detection.

MOTIVATION: Computational studies of molecular evolution are usually performed from a multiple alignment of homologous sequences, on which sequences resulting from a common ancestor are aligned so that equivalent residues are placed in the same position. Residues frequency patterns of a full alignment or from a subset of its sequences can be highly useful for suggesting positions under selection. Most methods mapping co-evolving or specificity determinant sites are focused on positions, however, they do not consider the case for residues that are specificity determinants in one subclass, but variable in others. In addition, many methods are impractical for very large alignments, such as those obtained from Pfam, or require a priori information of the subclasses to be analyzed. RESULTS: In this paper we apply the complex networks theory, widely used to analyze co-affiliation systems in the social and ecological contexts, to map groups of functional related residues. This methodology was initially evaluated in simulated environments and then applied to four different protein families datasets, in which several specificity determinant sets and functional motifs were successfully detected. AVAILABILITY AND IMPLEMENTATION: The algorithms and datasets used in the development of this project are available on http://www.biocomp.icb.ufmg.br/biocomp/software-and-databases/networkstats/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

PFstats: A Network-Based Open Tool for Protein Family Analysis.

PFstats is a software developed for the extraction of useful information from protein multiple sequence alignments. By analyzing positional conservation and residue coevolution networks, the software allows the identification of structurally and functionally important residue groups and the discovery of probable functional subclasses. Furthermore, it contains tools for the identification of the possible biological significance of these findings. PFstats contains methods for maximizing the significance of alignments through filtering and weighting, residue conservation and coevolution analysis, automatic UniprotKb queries for residue-position annotation and many possible data visualization methods.

Association between hospitalisation for ambulatory care-sensitive conditions and primary health care physician specialisation: a cross-sectional ecological study in Curitiba (Brazil).

INTRODUCTION: Hospitalisation for ambulatory care-sensitive conditions (HACSCs) is frequently used as an indicator of the quality and effectiveness of primary healthcare (PHC) services around the world. The aim of the present study was to evaluate whether the PHC model (family health strategy (FHS) x conventional) and the availability of specialised PHC physicians is associated or not with total hospitalisation or HACSCs in the National Health System (SUS) of the municipality of Curitiba, Paraná state (PR), Brazil. METHODOLOGY: This is a cross-sectional ecological study using multiple linear regression with socioeconomic and professional data from municipal health units (MHUs) between 1 April 2014 and 31 March 2015. RESULTS: After adjustment for age and sex and control of socioeconomic variables, the FHS model was associated with six fewer HACSCs a year per 10 000 inhabitants in relation to the conventional model and the availability of one family physician at each FHS model MHU per 10 000 inhabitants was associated with 1.1 fewer HACSCs for heart failure a year per 10 000 inhabitants. Basic specialists (clinicians, paediatricians and obstetrician/gynaecologists) and subspecialists showed no significant association with HACSC rates. CONCLUSION: These results obtained in a major Brazilian city reinforce the role of FHS as a priority PHC model in the country and indicate the potentially significant impact of specialising in family medicine on improving the health conditions of the population.

Sequence, structure and function relationships in flaviviruses as assessed by evolutive aspects of its conserved non-structural protein domains.

Flaviviruses are responsible for serious diseases such as dengue, yellow fever, and zika fever. Their genomes encode a polyprotein which, after cleavage, results in three structural and seven non-structural proteins. Homologous proteins can be studied by conservation and coevolution analysis as detected in multiple sequence alignments, usually reporting positions which are strictly necessary for the structure and/or function of all members in a protein family or which are involved in a specific sub-class feature requiring the coevolution of residue sets. This study provides a complete conservation and coevolution analysis on all flaviviruses non-structural proteins, with results mapped on all well-annotated available sequences. A literature review on the residues found in the analysis enabled us to compile available information on their roles and distribution among different flaviviruses. Also, we provide the mapping of conserved and coevolved residues for all sequences currently in SwissProt as a supplementary material, so that particularities in different viruses can be easily analyzed.

Serum levels of soluble TNF-a receptors but not BDNF are associated with apathy symptoms in mild Alzheimer's disease and amnestic mild cognitive impairment / Níveis Séricos de receptores Solúveis Do TNF-a mas não de BDNF estão associados a sintomas de apatia na doença de Alzheimer leve e no comprometimento cognitivo leve amnéstico

Apathy is intimately associated with dementia. Unfortunately, its pathophysiology remains poorly understood. The motivational impairment that characterizes this disorder might share the same inflammatory mechanisms, as suggested by the sickness behavior theory. OBJECTIVE: The primary aim of this study was to investigate the association between apathy symptoms and serum levels of tumor necrosis factor alpha (TNF-a) and its soluble receptors. Brain-derived neurotrophic factor (BDNF) levels were also analyzed since these have been associated with depression, a condition which shares abulic features with apathy. METHODS: The sample consisted of 27 subjects with mild Alzheimer's disease or amnestic mild cognitive impairment, who were submitted to specific apathy evaluation using the Apathy Scale (AS) and provided blood samples for biomarker analysis. Participants were categorized into two groups according to median AS scores (17 points). RESULTS: Subjects with higher apathy symptoms (n=13) displayed higher levels of TNF-a soluble receptors (type 1: p=0.03; type 2: p=0.04). No other difference was found between groups. CONCLUSION: These findings point to the involvement of inflammatory mediators in the genesis of apathy symptoms, as suggested by the sickness behavior theory.

Apatia está intimamente associada à demência. Lamentavelmente, sua fisiopatologia ainda é pouco compreendida. O comprometimento motivacional que caracteriza este transtorno poderia compartilhar mecanismos inflamatórios como sugere a teoria do comportamento associado à doença. OBJETIVO: O principal objetivo deste estudo foi investigar a associação entre apatia e os níveis séricos do fator de necrose tumoral alfa (TNF-a) e de seus receptores solúveis. Os níveis de fator neurotrófico derivado do cérebro também foram analisados já que estes foram associados à depressão, que compartilha aspectos abúlicos com a apatia. MÉTODOS: A amostra consistiu de 27 indivíduos com doença de Alzheimer leve ou com comprometimento cognitivo leve amnéstico, que foram submetidos à avaliação de apatia pela Escala de Apatia (EA), e proveram amostra de sangue para análise de biomarcadores. De acordo com a mediana de escores na EA (17 pontos), a amostra foi divida em dois grupos. RESULTADOS: O grupo com mais sintomas de apatia apresentou maiores níveis séricos de receptores solúveis de TNF-a (tipo 1: p=0,03 ; tipo 2: p=0,04). Nenhuma outra diferença foi encontrada entre os grupos.CONCLUSÃO: Estes achados sugerem o envolvimento de mediadores inflamatórios na gênese de sintomas de apatia, assim como sugere a teoria do comportamento associado à doença.

Residue correlation networks in nuclear receptors reflect functional specialization and the formation of the nematode-specific P-box.

BACKGROUND: Nuclear receptors (NRs) are transcription factors which bind small hormones, whose evolutionary history and the presence of different functional surfaces makes them an interesting target for a correlation based analysis. RESULTS: Correlation analysis of ligand binding domains shows that correlated residue subsets arise from the differences between functional sites in different nuclear receptor subfamilies. For the DNA binding domain, particularly, the analysis shows that the main source of correlation comes from residues that regulate hormone response element specificity, and one of the conserved residue sub-sets arises due to the presence of an unusual sequence for the DNA binding motif known as P-box in nematodes, suggesting the existence of different DBD-DNA specificities in nuclear receptors. CONCLUSIONS: We conclude that DNA specificity and functional surface specialization has independently driven nuclear receptor evolution, and suggest possible binding modes for the class of divergent nuclear receptors in nematodes.

Serum levels of soluble TNF-α receptors but not BDNF are associated with apathy symptoms in mild Alzheimer's disease and amnestic mild cognitive impairment.

Apathy is intimately associated with dementia. Unfortunately, its pathophysiology remains poorly understood. The motivational impairment that characterizes this disorder might share the same inflammatory mechanisms, as suggested by the sickness behavior theory. OBJECTIVE: The primary aim of this study was to investigate the association between apathy symptoms and serum levels of tumor necrosis factor alpha (TNF-α) and its soluble receptors. Brain-derived neurotrophic factor (BDNF) levels were also analyzed since these have been associated with depression, a condition which shares abulic features with apathy. METHODS: The sample consisted of 27 subjects with mild Alzheimer's disease or amnestic mild cognitive impairment, who were submitted to specific apathy evaluation using the Apathy Scale (AS) and provided blood samples for biomarker analysis. Participants were categorized into two groups according to median AS scores (17 points). RESULTS: Subjects with higher apathy symptoms (n=13) displayed higher levels of TNF-α soluble receptors (type 1: p=0.03; type 2: p=0.04). No other difference was found between groups. CONCLUSION: These findings point to the involvement of inflammatory mediators in the genesis of apathy symptoms, as suggested by the sickness behavior theory.

Apatia está intimamente associada à demência. Lamentavelmente, sua fisiopatologia ainda é pouco compreendida. O comprometimento motivacional que caracteriza este transtorno poderia compartilhar mecanismos inflamatórios como sugere a teoria do comportamento associado à doença. OBJETIVO: O principal objetivo deste estudo foi investigar a associação entre apatia e os níveis séricos do fator de necrose tumoral alfa (TNF-α) e de seus receptores solúveis. Os níveis de fator neurotrófico derivado do cérebro também foram analisados já que estes foram associados à depressão, que compartilha aspectos abúlicos com a apatia. MÉTODOS: A amostra consistiu de 27 indivíduos com doença de Alzheimer leve ou com comprometimento cognitivo leve amnéstico, que foram submetidos à avaliação de apatia pela Escala de Apatia (EA), e proveram amostra de sangue para análise de biomarcadores. De acordo com a mediana de escores na EA (17 pontos), a amostra foi divida em dois grupos. RESULTADOS: O grupo com mais sintomas de apatia apresentou maiores níveis séricos de receptores solúveis de TNF-α (tipo 1: p=0,03 ; tipo 2: p=0,04). Nenhuma outra diferença foi encontrada entre os grupos. CONCLUSÃO: Estes achados sugerem o envolvimento de mediadores inflamatórios na gênese de sintomas de apatia, assim como sugere a teoria do comportamento associado à doença.