SARS-CoV-2 intra-host diversity, antibody response, and disease severity after reinfection by the variant of concern Gamma in Brazil.

The rapid spread of the SARS-CoV-2 Variant of Concern (VOC) Gamma in Amazonas during early 2021 fueled a second large COVID-19 epidemic wave and raised concern about the potential role of reinfections. Very few cases of reinfection associated with the VOC Gamma have been reported to date, and their potential impact on clinical, immunological, and virological parameters remains largely unexplored. Here we describe 25 cases of SARS-CoV-2 reinfection in Brazil. SARS-CoV-2 genomic analysis confirmed that individuals were primo-infected with distinct viral lineages between March and December 2020 (B.1.1, B.1.1.28, B.1.1.33, B.1.195, and P.2) and reinfected with the VOC Gamma between 3 to 12 months after primo-infection. We found a similar mean cycle threshold (Ct) value and limited intra-host viral diversity in both primo-infection and reinfection samples. Sera of 14 patients tested 10-75 days after reinfection displayed detectable neutralizing antibodies (NAb) titers against SARS-CoV-2 variants that circulated before (B.1.*), during (Gamma), and after (Delta and Omicron) the second epidemic wave in Brazil. All individuals had milder or no symptoms after reinfection, and none required hospitalization. These findings demonstrate that individuals reinfected with the VOC Gamma may display relatively high RNA viral loads at the upper respiratory tract after reinfection, thus contributing to onward viral transmissions. Despite this, our study points to a low overall risk of severe Gamma reinfections, supporting that the abrupt increase in hospital admissions and deaths observed in Amazonas and other Brazilian states during the Gamma wave was mostly driven by primary infections. Our findings also indicate that most individuals analyzed developed a high anti-SARS-CoV-2 NAb response after reinfection that may provide some protection against reinfection or disease by different SARS-CoV-2 variants.

Implementation and evaluation of a remote geriatric assessment and intervention program in Brazil.

BACKGROUND: This study sought to determine the feasibility and acceptability of a remote geriatric assessment (GA) and implementation (GAIN) program in Brazil. The authors also explored the effect of this program on health-related quality of life (HR-QOL) outcomes 3 months after initiating treatment. METHODS: This is a longitudinal study enrolling older adults (65+ years), diagnosed with any type of solid tumor, scheduled to initiate chemotherapy in a networked Brazilian cancer center. The GA was performed through telehealth. We assessed the feasibility of the remote GA, acceptability to patients, and changes in patient-centered outcomes (HR-QOL, mood, function) from baseline to month 3. Linear mixed model analysis was done, adjusting for age, gender, race, income, and disease stage. RESULTS: Fifty-six patients completed all intended assessments. Notably, the threshold of feasibility was 70% and there was 92% complete adherence. Average age was 76 years old (SD = 7.2). Most patients were female (57%), married (59%), and had a college degree (46%). The most common diagnoses were gastrointestinal (39%) and gynecological cancers (18%); most were diagnosed at an advance disease stage (77%). A total of 32 patients were referred to a remote appointment and 86% followed this recommendation(s). Significant improvement in Functional Assessment of Cancer Therapy - General FACT-G (mean difference, 6.04; p < .001), Geriatric Depression Scale (mean difference, -0.86; p = .008), and instrumental activities of daily living ratio (mean difference, 0.17; p < .001) were found. CONCLUSION: Remote GAIN is feasible and acceptable to older adults with cancer receiving treatment in Brazil. The authors also found significant improvement in HR-QOL outcomes over time. Notably, this GAIN program could guide early detection of chemotherapy toxicity and improving patient-reported outcomes in low-resource environments.

Spread of Gamma (P.1) Sub-Lineages Carrying Spike Mutations Close to the Furin Cleavage Site and Deletions in the N-Terminal Domain Drives Ongoing Transmission of SARS-CoV-2 in Amazonas, Brazil.

The Amazonas was one of the most heavily affected Brazilian states by the COVID-19 epidemic. Despite a large number of infected people, particularly during the second wave associated with the spread of the Variant of Concern (VOC) Gamma (lineage P.1), SARS-CoV-2 continues to circulate in the Amazonas. To understand how SARS-CoV-2 persisted in a human population with a high immunity barrier, we generated 1,188 SARS-CoV-2 whole-genome sequences from individuals diagnosed in the Amazonas state from 1st January to 6th July 2021, of which 38 were vaccine breakthrough infections. Our study reveals a sharp increase in the relative prevalence of Gamma plus (P.1+) variants, designated Pango Lineages P.1.3 to P.1.6, harboring two types of additional Spike changes: deletions in the N-terminal (NTD) domain (particularly Δ144 or Δ141-144) associated with resistance to anti-NTD neutralizing antibodies or mutations at the S1/S2 junction (N679K or P681H) that probably enhance the binding affinity to the furin cleavage site, as suggested by our molecular dynamics simulations. As lineages P.1.4 (S:N679K) and P.1.6 (S:P681H) expanded (Re > 1) from March to July 2021, the lineage P.1 declined (Re < 1) and the median Ct value of SARS-CoV-2 positive cases in Amazonas significantly decreases. Still, we did not find an increased incidence of P.1+ variants among breakthrough cases of fully vaccinated patients (71%) in comparison to unvaccinated individuals (93%). This evidence supports that the ongoing endemic transmission of SARS-CoV-2 in the Amazonas is driven by the spread of new local Gamma/P.1 sublineages that are more transmissible, although not more efficient to evade vaccine-elicited immunity than the parental VOC. Finally, as SARS-CoV-2 continues to spread in human populations with a declining density of susceptible hosts, the risk of selecting more infectious variants or antibody evasion mutations is expected to increase. IMPORTANCE The continuous evolution of SARS-CoV-2 is an expected phenomenon that will continue to happen due to the high number of cases worldwide. The present study analyzed how a Variant of Concern (VOC) could still circulate in a population hardly affected by two COVID-19 waves and with vaccination in progress. Our results showed that the answer behind that was a new generation of Gamma-like viruses, which emerged locally carrying mutations that made it more transmissible and more capable of spreading, partially evading prior immunity triggered by natural infections or vaccines. With thousands of new cases daily, the current pandemics scenario suggests that SARS-CoV-2 will continue to evolve and efforts to reduce the number of infected subjects, including global equitable access to COVID-19 vaccines, are mandatory. Thus, until the end of pandemics, the SARS-CoV-2 genomic surveillance will be an essential tool to better understand the drivers of the viral evolutionary process.

Estimation, Forecasting, and Anomaly Detection for Nonstationary Streams Using Adaptive Estimation.

Streaming data provides substantial challenges for data analysis. From a computational standpoint, these challenges arise from constraints related to computer memory and processing speed. Statistically, the challenges relate to constructing procedures that can handle the so-called concept drift-the tendency of future data to have different underlying properties to current and historic data. The issue of handling structure, such as trend and periodicity, remains a difficult problem for streaming estimation. We propose the real-time adaptive component (RAC), a penalized-regression modeling framework that satisfies the computational constraints of streaming data, and provides the capability for dealing with concept drift. At the core of the estimation process are techniques from adaptive filtering. The RAC procedure adopts a specified basis to handle local structure, along with a least absolute shrinkage operator-like penalty procedure to handle over fitting. We enhance the RAC estimation procedure with a streaming anomaly detection capability. The experiments with simulated data suggest the procedure can be considered as a competitive tool for a variety of scenarios, and an illustration with real cyber-security data further demonstrates the promise of the method.

The AP-1 transcription factors c-Jun and JunB are essential for CD8α conventional dendritic cell identity.

Dendritic cell (DC) development is orchestrated by lineage-determining transcription factors (TFs). Although, members of the activator-protein-1 (AP-1) family, including Batf3, have been implicated in conventional (c)DC specification, the role of Jun proteins is poorly understood. Here, we identified c-Jun and JunB as essential for cDC1 fate specification and function. In mice, Jun proteins regulate extrinsic and intrinsic pathways, which control CD8α cDC1 diversification, whereas CD103 cDC1 development is unaffected. The loss of c-Jun and JunB in DC progenitors diminishes the CD8α cDC1 pool and thus confers resistance to Listeria monocytogenes infection. Their absence in CD8α cDC1 results in impaired TLR triggering and antigen cross-presentation. Both TFs are required for the maintenance of the CD8α cDC1 subset and suppression of cDC2 identity on a transcriptional and phenotypic level. Taken together, these results demonstrate the essential role of c-Jun and JunB in CD8α cDC1 diversification, function, and maintenance of their identity.

Psoriatic skin inflammation is promoted by c-Jun/AP-1-dependent CCL2 and IL-23 expression in dendritic cells.

Toll-like receptor (TLR) stimulation induces innate immune responses involved in many inflammatory disorders including psoriasis. Although activation of the AP-1 transcription factor complex is common in TLR signaling, the specific involvement and induced targets remain poorly understood. Here, we investigated the role of c-Jun/AP-1 protein in skin inflammation following TLR7 activation using human psoriatic skin, dendritic cells (DC), and genetically engineered mouse models. We show that c-Jun regulates CCL2 production in DCs leading to impaired recruitment of plasmacytoid DCs to inflamed skin after treatment with the TLR7/8 agonist Imiquimod. Furthermore, deletion of c-Jun in DCs or chemical blockade of JNK/c-Jun signaling ameliorates psoriasis-like skin inflammation by reducing IL-23 production in DCs. Importantly, the control of IL-23 and CCL2 by c-Jun is most pronounced in murine type-2 DCs. CCL2 and IL-23 expression co-localize with c-Jun in type-2/inflammatory DCs in human psoriatic skin and JNK-AP-1 inhibition reduces the expression of these targets in TLR7/8-stimulated human DCs. Therefore, c-Jun/AP-1 is a central driver of TLR7-induced immune responses by DCs and JNK/c-Jun a potential therapeutic target in psoriasis.

Modafinil for poststroke patients: A systematic review.

INTRODUCTION: Stroke is a major cause of death and disability worldwide. The use of modafinil, a wakefulness-promoting agent, is hypothesised to benefit stroke patients. METHODS: We performed a systematic review in accordance with the Cochrane Handbook for Systematic Reviews of Interventions recommendations to assess the efficacy and safety of modafinil in poststroke patients. We prospectively registered the review protocol in PROSPERO (CRD42017078465) and reported the systematic review following the PRISMA statement. RESULTS: Two published studies (77 participants) and one ongoing randomised controlled trial, with limited methodological quality, assessed the effects of modafinil (200 mg or 400 mg) for adults from 14 days poststroke up to 3 months poststroke and fulfilled our inclusion criteria. The clinical and methodological variability between studies precluded meta-analyses. Overall, these studies showed some benefit of modafinil for fatigue, but no benefit for disability, cognition, and for subscores of stroke-specific quality of life. Data for adverse events were scarce and mortality was not considered by studies. Due to very low quality related to the evidence, we are uncertain about the effects of modafinil for all outcomes assessed by our systematic review. CONCLUSION: Based on two small randomised controlled trial, which provided very low quality evidence, the effects (benefits and harms) of modafinil for stroke patients are unclear and do not support its routinely use in clinical practice for this clinical situation. Number of Protocol registration in PROSPERO database: CRD42017078465 (available from http://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42017078465).

A informação do setor de faturamento como suporte à tomada de decisão: um estudo de caso no Hospital Universitário da UFGD / Information from the invoicing sector as support for decision-making: a case study at the University Hospital of the Federal University of Grande Dourados (UFGD)

O setor público é o principal financiador das internações hospitalares e as informações geradas vão constituir o sistema de informação hospitalar do Sistema Único de Saúde (SUS). O objetivo deste artigo é estruturar um modelo de relatório visando à utilização em hospitais universitários, para a tomada de decisão. Como referencial teórico, buscou-se suporte nas discussões acerca de: SUS, instituição hospitalar, sistemas de informações hospitalares e tomada de decisão. Quanto aos procedimentos metodológicos, o mesmo caracteriza-se como qualitativo-descritivo, sendo desenvolvido por meio de um estudo de caso único e pesquisa-ação. As análises dos dados primários foram realizadas em dois momentos: de janeiro a dezembro de 2007 e de janeiro a dezembro de 2008. Baseado nestes períodos é descrito o que foi constatado e apresentado para a construção de novos relatórios, explicando a importância e a necessidade de cada. Por fim, é estruturado um modelo de relatório sintético para o caso das informações discutidas no artigo serem contempladas. Conclui-se que o sistema de informação hospitalar pode se tornar uma potencial ferramenta de suporte, à medida que se façam ajustes e que o relatório estruturado possa prover a instituição à tomada de decisão com uma comunicação objetiva.

The public sector is the main financing agent of hospital admissions and the information generated constitutes the input for the hospital information network of the Unified Health System (SUS). This paper seeks to design a report template to be used for decision-making in both public and university hospitals. The theoretical approach sought inspiration in discussions about the SUS, hospital institutions, hospital information systems and decision-making. The methodological procedures used are characterized as qualitative-descriptive methods and were conducted in a single case study and action research. The primary data analysis was carried out in two stages from January through December 2007 and from January through December 2008. Based on these periods, the findings were described and the elaboration of new reports was presented, with the importance and need for each being duly emphasized. Lastly, a structured report template was created for the case study that includes information discussed in the article. The conclusion reached is that the hospital information system can become a potential support tool, as the necessary adjustments are made and the report is structured to furnish the institution with an objective communication tool for decision-making.

[Information from the invoicing sector as support for decision-making: a case study at the University Hospital of the Federal University of Grande Dourados (UFGD)]. / A informação do setor de faturamento como suporte à tomada de decisão: um estudo de caso no Hospital Universitário da UFGD.

The public sector is the main financing agent of hospital admissions and the information generated constitutes the input for the hospital information network of the Unified Health System (SUS). This paper seeks to design a report template to be used for decision-making in both public and university hospitals. The theoretical approach sought inspiration in discussions about the SUS, hospital institutions, hospital information systems and decision-making. The methodological procedures used are characterized as qualitative-descriptive methods and were conducted in a single case study and action research. The primary data analysis was carried out in two stages from January through December 2007 and from January through December 2008. Based on these periods, the findings were described and the elaboration of new reports was presented, with the importance and need for each being duly emphasized. Lastly, a structured report template was created for the case study that includes information discussed in the article. The conclusion reached is that the hospital information system can become a potential support tool, as the necessary adjustments are made and the report is structured to furnish the institution with an objective communication tool for decision-making.

[Temporal pattern of diarrhea hospitalizations and deaths in children, 1995 to 1998, Brazil]. / Padrão temporal das internações e óbitos por diarréia em crianças, 1995 a 1998, Rio de Janeiro.

OBJECTIVE: To analyze the temporal pattern of hospitalization and deaths due to diarrhea among children less than five years old between 1995 and 1998 to support specific prevention actions and disease control strategies. METHODS: Data was collected from the Ministry of Health's Mortality Data System and Hospitalization Data System. Monthly time series of diarrhea hospitalizations and deaths were decomposed into stochastic linear trend, deterministic seasonal and irregular components using structural time series models. RESULTS: The levels of both series showed a decline in time. This pattern being more evident in the hospitalization series. The slope variation was constant in both series; on average less than 5.3 hospitalizations/month (p-value <0.001), and less than 1 death/month (p-value <0.1). The residual analysis of the hospitalization series revealed a positive trend change in January 1996. The seasonal component for both models was statistically significant (p-value <0.0001) with May and June as months of highest hospitalizations and deaths. Normality and time independence assumptions of errors could not be rejected at a 0.05 significance level. CONCLUSIONS: The temporal pattern of moderate and severe diarrhea described and estimated in this study suggests that rotavirus might be a predominant disease agent. In this context, targeted vaccination is recommended for prevention and control. However, further studies on the efficacy of rotavirus candidate vaccines are necessary in order to implement this strategy in Brazil.

Padräo temporal das internações e óbitos por diarréia em crianças, 1995 a 1998, Rio de Janeiro / Temporal pattern of diarrhea hospitalizations and deaths in children, 1995 to 1998, Brazil

OBJETIVO: Analisar o padräo temporal dos óbitos e internações, no período de 1995 a 1998, associadas à diarréia em crianças menores de cinco anos de idade para subsidiar ações específicas de prevençäo e controle dessa doença. MÉTODOS: Os dados foram obtidos do Sistema de Informações sobre Mortalidade (SIM) e Sistema de Internações Hospitalares (SIH) do Ministério da Saúde. As séries mensais de internações e de óbitos por diarréia foram decompostas em componentes de tendência linear estocástica, sazonalidade determinística e irregularidades mediante a aplicaçäo dos modelos estruturais para análise de séries temporais. RESULTADOS: Os níveis de ambas as séries apresentaram mudanças ao longo do tempo, com declínio mais perceptível na série de internações. A variaçäo das taxas de inclinaçäo foi constante para cada uma das séries, em média, a menos 5,3 internações por mês (p-valor <0,001) e menos um óbito por mês (p-valor <0,1), respectivamente. Na análise dos resíduos do modelo de internações, observou-se mudança no nível da tendência em janeiro de 1996. O componente sazonal de ambos os modelos foi estatisticamente significante (p-valor <0,0001), sendo maio e junho os meses com maior excesso de internações e óbitos. Os pressupostos de normalidade e de independência temporal dos resíduos näo puderam ser rejeitados ao nível de 0,05. CONCLUSÕES: Os resultados sugerem a predominância da etiologia viral das diarréias moderadas e graves. Neste caso, a vacinaçäo específica é a medida mais eficaz na prevençäo e controle, sendo necessários estudos de eficácia de novas candidatas à vacina contra o rotavírus no Brasil.

Segmentação da demanda dos planos e seguros privados de saúde: uma análise das informações da PNAD/98 / Segmentation of the demand of the plans and private insurances of health: an analysis of the information of PNAD/98

Este artigo apresenta uma investigação preliminar da presença da seleção adversa e do risco moral (moral hazard) na demanda ativa por planos de saúde no Brasil, a partir dos dados da PNAD/98. O presente estudo compara indivíduos cujas coberturas decorrem do vínculo de trabalho, com aqueles cujos planos resultam de uma demanda individual às empresas que os comercializam e os que não têm acesso a esquemas assistenciais alternativos ao SUS. A elaboração de uma tipologia de planos de saúde, combinada com variáveis relacionadas com as condições de saúde, utilização de serviços e gastos com saúde, sugere a existência de falhas de mercado. A percepção de uma condição de saúde mais desfavorável parece estar associada à busca de cobertura e o tipo de cobertura com o maior uso de serviços de saúde. Quando analisadas através de dois modelos de regressão logística com múltiplos controles, onde a variável de desfecho é indicadora de seleção adversa ou moral hazard, essas diferenças se atenuam, com exceção dos gastos com saúde. Os resultados não evidenciam uma inquestionável assimetria de informações, mas sinalizam a necessidade de aprofundar o conhecimento sobre as relações entre morbidade, utilização de serviços de saúde, gastos com saúde e tipo de cobertura.

Desigualdades geográficas e sociais na utilizaçäo de serviços de saúde no Brasil / Social and geographical inequalities in health services utilization in Brazil

O consumo de serviços de saúde e a funçäo das necessidades e do comportamento dos indivíduos em relaçäo a seus problemas de saúde, bem como das formas de financiamento e dos serviços e recursos disponíveis para a populaçäo. A Constituiçäo brasileira de 1988 estabelece o Sistema Unico de Saúde (SUS) com base na institucionalizaçäo da universalidade da cobertura e do atendimento. O sistema foi implementado em 1990 e pode ser traduzido como igualdade de oportunidade de acesso aos serviços de saúde para necessidades iguais. Estuda a eqüidade no uso de serviços de saúde a partir de duas dimensöes: a geográfica e a social. Os dados utilizados säo de pesquisas realizadas em 1989 e 1996-1997, pelo IBGE. Para avaliar as desigualdades geográficas no consumo de serviços de saúde foram calculadas taxas padronizadas de utilizaçäo de serviços. Comparou-se também a dimensäo do gasto privado domiciliar com medicamentos e com planos de saúde. Para avaliar as desigualdades sociais, estimou-se a razäo de odds para três grupos de renda e para as pessoas com e sem cobertura de plano de saúde. Observou-se pequena reduçäo dos níveis de desigualdades no período analisado (1989-1996/1997), com o sistema de saúde atual mantendo-se caracterizado por marcadas iniqüidades.

Produçäo de serviços e qualidade da assistência hospitalar no Estado do Rio de Janeiro - 1992 a 1995 / Production of services and quality of hospital care in a Southeastern State of Brazil - 1992 to 1995

Objetivou-se analisar as tendências recentes na assistência hospitalar no Estado do Rio de Janeiro. Os dados originam-se da prestaçäo mensal de serviços dos subsetores, universitários e privado, credenciados ao Sistema Unico de Saúde (SUS), entre janeiro de 1992 e outubro de 1995. Foram utilizadas as informaçöes registradas nos formulários de Autorizaçäo de Internaçäo Hospitalar, processadas pelo Sistema de Informaçöes Hospitalares do SUS (SIH-SUS). A análise comparativa dos três subsetores centrou-se na produçäo dos serviços e resultados. Tais comparaçöes foram realizadas utilizando-se modelos estruturais de séries temporais, que se baseiam na decomposiçäo de componentes de interesse, como tendência, sazonalidade e irregularidade. A frequência de internaçöes no Estado tendeu ao declínio, em decorrência especialmente da retraçäo do subsetor público a partir de 1993. Essa reduçäo foi seletiva - no que se refere à distribuiçäo por faixas etárias - concetrando-se nos adultos e idosos. Somente o subsetor universitário aumentou gradativamente o volume de admissöes. A qualidade da assistência foi avaliada por meio da abordagem de eventos-sentinelas. A ocorrência de óbitos evitáveis nas internaçöes no Estado apresentou discreta tendência ao declínio, detectada pela sua reduçäo no subsetor privado. Nos subsetores público e universitário, a frequência dos óbitos evitáveis manteve-se estável. A ocorrência de óbitos maternos no Estado permaneceu alta e estável, enquanto os índices de cesárea revelaram siginificativo crescimento, apesar de já ter sido observado, desde o início do período, valores bastante altos. Há problemas sérios na qualidade da atençäo hospitalar prestada pelo SUS, no Estado, os quais, a julgar pela situaçäo apresentada nos indicadores utilizados, vêm se agravando. Embora exiba limitaçöes, o banco de dados do SIH-SUS mostrou ser instrumento útil para o monitoramento dos serviços hospitalares