The effect of thioredoxin-1 in a rat model of traumatic brain injury depending on diurnal variation.

INTRODUCTION: Traumatic brain injury (TBI) is a public health concern with limited treatment options because it causes a cascade of side effects that are the leading cause of hospital death. Thioredoxin is an enzyme with neuroprotective properties such as antioxidant, antiapoptotic, immune response modulator, and neurogenic, among others; it has been considered a therapeutic target for treating many disorders. METHODS: The controlled cortical impact (CCI) model was used to assess the effect of recombinant human thioredoxin 1 (rhTrx1) (1 µg/2 µL, intracortical) on rats subjected to TBI at two different times of the light-dark cycle (01:00 and 13:00 h). We analyzed the food intake, body weight loss, motor coordination, pain perception, and histology in specific hippocampus (CA1, CA2, CA3, and Dental Gyrus) and striatum (caudate-putamen) areas. RESULTS: Body weight loss, reduced food intake, spontaneous pain, motor impairment, and neuronal damage in specific hippocampus and striatum regions are more evident in rats subjected to TBI in the light phase than in the dark phase of the cycle and in groups that did not receive rhTrx1 or minocycline (as positive control). Three days after TBI, there is a recovery in body weight, food intake, motor impairment, and pain, which is more pronounced in the rats subjected to TBI at the dark phase of the cycle and those that received rhTrx1 or minocycline. CONCLUSIONS: Knowing the time of day a TBI occurs in connection to the neuroprotective mechanisms of the immune response in diurnal variation and the usage of the Trx1 protein might have a beneficial therapeutic impact in promoting quick recovery after a TBI.

Characterization of the rat pituitary capsule: Evidence that the cerebrospinal fluid filled the pituitary cleft and the inner side of the capsule.

In humans, the pituitary gland is covered by a fibrous capsule and is considered a continuation of the meningeal sheath. However, in rodents some studies concluded that only the pars tuberalis (PT) and pars nervosa (PN) are enwrapped by the pia mater, while others showed that the whole gland is covered by this sheath. At PT the median eminence subarachnoid drains cerebrospinal fluid (CSF) to its cisternal system representing a pathway to the hypothalamus. In the present study we examined the rat pituitary capsule to elucidate its configuration, its physical interaction with the pituitary border and its relationship with the CSF. Furthermore, we also revisited the histology of the pituitary cleft and looked whether CSF drained in it. To answer such questions, we used scanning and transmission electron microscopy, intracerebroventricular infusion of Evan´s blue, fluorescent beads, and sodium fluorescein. The latter was measured in the pars distalis (PD) and various intracranial tissues. We found a pituitary capsule resembling leptomeninges, thick at the dorsal side of the pars intermedia (PI) and PD, thicker at the level of PI in contiguity with the PN and thinner at the rostro-ventral side as a thin membrane of fibroblast-like cells embedded in a fibrous layer. The capsule has abundant capillaries on all sides. Our results showed that the CSFs bathe between the capsule and the surface of the whole gland, and ciliate cells are present in the pituitary border. Our data suggest that the pituitary gland intercommunicates with the central nervous system (CNS) through the CSF.

Quality of life in children and adolescents with hemophilia A: A systematic review and meta-analysis.

Background: Various instruments have been used to assess health-related quality of life (HRQoL) in children and adolescents with hemophilia A. Objective: We systematically reviewed the literature to summarize HRQoL measurement instruments and outcomes in this population. Methods: MEDLINE, Embase, Cochrane CENTRAL, and LILACS databases were searched. Studies published from 2010 to 2021, reporting HRQoL assessed by generic or hemophilia-specific instruments in individuals aged 0 to 18 years were included. Two independent reviewers performed screening, selection, and data abstraction. Data were meta-analyzed using the generic inverse variance method with the random-effects model for single-arm studies reporting instrument-specific mean total HRQoL scores. Prespecified subgroup meta-analyses were performed. Heterogeneity among studies was assessed using the I 2 statistic. Results: Six instruments were identified in 29 studies meeting the following inclusion criteria: 4 generic instruments (PedsQL [5 studies], EQ-5D-3L [3 studies], KIDSCREEN-52 [1 study], and KINDL [1 study]) and 2 hemophilia-specific instruments (Haemo-QoL [17 studies] and CHO-KLAT [3 studies]). The overall risk of bias was moderate to low. There was a substantial variability in the primary outcome (mean total HRQoL score) among studies using the same instrument (Haemo-QoL), with scores ranging from 24.10 to 89.58 on a scale from 0 to 100 (higher scores indicating higher HRQoL). Meta-regression with 14 studies using the Haemo-QoL questionnaire demonstrated that 79.34% (R 2 ) of the observed 94.67% total heterogeneity (I 2 ) was explained by the proportion of patients receiving effective prophylactic treatment. Conclusion: HRQoL assessment in young people with hemophilia A is heterogeneous and context specific. The proportion of patients on effective prophylactic treatment is positively correlated with HRQoL. The review protocol was registered prospectively with PROSPERO (CRD42021235453).

Analysis of epidemiological and economic data of hemophilia A patients in Brazil / Análise de dados epidemiológicos e econômicos de pacientes com hemofilia A no Brasil

Objective: To describe the annual medical direct costs per hemophilia A (HA) patient in the Brazilian public healthcare system (SUS) and to understand and describe the patients' hospital journey, demographical characteristics, and the procedures in the. Methods: This retrospective analysis of DataSUS databases. Data from individuals with registries of HA treatment were gathered between January 1st, 2018, and June 30th, 2021. Besides the D66 ICD-10th code (HA), were also considered the occurrence of some procedures like factor VIII dosage and by-pass therapy dispensation or administration as inclusion criteria. Exclusion criteria were occurrence of factor IX dispensation and female patients were excluded, among others. A record linkage using sociodemographic characteristics was conducted to identify unique patients. Results: Were identified 2,298 individuals underwent ambulatory and 1,018 underwent hospital treatments. The results show that most patients are from the Southeast region of the country, white and middle-aged individuals. The median cost of HA treatment per patient-year was BRL 90.36 for ambulatory care and BRL 1,015.31 for hospital care procedures. The costs were significantly higher for more severe patients and for those between 12 and 18 years old (BRL 1,974.75 and BRL 1,049.09, respectively). Conclusion: The evidence demonstrated encourages the implementation of policies aiming to improve the quality of care provided to patients with HA. Providing referral centers for hemophiliac patients is primordial for the success of the treatment and can result in efficiency.

Objetivo: Descrever os custos médicos diretos anuais por paciente com hemofilia A (HA) no sistema público de saúde brasileiro (SUS) e compreender e descrever a jornada do paciente em âmbito hospitalar, as características demográficas e os procedimentos realizados no SUS. Métodos: Análise retrospectiva das bases de dados do DataSUS. Foram coletados dados de indivíduos com registro de tratamento de HA entre 1º de janeiro de 2018 e 30 de junho de 2021. Além do código D66 CID-10 (HA), foi considerada a ocorrência de procedimentos como dosagem do fator VIII e dispensação ou administração de terapia de by-pass como critérios de inclusão. Dentre os critérios de exclusão, destacam-se a dispensação do fator IX e indivíduos do sexo feminino. Um pareamento de registros usando características sociodemográficas foi realizado para identificar pacientes únicos. Resultados: Foram identificados 2.298 indivíduos em tratamento ambulatorial e 1.018 em tratamento hospitalar. Os resultados mostraram que a maioria dos pacientes são da região Sudeste do país, brancos e de meia-idade. O custo médio do tratamento da HA por paciente-ano foi de R$ 90,36 para atendimento ambulatorial e de R$ 1.015,31 para atendimento hospitalar. Os custos foram significativamente maiores para pacientes mais graves e entre 12 e 18 anos (R$ 1.974,75 e R$ 1.049,09, respectivamente). Conclusão: As evidências demonstradas incentivam a implementação de políticas que visem melhorar a qualidade da assistência prestada aos pacientes com HA. A disponibilização de centros de referência para pacientes hemofílicos é primordial para o sucesso do tratamento e pode resultar em maior eficiência.

Statements about hemophilia A in Brazil: an expert Delphi panel / Consensos em hemofilia A no Brasil: painel Delphi de especialistas

Objective: Understanding unmet needs related to hemophilia A management in Brazil is critical for supporting decision-making. Methods: A modified Delphi consensus panel was conducted. Hematologists with extensive experience treating hemophilia in the Brazilian Public Health System were invited to answer questions regarding indicators of severe hemophilia prophylaxis effectiveness, emicizumab treatment indications, and bypassing agents used to reduce bleeding in patients with inhibitors, immune tolerance induction (ITI) use, and adherence. The consensus was defined as ≥75% of votes in Round 1 or using a 5-point Likert-type scale (1 = strongly disagree, 2 = disagree, 3 = neither agree nor disagree, 4 = agree, and 5 = strongly agree) in Round 2, which included questions not reaching minimum cut-off in the first step. Results: Nine expert panelists with extensive experience in the Brazilian Public Health System participated. The panel reached an agreement on recommendations about prophylaxis, bleeding treatment patterns, and bleeding sites. From patients' perspectives, venous access and infusion frequency were the most significant barriers to improving patient treatment. According to most experts, emicizumab will not replace ITI or long-term factor VIII therapy. Still, emicizumab was thought to be a good therapeutic option for patients with difficult venous access, patients requiring central venous access, in the presence of inhibitors, or patients experiencing infusion-related pain. Conclusion: The information gleaned from this study may be helpful to both decision-makers and those in charge of developing healthcare economic models for the treatment of hemophilia A in Brazil.

Objetivo: É fundamental entender as necessidades não atendidas relacionadas ao manejo da hemofilia A no Brasil. Métodos: Foi conduzido um painel Delphi modificado. Foram convidados hematologistas com vasta experiência no tratamento de hemofilia no SUS para responder a perguntas sobre indicadores de eficácia da profilaxia, indicações de tratamento com emicizumabe, uso de agentes de bypass, uso de indução de tolerância imunológica (ITI) e adesão. O consenso foi definido como ≥75% dos votos na rodada 1 ou usando uma escala do tipo Likert de 5 pontos (1 = discordo totalmente, 2 = discordo, 3 = não concordo nem discordo, 4 = concordo e 5 = concordo totalmente) na segunda rodada, que incluiu questões que não atingiram o corte mínimo na primeira etapa. Resultados: Nove especialistas participaram e houve consenso sobre recomendações para profilaxia, padrões de tratamento de sangramento e locais de sangramento. O acesso venoso e a frequência da infusão foram identificados como as barreiras mais significativas para melhorar o tratamento do paciente. De acordo com a maioria, emicizumabe não substituirá a ITI ou tratamento com fator VIII de longo prazo. Emicizumabe foi considerado uma boa opção terapêutica para

Exposure to Sub-Lethal Doses of Permethrin Is Associated with Neurotoxicity: Changes in Bioenergetics, Redox Markers, Neuroinflammation and Morphology.

Permethrin (PERM) is a member of the class I family of synthetic pyrethroids. Human use has shown that it affects different systems, with wide health dysfunctions. Our aim was to determine bioenergetics, neuroinflammation and morphology changes, as redox markers after subacute exposure to PERM in rats. We used MDA determination, protein carbonyl assay, mitochondrial O2 consumption, expression of pro-inflammatory cytokines and a deep histopathological analysis of the hippocampus. PERM (150 mg/kg and 300 mg/kg body weight/day, o.v.) increased lipoperoxidation and carbonylated proteins in a dose-dependent manner in the brain regions. The activities of antioxidant enzymes glutathione peroxidase, reductase, S-transferase, catalase, and superoxide dismutase showed an increase in all the different brain areas, with dose-dependent effects in the cerebellum. Cytokine profiles (IL-1ß, IL-6 and TNF-α) increased in a dose-dependent manner in different brain tissues. Exposure to 150 mg/kg of permethrin induced degenerated and/or dead neurons in the rat hippocampus and induced mitochondrial uncoupling and reduction of oxidative phosphorylation and significantly decreased the respiratory parameters state 3-associated respiration in complex I and II. PERM exposure at low doses induces reactive oxygen species production and imbalance in the enzymatic antioxidant system, increases gene expression of pro-inflammatory interleukins, and could lead to cell damage mediated by mitochondrial functional impairment.

Healthcare resource utilization of spinal muscular atrophy in the Brazilian Unified Health System: a retrospective database study / Utilização de Recursos em Saúde para pacientes de atrofia muscula espinhal (AME 5q) no Sistema de Saúde Público brasileiro: um estudo retrospectivo em base de dados

Objective: To describe the healthcare resource utilization (HCRU) related to patients with spinal muscular atrophy (SMA) treated at the Brazilian Unified Health System (SUS) since 2015 according to age-groups. Methods: This study analyzed outpatient and inpatient data for SMA patients from the Brazilian Unified Health System database (DATASUS) from January 2015 to September 2020. Data were collected from patients with ICD-10 codes G12.0 (Infantile spinal muscular atrophy, type I [Werdnig-Hoffman]) or G12.1 (Other inherited spinal muscular atrophy), plus with at least one claim of nusinersen OR at least one claim of any SMA-related procedure groups codes since 2010. SMA-related procedures were defined based on collaborative work involving authors from medical boarding composed by physicians from SUS. Results: In total, 3,775 patients with SMA fulfilled the eligibility criteria. Physiotherapy changed from 11.34 (2.49 ­ 24.40) procedures PPPY in the 0 - 6-month old group to 3.30 (0.84 ­ 11.76) procedures PPPY in the > 36-month old group. The median of orthosis was 1.64 (0.66 ­ 3.41) procedures PPPY in the 0 ­ 6-month old group and 0.63 (0.34 ­ 1.33) PPPY in the > 36-month-old group. Exams were primarily performed for younger groups (0 ­ 6 months and > 6 ­ 18 months). The percentage of patients that needed some ventilatory care seems greater, and the speech therapy and the use of nusinersen seem lower along with age. Conclusion: This study has demonstrated important HCRU at the SUS setting with SMA patients. In addition, our results highlight the need to implement evidence-based strategies to manage SMA patients and drive cost savings for the health care system.

Objetivo: Descrever a utilização de recursos em saúde de pacientes com atrofia muscular espinhal (AME) no Sistema Público de Saúde Brasileiro (SUS) desde 2015, de acordo com a faixa etária. Métodos: Analisaram-se os dados hospitalares e ambulatoriais de pacientes com AME no DATASUS de janeiro de 2015 a setembro de 2020. Foram incluídos pacientes com código de CID-10 G12.0 (atrofia muscular espinhal infantil tipo I ­ Werdning-Hoffman) ou G12.1 (outras atrofias medulares espinhais hereditárias) com pelo menos um registro utilizando o código de nusinersena ou o código de procedimento relacionado à doença desde 2010. Os procedimentos relacionados à doença foram definidos por meio de trabalho colaborativo entre autores, incluindo três autores médicos que atuam no SUS. Resultados: No total, 3.775 pacientes com AME preencheram os critérios de elegibilidade. Procedimentos de fisioterapia passaram de 11,34 (2,49 ­ 24,40) por paciente por ano (PPPY) no grupo 0 ­ 6 meses para 3,30 (0,84 ­ 11,76) PPPY no grupo > 36 meses. A mediada de procedimentos de órteses foi de 1,64 (0,66 ­ 3,41) PPPY no grupo 0 ­ 6 meses para 0,63 (0,34­ 1,33) PPPY no grupo > 36 meses. Exames foram realizados principalmente por pacientes mais jovens (0 ­ 6 meses e > 6 ­ 18 meses). A porcentagem de pacientes que realizaram procedimentos ventilatórios parece aumentar ao longo da idade, já a fonoterapia e o uso de nusinersena parecem reduzir. Conclusão: Este estudo demonstra uma importante utilização de recursos em saúde no SUS pelos pacientes com AME e destaca a necessidade de implementação de estratégias baseadas em evidência para gerenciar esses pacientes e o uso de recursos no sistema de saúde

Diurnal Variation Induces Neurobehavioral and Neuropathological Differences in a Rat Model of Traumatic Brain Injury.

Traumatic brain injury (TBI) induces two types of brain damage: primary and secondary. Damage initiates a series of pathophysiological processes, such as metabolic crisis, excitotoxicity with oxidative stress-induced damage, and neuroinflammation. The long-term perpetuation of these processes has deleterious consequences for neuronal function. However, it remains to be elucidated further whether physiological variation in the brain microenvironment, depending on diurnal variations, influences the damage, and consequently, exerts a neuroprotective effect. Here, we established an experimental rat model of TBI and evaluated the effects of TBI induced at two different time points of the light-dark cycle. Behavioral responses were assessed using a 21-point neurobehavioral scale and the cylinder test. Morphological damage was assessed in different regions of the central nervous system. We found that rats that experienced a TBI during the dark hours had better behavioral performance than those injured during the light hours. Differences in behavioral performance correlated with less morphological damage in the perilesional zone. Moreover, certain brain areas (CA1 and dentate gyrus subregions of the hippocampus) were less prone to damage in rats that experienced a TBI during the dark hours. Our results suggest that diurnal variation is a crucial determinant of TBI outcome, and the hour of the day at which an injury occurs should be considered for future research.

Rapid immunochromatographic tests for the diagnosis of dengue: a systematic review and meta-analysis.

Dengue is an important arthropod-borne viral disease in terms of morbidity, mortality, economic impact and challenges in vector control. Benchmarks are expensive, time consuming and require trained personnel. Preventing dengue complications with rapid diagnosis has been based on the testing of easy-to-perform optimized immunochromatographic methods (ICT). This is a systematic meta-analysis review of the diagnostic accuracy of IgA, NS1, IgM and/or IgG ICT studies in suspected cases of acute or convalescent dengue, using a combination of RT-PCR, ELISA NS1, IgM IgG or viral isolation as a reference standard. This protocol was registered in PROSPERO (CRD42014009885). Two pairs of reviewers searched the PubMed, BIREME, Science Direct, Scopus, Web of Science, Ovid MEDLINE JBrigs, SCIRUS and EMBASE databases, selected, extracted, and quality-assessed by QUADAS 2. Of 3,783 studies, we selected 57, of which 40 in meta-analyses according to the analyte tested, with high heterogeneity (I2 > 90%), as expected for diagnostic tests. We detected higher pooled sensitivity in acute phase IgA (92.8%) with excellent (90%) specificity. ICT meta-analysis with NS1/IgM/IgG showed 91% sensitivity and 96% specificity. Poorer screening performance was for IgM/IgG ICT (sensitivity = 56%). Thus, the studies with NS1/IgM/IgG ICT showed the best combined performance in the acute phase of the disease.

Diagnostic parameters and reliability of four rapid immunochromatographic tests for dengue 4

ABSTRACT Background: Although performance of rapid immunochromatographic tests (RITs) for dengue virus (DENV) serotypes 1, 2 and 3 is relatively settled, evidence on accuracy of RITs for DENV-4 are based on studies with small sample sizes and with discrepant results. Objectives: To assess accuracy and inter-observer agreement of RITs targeting dengue nonstructural protein-1 (NS1) antigen - Dengue NS1-Bioeasy™, Dengue NS1 Ag Strip-Bio-Rad™, IVB Dengue Ag NS1-Orangelife™ and Dengue NS1-K130-Bioclin™ in DENV-4 samples. Methods: Study sample (n = 324) included adults presenting at an emergency unit in Rio de Janeiro, Brazil, with fever of ≤72 h and two or more dengue symptoms. A serum sample from each patient was tested by each RIT. A positive reverse-transcription polymerase chain reaction was considered as the reference standard for dengue diagnosis. The diagnostic parameters analyzed for each RIT were sensitivity, specificity, positive and negative predictive values, and likelihood ratios. Each RIT was read by homogeneous (two junior nurses) or heterogeneous (one junior nurse and one senior biologist) pairs. Agreement was estimated by simple kappa with 95% confidence interval, positive (Ppos) and negative (Pneg) proportion concordance and prevalence and bias adjusted kappa, rated from poor (k < 0.0) to almost perfect (0.8 < k < 1.0), and perfect (k = 1). Results: NS1 RITs for DENV-4 diagnosis showed high specificity (95.9%-99.4%), but low sensitivity (14.7%-45.4%). Bioeasy™ had the best performance, with a positive likelihood ratio of 26.0 (95% CI: 8.4;81.0). Inter-observer agreement was almost perfect for all evaluated RITs. Mismatches in confirmed dengue were more common for the Bioclin™ (Ppos 88.3-90.0 %) and Orangelife™ (Ppos 91.7-94.1 %) tests. Conclusions: For DENV-4, the tested RITs had high specificity, but lower sensitivity compared to published results for other serotypes. They should not be used for screening purposes. Different brands may have very different performances. This should be considered upon deciding of using RITs in DENV-4 outbreaks.

Diagnostic parameters and reliability of four rapid immunochromatographic tests for dengue 4.

BACKGROUND: Although performance of rapid immunochromatographic tests (RITs) for dengue virus (DENV) serotypes 1, 2 and 3 is relatively settled, evidence on accuracy of RITs for DENV-4 are based on studies with small sample sizes and with discrepant results. OBJECTIVES: To assess accuracy and inter-observer agreement of RITs targeting dengue nonstructural protein-1 (NS1) antigen - Dengue NS1-Bioeasy™, Dengue NS1 Ag Strip-Bio-Rad™, IVB Dengue Ag NS1-Orangelife™ and Dengue NS1-K130-Bioclin™ in DENV-4 samples. METHODS: Study sample (n = 324) included adults presenting at an emergency unit in Rio de Janeiro, Brazil, with fever of ≤72 h and two or more dengue symptoms. A serum sample from each patient was tested by each RIT. A positive reverse-transcription polymerase chain reaction was considered as the reference standard for dengue diagnosis. The diagnostic parameters analyzed for each RIT were sensitivity, specificity, positive and negative predictive values, and likelihood ratios. Each RIT was read by homogeneous (two junior nurses) or heterogeneous (one junior nurse and one senior biologist) pairs. Agreement was estimated by simple kappa with 95% confidence interval, positive (Ppos) and negative (Pneg) proportion concordance and prevalence and bias adjusted kappa, rated from poor (k < 0.0) to almost perfect (0.8 < k < 1.0), and perfect (k = 1). RESULTS: NS1 RITs for DENV-4 diagnosis showed high specificity (95.9%-99.4%), but low sensitivity (14.7%-45.4%). Bioeasy™ had the best performance, with a positive likelihood ratio of 26.0 (95% CI: 8.4;81.0). Inter-observer agreement was almost perfect for all evaluated RITs. Mismatches in confirmed dengue were more common for the Bioclin™ (Ppos 88.3-90.0 %) and Orangelife™ (Ppos 91.7-94.1 %) tests. CONCLUSIONS: For DENV-4, the tested RITs had high specificity, but lower sensitivity compared to published results for other serotypes. They should not be used for screening purposes. Different brands may have very different performances. This should be considered upon deciding of using RITs in DENV-4 outbreaks.

Rapid immunochromatographic tests for the diagnosis of dengue: a systematic review and meta-analysis / Testes imunocromatográficos rápidos para o diagnóstico da dengue: uma revisão sistemática e metanálise / Pruebas inmunocromatográficas rápidas para la diagnosis del dengue: una revisión sistemática y metaanálisis

Abstract: Dengue is an important arthropod-borne viral disease in terms of morbidity, mortality, economic impact and challenges in vector control. Benchmarks are expensive, time consuming and require trained personnel. Preventing dengue complications with rapid diagnosis has been based on the testing of easy-to-perform optimized immunochromatographic methods (ICT). This is a systematic meta-analysis review of the diagnostic accuracy of IgA, NS1, IgM and/or IgG ICT studies in suspected cases of acute or convalescent dengue, using a combination of RT-PCR, ELISA NS1, IgM IgG or viral isolation as a reference standard. This protocol was registered in PROSPERO (CRD42014009885). Two pairs of reviewers searched the PubMed, BIREME, Science Direct, Scopus, Web of Science, Ovid MEDLINE JBrigs, SCIRUS and EMBASE databases, selected, extracted, and quality-assessed by QUADAS 2. Of 3,783 studies, we selected 57, of which 40 in meta-analyses according to the analyte tested, with high heterogeneity (I2 > 90%), as expected for diagnostic tests. We detected higher pooled sensitivity in acute phase IgA (92.8%) with excellent (90%) specificity. ICT meta-analysis with NS1/IgM/IgG showed 91% sensitivity and 96% specificity. Poorer screening performance was for IgM/IgG ICT (sensitivity = 56%). Thus, the studies with NS1/IgM/IgG ICT showed the best combined performance in the acute phase of the disease.

Resumo: A dengue é uma importante arbovirose em termos de morbidade, mortalidade, impacto econômico e controle do vetor. Os testes de referência são dispendiosos e demorados e exigem pessoal capacitado. A prevenção das complicações da dengue com o diagnóstico rápido tem tomado como base a testagem com métodos imunocromatográficos (ICT). O estudo é uma revisão sistemática e meta-análise da acurácia diagnóstica de estudos de ICT de IgA, NS1, IgM e/ou IgG em casos suspeitos de dengue aguda ou convalescente, usando uma combinação de RT-PCR, ELISA NS1, IgM IgG ou isolamento viral como padrão de referência. O projeto foi registrado na base PROSPERO (CRD42014009885). Dois pares de revisores realizaram as buscas nas bases de dados PubMed, BIREME, Science Direct, Scopus, Web of Science, Ovid MEDLINE JBrigs, SCIRUS e EMBASE, além da seleção, extração e avaliação de qualidade com a ferramenta QUADAS 2. A partir de 3.783 estudos, selecionamos 57, dos quais 40 foram incluídos nas meta-análises de acordo com o analito testado, com alta heterogeneidade (I2 > 90%), conforme esperado para testes diagnósticos. Foi detectada a maior sensibilidade conjunta no IgA de fase aguda (92,8%), com excelente especificidade (90%). A meta-análise de ICT com NS1/IgM/IgG mostrou sensibilidade de 91% e especificidade de 96%. O pior desempenho para triagem foi com o ICT de IgM/IgG (sensibilidade = 56%). Portanto, os estudos de ICT com NS1/IgM/IgG mostraram o melhor desempenho combinado na fase aguda da doença.

Resumen: El dengue es una importante enfermedad arboviral, en términos de morbilidad, mortalidad, impacto económico y desafíos en el control del vector. Las mejores prácticas son caras, consumen mucho tiempo y requieren personal formado. Prevenir las complicaciones del dengue con un rápido diagnóstico se ha basado en pruebas con métodos inmunocromatográficos optimizados fáciles de realizar (ICT por sus siglas en inglés). Se trata de una revisión sistemática de metaanálisis sobre la precisión diagnóstica de estudios de IgA, NS1, IgM y/o IgG ICT en casos sospechosos de fases agudas o convalecientes de dengue, usando la combinación de RT-PCR, ELISA NS1, IgM IgG o el aislamiento viral como referencia estándar. Este proyecto se registró en PROSPERO (CRD42014009885). Dos parejas de revisores investigaron en las bases de datos de: PubMed, BIREME, Science Direct, Scopus, Web of Science, Ovid MEDLINE JBrigs, SCIRUS y EMBASE, seleccionaron, extrajeron, y realizaron la evaluación de calidad mediante QUADAS 2. De 3.783 estudios, se seleccionaron 57, de los cuales 40 fueron metaanálisis, según el analito probado, con una alta heterogeneidad (I2 > 90%), como se esperaba en las pruebas de diagnóstico. Detectamos una sensibilidad más alta combinada en la fase aguda IgA (92.8%) con una excelente (90%) especificidad. Los metaanálisis ICT con NS1/IgM/ IgG mostraron un 91% de sensibilidad y un 96% de especificidad. Se produjo un rendimiento más pobre en el diagnóstico IgM/IgG ICT (sensibilidad = 56%). De este modo, los estudios con NS1/IgM/IgG ICT mostraron un rendimiento mejor combinado en la fase aguda de la enfermedad.

Horizon scanning in Brazil: outputs and repercussions.

OBJECTIVE: To describe the four types of horizon scanning (HS) outputs developed by the National Committee for Health Technology Incorporation (CONITEC) and show their main repercussions on the decision-making processes of the Brazilian Ministry of Health (MH). METHODS: Descriptive study based on participant observation and document analysis of HS outputs (internal reports, alert reports, briefs and sections for CONITEC recommendation reports) developed between January 2014 and July 2018. RESULTS: Fifteen internal reports, six alert reports, two briefs and 57 HS sections were produced. Each output has a specific structure according to its purpose. The methodological approach adopted for developing HS outputs in Brazil is described by EuroScan International Network. The outputs had institutional and international repercussions. The activities resulted in the inclusion of HS as a tool for reducing health lawsuits in the legal framework of the MH. One of the internal reports on a high-cost drug not approved in Brazil for a rare disease was requested by the Health Technology Assessments Network for the Americas (RedETSA), showing the international relevance of the outputs. The HS sections in recommendation reports influenced discussions about incorporating technologies into the Unified Health System. CONCLUSIONS: The developed outputs have purposes ranging from helping build arguments for defense of the MH in cases of health judicialization to inform decision-making processes. In addition, HS sections in recommendation reports have grown in importance recently. CONITEC's HS system has been structured, and its role as a tool to inform health managers has shown to be been relevant.

Correction to: Accuracy and reliability of an NS1 rapid immunochromatographic test for DENV-1 diagnosis at point of care and in the laboratory.

An error occurred during the publication of the original article [1].

Precisão e confiabilidade de um teste imuno-cromatográfico rápido NS1 para diagnóstico DENV-1 no ponto de atendimento e no laboratório.

BACKGROUND: Rapid immunochromatographic tests (ICT) for dengue non-structural protein 1 (NS1) have shown good performance for diagnosing acute-phase dengue in serum in laboratory settings, but rarely have been assessed in whole blood and at point of care (POC). This study compare the accuracy and inter- and intra-observer reliability of the NS1 Bioeasy™ ICT in whole blood at POC versus serum in the laboratory, during a DENV-1 epidemic. METHODS: Cross-sectional study involving 144 adults spontaneously demanding care in an emergency department within 4 days of onset of acute febrile illness. Accuracy of NS1 Bioeasy™ ICT was compared in whole blood and serum, both at 15 and 30 min, blinded to the reference RT-PCR or NS1 ELISA. Non-dengue patients were also tested for Zika virus with RT-PCR. Reliability of whole blood and serum readings by the same or different observers was measured by simple kappa (95% CI). RESULTS: At 15 min, sensitivity (Sn) of NS1 Bioeasy™ ICT in whole blood/POC was 76.7% (95% CI: 68.0-84.1) and specificity (Sp) was 87.0% (95% CI: 66.4-97.2). Sn in serum/laboratory was 82% (95% CI: 74.1-88.6) and Sp 100% (95% CI: 85.8-100). Positive likelihood ratio was 5.9 (95% CI: 2.0-17.0) for whole blood/POC and 19.8 (95% CI: 2.9-135.1) for serum/laboratory. Reliability of matched readings of whole blood/POC and serum/laboratory by the same observer (k = 0.83, 95% CI: 0.74-0.93) or different observers (k = 0.81, 95% CI: 0.72-0.92) was almost perfect, with higher discordant levels in the absence of dengue. Results did not differ statistically at 5%. CONCLUSIONS: NS1 Bioeasy™ ICT in DENV-1 epidemics is a potentially confirmatory test. Invalid results at 15 min should be reread at 30 min. To optimize impact of implementing ICT in the management of false-negatives it should be incorporated into an algorithm according to setting and available specimen. TRIAL REGISTRATION: UTN U1111-1145-9451 .

Innate immunity modulation in the duodenal mucosa induced by REM sleep deprivation during infection with Trichinella spirallis.

Sleep is considered to be an important predictor of the immunity, since the absence of sleep can affect the development of the immune response, and consequently increase the susceptibility to contract an infection. The aim of the present study was to investigate if sleep deprivation and stress induce dysregulation of the duodenal mucous membrane during the acute infection with Trichinella spiralis. Our results shows that, in the intestinal mucous membrane, stress and sleep deprivation, produces different effect in the cells, and this effect depends on the studied duodenal compartment, glands or villi. The sleep deprivation affect mast cells mainly, and the stress response is more heterogeneous. Interestingly, in the duodenal mucous membrane, none population of cells in the infected groups responded equally to both conditions. These findings suggest that the response of the intestinal mucous membrane during the infection caused for T. spiralis turns out to be affected in the sleep-deprived rats, therefore, the results of the present study sustain the theory that sleep is a fundamental process that is capable of modulating the immune response of mucous membranes, particularly the one generated against the parasite Trichinella spiralis.

Maternal protein restriction during gestation impairs female offspring pancreas development in the rat.

A maternal low-protein (LP) diet programs fetal pancreatic islet ß-cell development and function and predisposes offspring to metabolic dysfunction later in life. We hypothesized that maternal protein restriction during pregnancy differentially alters ß- and α-cell populations in offspring by modifying islet ontogeny and function throughout life. We aimed to investigate the effect of an LP maternal diet on pancreatic islet morphology and cellular composition in female offspring on postnatal days (PNDs) 7, 14, 21, 36, and 110. Mothers were divided into 2 groups: during pregnancy, the control group (C) was fed a diet containing 20% casein, and the LP group was fed an isocaloric diet with 10% casein. Offspring pancreases were obtained at each PND and then processed. ß and α cells were detected by immunohistochemistry, and cellular area and islet size were quantified. Islet cytoarchitecture and total area were similar in C and LP offspring at all ages studied. At the early ages (PNDs 7-21), the proportion of ß cells was lower in LP than C offspring. The proportion of α cells was lower in LP than C offspring on PND 14 and higher on PND 21. The ß/α-cell ratio was lower in LP compared with C offspring on PNDs 7 and 21 and higher on PND 36 (being similar on PNDs 14 and 110). We concluded that maternal protein restriction during pregnancy modifies offspring islet cell ontogeny by altering the proportions of islet sizes and by reducing the number of ß cells postnatally, which may impact pancreatic function in adult life.

Immunization with a neural-derived peptide protects the spinal cord from apoptosis after traumatic injury.

Apoptosis is one of the most destructive mechanisms that develop after spinal cord (SC) injury. Immunization with neural-derived peptides (INDPs) such as A91 has shown to reduce the deleterious proinflammatory response and the amount of harmful compounds produced after SC injury. With the notion that the aforementioned elements are apoptotic inducers, we hypothesized that INDPs would reduce apoptosis after SC injury. In order to test this assumption, adult rats were subjected to SC contusion and immunized either with A91 or phosphate buffered saline (PBS; control group). Seven days after injury, animals were euthanized to evaluate the number of apoptotic cells at the injury site. Apoptosis was evaluated using DAPI and TUNEL techniques; caspase-3 activity was also evaluated. To further elucidate the mechanisms through which A91 exerts this antiapoptotic effects we quantified tumor necrosis factor-alpha (TNF-α). To also demonstrate that the decrease in apoptotic cells correlated with a functional improvement, locomotor recovery was evaluated. Immunization with A91 significantly reduced the number of apoptotic cells and decreased caspase-3 activity and TNF-α concentration. Immunization with A91 also improved the functional recovery of injured rats. The present study shows the beneficial effect of INDPs on preventing apoptosis and provides more evidence on the neuroprotective mechanisms exerted by this strategy.

Análise dos custos associados ao cateterismo vesical de demora em pacientes hospitalizados: revisão integrativa / Analysis of costs associated with the late vesical catheterization in hospitalized patients: integrative review

Objetivo: buscar artigos que avaliam os custos relacionados ao cateterismo vesical de demora (CVD) no ambiente hospitalar (AH) e das complicações relacionadas. Método: revisão integrativa, com a busca de resposta para as seguintes questões: a) Qual o custo do cateterismo vesical de demora no ambiente hospitalar? b) Qual o custo das complicações relacionadas ao cateterismo vesical de demora no ambiente hospitalar? Foram selecionados 25 artigos. Resultados: os custos relacionados a complicações envolvem não somente o tratamento antimicrobiano, mas todos os procedimentos que são necessários para o diagnóstico e controle da infecção. Conclusão: custos com pacientes com infecção trato urinário (ITU) foram de 1,42 vezes maiores que o custo médio em pacientes sem a infecção. Outros cateteres vesicais, como os revestidos com antimicrobianos, embora com custo unitário maior, apresentam resultados efetivos quanto à diminuição do tempo de internação, redução das taxas de ITU e redução do tempo de internação para tratamento de complicações relacionadas.(AU)

Objective: to find articles that assess the costs related to the catheterization urinary catheter (CVD) in the hospital (AH) and its related complications. Method: an integrative review, with the search for answers to the following questions: a) What is the cost of vesical catheterization in the hospital? b) What is the cost of complications related to catheterization of delay in hospital? We selected 25 articles. Results: The costs associated with complications involve not only antimicrobial treatment, but all procedures that are needed for the diagnosis and control of infection. Conclusion: costs to patients with urinary tract infection (UTI) were 1,42 times greater than the average cost for patients without infection. Other bladder catheters, such as those coated with antimicrobial agents, although with higher unit cost, feature actual results and decreased length of stay, reduce UTI rates and reduced length of hospital stay for treatment of related complications.(AU)

Objetivo: encontrar los artículos que evalúan los costos relacionados con el catéter urinario cateterismo (ECV) en el hospital (AH) y sus complicaciones relacionadas. Método: revisión integradora, con la búsqueda de respuestas a las siguientes preguntas: a) ¿Cuál es el costo de cateterismo vesical en el hospital? b) ¿Cuál es el coste de las complicaciones relacionadas con la cateterización de retraso en el hospital? Se seleccionaron 25 artículos. Resultados: Los costos asociados con complicaciones implican no sólo el tratamiento antimicrobiano, pero todos los procedimientos que son necesarios para el diagnóstico y control de la infección. Conclusión: los costos para los pacientes con infección del tracto urinario (ITU) fueron 1,42 veces mayor que el costo promedio para los pacientes sin infección. Otros catéteres vesicales, como los recubiertos con agentes antimicrobianos, aunque con mayor coste unitario, los resultados reales y disminución de la función de la duración, reducir las tasas de infección del tracto urinario y la duración de la estancia hospitalaria reducida para el tratamiento de las complicaciones relacionadas.(AU)