High-risk space-time clusters of mortality in children 5 to 14 years of age in Mato Grosso state, Brazil. / Clusters Espaço-Temporais de Alto Risco da Mortalidade Infantojuvenil em Mato Grosso, Brasil.

The study aimed to detect high-risk areas for deaths of children and adolescents 5 to 14 years of age in the state of Mato Grosso, Brazil, from 2009 to 2020. This was an exploratory ecological study with municipalities as the units of analysis. Considering mortality data from the Mortality Information System (SIM) and demographic data from the Brazilian Institute of Geography and Statistics (IBGE), the study used multivariate statistics to identify space-time clusters of excess mortality risk in this age group. From 5 to 9 years of age, two clusters with high mortality risk were detected; the most likely located in the state's southern mesoregion (RR: 1.6; LRT: 8,53). Among the 5 clusters detected in the 10-14-year age group, the main cluster was in the state's northern mesoregion (RR: 2,26; LRT: 7,84). A reduction in mortality rates was observed in the younger age group and an increase in these rates in the older group. The identification of these clusters, whose analysis merits replication in other parts of Brazil, is the initial stage in the investigation of possible factors associated with morbidity and mortality in this group, still insufficiently explored, and for planning adequate interventions.

O objetivo deste estudo é detectar as áreas de maior risco para óbitos de crianças e adolescentes de 5 a 14 anos no estado de Mato Grosso entre os anos de 2009 e 2020. Estudo ecológico, tipo exploratório, cuja unidade de análise foram os municípios. Considerando dados de mortalidade do SIM e os demográficos do IBGE, o estudo utilizou a estatística multivariada para a identificação dos clusters espaço-temporais de sobrerrisco de mortalidade nesta faixa etária. Dos 5 aos 9 anos, dois clusters de alto risco de mortalidade foram detectados; o mais provável localizado na mesorregião sul (RR: 1,6; LRV: 8,53). Dentre os 5 clusters detectados na faixa etária dos 10 aos 14 anos, o principal foi localizado na mesorregião norte (RR: 2,26; LRV: 7,84). Foi identificada redução das taxas de mortalidade na faixa etária mais jovem e aumento destas taxas na faixa etária mais velha. A identificação destes clusters, cuja análise merece ser replicada a outras partes do território nacional, é a etapa inicial para a investigação de possíveis fatores associados à morbi-mortalidade deste grupo ainda pouco explorado e para o planejamento de intervenções adequadas.

High-Risk Areas for Congenital Zika Syndrome in Rio de Janeiro: Spatial Cluster Detection.

Brazil reported 18,282 suspected congenital Zika syndrome (CZS) cases up to 2018 and accounts for 61.4% of the total reported Zika cases in the Americas in the period. To detect high-risk areas for children with CZS in the city of Rio de Janeiro, we used cluster detection and thematic maps. We analyzed data using a Poisson model in Satscan 10.1.3 software. We also analyzed the records of children with CZS from 2015 to 2016 to describe the clinical and epidemiological maternal and child profile, as well as live births in 2016 and the social development index (SDI) by neighborhood. In 2015 and 2016, the incidence rates of CZS were 8.84 and 46.96 per 100,000 live births in the city, respectively. Severe congenital findings such as microcephaly and brain damage, osteoarticular impairment, ocular abnormalities, and hearing loss were observed in 47 children. The spatial distribution of CZS was concentrated in the north and west zones in heterogeneous neighborhoods. The neighborhoods with the highest occurrence of CZS cases were found to have the worst SDIs. Stascan detected three spatial clusters in the north zone, where the SDI is lower. The clusters presented high relative risks for CZS (7.86, 1.46, and 2.08), although they were not statistically significant. Our findings highlight a higher occurrence of CZS in areas with less favorable socioeconomic conditions.

[Space-time heterogeneity of measles, mumps, and rubella vaccination indicators in children from BrazilHeterogeneidad espaciotemporal de los indicadores de inmunización con la vacuna triple viral en la población infantil de Brasil]. / Heterogeneidade espaço-temporal dos indicadores de imunização da vacina tríplice viral em crianças no Brasil.

Objective: To evaluate immunization coverage and dropout rates of the measles, mumps, and rubella vaccine across Brazilian regions. Methods: This ecological study employing a space-time approach used data from the National Immunization Program (PNI) and the Live Births Information System (SINASC). We estimated the annual variation (2014 to 2021) in immunization coverage and dropout rate of the measles, mumps, and rubella vaccine in children aged 12 and 15 months in the 5 570 Brazilian municipalities. Statistical analysis was conducted for the municipalities contained in each Brazilian region using the space-time scan technique, considering the Poisson probabilistic model and the hypothesis that municipalities with lower immunization coverage or high dropout rates would form space-time clusters. Results: From 2014 to 2021, 38.3% and 12.9% of municipalities achieved a coverage ≥ 95.0% in the first and second doses respectively; 53.6% of municipalities had a high dropout rate (20.0% to 49.9%) and 37.2% had a very high dropout rate. The Northeast region had primary clusters for low coverage of the first (2018 to 2021) and second vaccine doses (2020 to 2021) with higher relative risks (RR) compared to other primary clusters. The RR for high dropout rate was elevated in all Brazilian regions (1.57 to 26.23). Conclusions: In some Brazilian regions, the dropout rate has been high since 2014, signaling a risk of measles resurgence. In turn, space-time analysis indicated lower vaccination coverage in 2020, suggesting the influence of the COVID-19 pandemic.

Objetivo: Evaluar la cobertura de vacunación y las tasas de incumplimiento del esquema de vacunación triple viral en las macrorregiones de Brasil. Métodos: En este estudio ecológico, con un enfoque espaciotemporal, se utilizaron datos del Programa Nacional de Inmunización y del Sistema de Información sobre Recién Nacidos Vivos. Se estimó la variación anual de la cobertura de vacunación y la tasa de incumplimiento del esquema de vacunación triple viral en niños de 12 y 15 meses en 5570 municipios brasileños (en el período 2014-2021). El análisis estadístico se realizó en el conjunto de municipios de cada macrorregión brasileña mediante la técnica de barrido espaciotemporal, con un modelo probabilístico de Poisson y con la hipótesis de que los municipios con menor cobertura de vacunación o tasas altas de incumplimiento formarían conglomerados espaciotemporales. Resultados: En el período 2014-2021, el 38,3% y el 12,9% de los municipios alcanzó una cobertura ≥95,0% para la primera y la segunda dosis de la vacuna triple viral, respectivamente; el 53,6% de los municipios tuvo una tasa de incumplimiento alta (del 20,0% al 49,9%) y el 37,2% una tasa extremadamente alta. En la zona del nordeste se observaron los conglomerados primarios de cobertura baja de la primera y la segunda dosis de la vacuna triple viral (administradas en los períodos 2018-2021 y 2020-2021, respectivamente) con un mayor riesgo relativo (RR), en comparación con los demás conglomerados primarios. Se observó un RR alto de tener una tasa elevada de incumplimiento en todas las macrorregiones de Brasil (de entre 1,57 y 26,23). Conclusiones: En algunas macrorregiones, la tasa de incumplimiento había sido elevada desde el 2014, lo cual indica un riesgo de resurgimiento del sarampión. A su vez, en el análisis espaciotemporal se observó una menor cobertura de vacunación en el 2020, lo que denota la influencia de la pandemia de COVID-19.

Study protocol: improving response to malaria in the Amazon through identification of inter-community networks and human mobility in border regions of Ecuador, Peru and Brazil.

INTRODUCTION: Understanding human mobility's role in malaria transmission is critical to successful control and elimination. However, common approaches to measuring mobility are ill-equipped for remote regions such as the Amazon. This study develops a network survey to quantify the effect of community connectivity and mobility on malaria transmission. METHODS: We measure community connectivity across the study area using a respondent driven sampling design among key informants who are at least 18 years of age. 45 initial communities will be selected: 10 in Brazil, 10 in Ecuador and 25 in Peru. Participants will be recruited in each initial node and administered a survey to obtain data on each community's mobility patterns. Survey responses will be ranked and the 2-3 most connected communities will then be selected and surveyed. This process will be repeated for a third round of data collection. Community network matrices will be linked with each country's malaria surveillance system to test the effects of mobility on disease risk. ETHICS AND DISSEMINATION: This study protocol has been approved by the institutional review boards of Duke University (USA), Universidad San Francisco de Quito (Ecuador), Universidad Peruana Cayetano Heredia (Peru) and Universidade Federal Minas Gerais (Brazil). Results will be disseminated in communities by the end of the study.

Clusters Espaço-Temporais de Alto Risco da Mortalidade Infantojuvenil em Mato Grosso, Brasil / High-risk space-time clusters of mortality in children 5 to 14 years of age in Mato Grosso state, Brazil

Resumo O objetivo deste estudo é detectar as áreas de maior risco para óbitos de crianças e adolescentes de 5 a 14 anos no estado de Mato Grosso entre os anos de 2009 e 2020. Estudo ecológico, tipo exploratório, cuja unidade de análise foram os municípios. Considerando dados de mortalidade do SIM e os demográficos do IBGE, o estudo utilizou a estatística multivariada para a identificação dos clusters espaço-temporais de sobrerrisco de mortalidade nesta faixa etária. Dos 5 aos 9 anos, dois clusters de alto risco de mortalidade foram detectados; o mais provável localizado na mesorregião sul (RR: 1,6; LRV: 8,53). Dentre os 5 clusters detectados na faixa etária dos 10 aos 14 anos, o principal foi localizado na mesorregião norte (RR: 2,26; LRV: 7,84). Foi identificada redução das taxas de mortalidade na faixa etária mais jovem e aumento destas taxas na faixa etária mais velha. A identificação destes clusters, cuja análise merece ser replicada a outras partes do território nacional, é a etapa inicial para a investigação de possíveis fatores associados à morbi-mortalidade deste grupo ainda pouco explorado e para o planejamento de intervenções adequadas.

Abstract The study aimed to detect high-risk areas for deaths of children and adolescents 5 to 14 years of age in the state of Mato Grosso, Brazil, from 2009 to 2020. This was an exploratory ecological study with municipalities as the units of analysis. Considering mortality data from the Mortality Information System (SIM) and demographic data from the Brazilian Institute of Geography and Statistics (IBGE), the study used multivariate statistics to identify space-time clusters of excess mortality risk in this age group. From 5 to 9 years of age, two clusters with high mortality risk were detected; the most likely located in the state's southern mesoregion (RR: 1.6; LRT: 8,53). Among the 5 clusters detected in the 10-14-year age group, the main cluster was in the state's northern mesoregion (RR: 2,26; LRT: 7,84). A reduction in mortality rates was observed in the younger age group and an increase in these rates in the older group. The identification of these clusters, whose analysis merits replication in other parts of Brazil, is the initial stage in the investigation of possible factors associated with morbidity and mortality in this group, still insufficiently explored, and for planning adequate interventions.

Heterogeneidade espaço-temporal dos indicadores de imunização da vacina tríplice viral em crianças no Brasil / Space-time heterogeneity of measles, mumps, and rubella vaccination indicators in children from Brazil / Heterogeneidad espaciotemporal de los indicadores de inmunización con la vacuna triple viral en la población infantil de Brasil

RESUMO Objetivo. Avaliar a cobertura vacinal e as taxas de abandono da vacina tríplice viral nas macrorregiões brasileiras. Métodos. Este estudo ecológico, com abordagem espaço-temporal, utilizou dados do Programa Nacional de Imunizações e do Sistema de Informação sobre Nascidos Vivos. Estimou-se a variação anual (2014 a 2021) da cobertura vacinal e da taxa de abandono da vacina tríplice viral em crianças de 12 meses e 15 meses de idade nos 5 570 municípios brasileiros. A análise estatística foi realizada para o conjunto de municípios de cada macrorregião brasileira usando a técnica de varredura espaço-temporal, considerando o modelo probabilístico de Poisson e a hipótese de que os municípios com menores coberturas vacinais ou altas taxa de abandono formariam aglomerados (clusters) espaço-temporais. Resultados. De 2014 a 2021, 38,3% e 12,9% dos municípios alcançaram cobertura da vacina tríplice viral ≥ 95,0% na primeira e segunda doses, respectivamente; 53,6% dos municípios tiveram alta taxa de abandono (20,0% a 49,9%) e 37,2% tiveram altíssima taxa de abandono. O Nordeste apresentou os clusters primários para baixa cobertura da primeira (2018 a 2021) e da segunda doses (2020 a 2021) da vacina tríplice viral com maiores riscos relativos (RR) em relação aos demais clusters primários. O RR para alta taxa de abandono foi elevado em todas as macrorregiões brasileiras (1,57 a 26,23). Conclusões. Em algumas macrorregiões, a taxa de abandono era alta desde 2014, sinalizando risco de ressurgimento do sarampo. Por sua vez, a análise espaço-temporal indicou mais baixas coberturas vacinais em 2020, sugerindo influência da pandemia de covid-19.

ABSTRACT Objective. To evaluate immunization coverage and dropout rates of the measles, mumps, and rubella vaccine across Brazilian regions. Methods. This ecological study employing a space-time approach used data from the National Immunization Program (PNI) and the Live Births Information System (SINASC). We estimated the annual variation (2014 to 2021) in immunization coverage and dropout rate of the measles, mumps, and rubella vaccine in children aged 12 and 15 months in the 5 570 Brazilian municipalities. Statistical analysis was conducted for the municipalities contained in each Brazilian region using the space-time scan technique, considering the Poisson probabilistic model and the hypothesis that municipalities with lower immunization coverage or high dropout rates would form space-time clusters. Results. From 2014 to 2021, 38.3% and 12.9% of municipalities achieved a coverage ≥ 95.0% in the first and second doses respectively; 53.6% of municipalities had a high dropout rate (20.0% to 49.9%) and 37.2% had a very high dropout rate. The Northeast region had primary clusters for low coverage of the first (2018 to 2021) and second vaccine doses (2020 to 2021) with higher relative risks (RR) compared to other primary clusters. The RR for high dropout rate was elevated in all Brazilian regions (1.57 to 26.23). Conclusions. In some Brazilian regions, the dropout rate has been high since 2014, signaling a risk of measles resurgence. In turn, space-time analysis indicated lower vaccination coverage in 2020, suggesting the influence of the COVID-19 pandemic.

RESUMEN Objetivo. Evaluar la cobertura de vacunación y las tasas de incumplimiento del esquema de vacunación triple viral en las macrorregiones de Brasil. Métodos. En este estudio ecológico, con un enfoque espaciotemporal, se utilizaron datos del Programa Nacional de Inmunización y del Sistema de Información sobre Recién Nacidos Vivos. Se estimó la variación anual de la cobertura de vacunación y la tasa de incumplimiento del esquema de vacunación triple viral en niños de 12 y 15 meses en 5570 municipios brasileños (en el período 2014-2021). El análisis estadístico se realizó en el conjunto de municipios de cada macrorregión brasileña mediante la técnica de barrido espaciotemporal, con un modelo probabilístico de Poisson y con la hipótesis de que los municipios con menor cobertura de vacunación o tasas altas de incumplimiento formarían conglomerados espaciotemporales. Resultados. En el período 2014-2021, el 38,3% y el 12,9% de los municipios alcanzó una cobertura ≥95,0% para la primera y la segunda dosis de la vacuna triple viral, respectivamente; el 53,6% de los municipios tuvo una tasa de incumplimiento alta (del 20,0% al 49,9%) y el 37,2% una tasa extremadamente alta. En la zona del nordeste se observaron los conglomerados primarios de cobertura baja de la primera y la segunda dosis de la vacuna triple viral (administradas en los períodos 2018-2021 y 2020-2021, respectivamente) con un mayor riesgo relativo (RR), en comparación con los demás conglomerados primarios. Se observó un RR alto de tener una tasa elevada de incumplimiento en todas las macrorregiones de Brasil (de entre 1,57 y 26,23). Conclusiones. En algunas macrorregiones, la tasa de incumplimiento había sido elevada desde el 2014, lo cual indica un riesgo de resurgimiento del sarampión. A su vez, en el análisis espaciotemporal se observó una menor cobertura de vacunación en el 2020, lo que denota la influencia de la pandemia de COVID-19.

Network Profile: Improving Response to Malaria in the Amazon through Identification of Inter-Community Networks and Human Mobility in Border Regions of Ecuador, Peru, and Brazil.

Objectives: Understanding human mobility's role on malaria transmission is critical to successful control and elimination. However, common approaches to measuring mobility are ill-equipped for remote regions such as the Amazon. This study develops a network survey to quantify the effect of community connectivity and mobility on malaria transmission. Design: A community-level network survey. Setting: We collect data on community connectivity along three river systems in the Amazon basin: the Pastaza river corridor spanning the Ecuador-Peru border; and the Amazon and Javari river corridors spanning the Brazil-Peru border. Participants: We interviewed key informants in Brazil, Ecuador, and Peru, including from indigenous communities: Shuar, Achuar, Shiwiar, Kichwa, Ticuna, and Yagua. Key informants are at least 18 years of age and are considered community leaders. Primary outcome: Weekly, community-level malaria incidence during the study period. Methods: We measure community connectivity across the study area using a respondent driven sampling design. Forty-five communities were initially selected: 10 in Brazil, 10 in Ecuador, and 25 in Peru. Participants were recruited in each initial node and administered a survey to obtain data on each community's mobility patterns. Survey responses were ranked and the 2-3 most connected communities were then selected and surveyed. This process was repeated for a third round of data collection. Community network matrices will be linked with eadch country's malaria surveillance system to test the effects of mobility on disease risk. Findings: To date, 586 key informants were surveyed from 126 communities along the Pastaza river corridor. Data collection along the Amazon and Javari river corridors is ongoing. Initial results indicate that network sampling is a superior method to delineate migration flows between communities. Conclusions: Our study provides measures of mobility and connectivity in rural settings where traditional approaches are insufficient, and will allow us to understand mobility's effect on malaria transmission.

Deucravacitinib, a tyrosine kinase 2 pseudokinase inhibitor, protects human EndoC-ßH1 ß-cells against proinflammatory insults.

Introduction: Type 1 diabetes is characterized by pancreatic islet inflammation and autoimmune-driven pancreatic ß-cell destruction. Interferon-α (IFNα) is a key player in early human type 1 diabetes pathogenesis. IFNα activates the tyrosine kinase 2 (TYK2)-signal transducer and activator of transcription (STAT) pathway, leading to inflammation, HLA class I overexpression, endoplasmic reticulum (ER) stress, and ß-cell apoptosis (in synergy with IL-1ß). As TYK2 inhibition has raised as a potential therapeutic target for the prevention or treatment of type 1 diabetes, we investigated whether the selective TYK2 inhibitor deucravacitinib could protect ß-cells from the effects of IFNα and other proinflammatory cytokines (i.e., IFNγ and IL-1ß). Methods: All experiments were performed in the human EndoC-ßH1 ß-cell line. HLA class I expression, inflammation, and ER stress were evaluated by real-time PCR, immunoblotting, and/or immunofluorescence. Apoptosis was assessed by the DNA-binding dyes Hoechst 33342 and propidium iodide or caspase 3/7 activity. The promoter activity was assessed by luciferase assay. Results: Deucravacitinib prevented IFNα effects, such as STAT1 and STAT2 activation and MHC class I hyperexpression, in a dose-dependent manner without affecting ß-cell survival and function. A comparison between deucravacitinib and two Janus kinase inhibitors, ruxolitinib and baricitinib, showed that deucravacitinib blocked IFNα- but not IFNγ-induced signaling pathway. Deucravacitinib protected ß-cells from the effects of two different combinations of cytokines: IFNα + IL-1ß and IFNγ + IL-1ß. Moreover, this TYK2 inhibitor could partially reduce apoptosis and inflammation in cells pre-treated with IFNα + IL-1ß or IFNγ + IL-1ß. Discussion: Our findings suggest that, by protecting ß-cells against the deleterious effects of proinflammatory cytokines without affecting ß-cell function and survival, deucravacitinib could be repurposed for the prevention or treatment of early type 1 diabetes.

Temporal trend of the dropout rate and vaccination coverage of the triple viral vaccine in Brazil, 2014-2021.

MAIN RESULTS: Annual vaccination coverage was below 95% in Brazil. The second dose of the vaccine showed stationary and decreasing trends in the country's Federative Units. The dropout rate varied greatly throughout the study period. IMPLICATIONS FOR SERVICES: The results found regarding the trends serve to inform and point to the urgency of planning actions aimed at improving coverage of the triple viral vaccine nationally in Brazil. PERSPECTIVES: Investments in enhanced training of epidemiological surveillance professionals and enhanced computerized systems are necessary, with a view to continuous monitoring, to support actions to promote better and timely vaccine coverage. OBJECTIVE: to analyze the temporal trend of coverage and dropout rate for triple viral vaccine in Brazil, according to the country's Federative Units and Macro-Regions, between 2014 and 2021. METHODS: this was an ecological time series study, using data from the National Immunization Program Information System and the Live Birth Information System; joinpoint regression models were used. RESULTS: in Brazil as a whole annual vaccination coverage was below 95% and ranged from 92.3% (2015) to 54.4% (2021); the second dose of the vaccine showed a decreasing temporal trend in the period (average change over the period = -5.8; 95%CI -10.5;-0.8); the temporal trends were stationary and decreasing in the country's Federative Units; the dropout rate ranged from 22.2% (2014) to 37.4% (2021). CONCLUSION: there was a downward trend in vaccination coverage and an increase in the dropout rate in Brazil as a whole and in the country's Federative Units.

First, Be a Good Citizen: Organizational Citizenship Behaviors, Well-Being at Work and the Moderating Role of Leadership Styles.

The study investigates the effect of organizational citizenship behavior (OCB) on well-being at work. The study further examines the moderating role of people and task-focused leadership styles between OCB on well-being at work. Individual-directed organizational citizenship behaviors (OCBI) and organizational-directed organizational citizenship behaviors (OCBO) will also be analyzed. A quantitative study was conducted and convenient sampling was adopted in selecting respondent workers (n = 200) in different Portuguese organizations. The results show that OCBs positively and significantly influence well-being at work. The strength of individual-directed organizational citizenship behaviors (OCBI) on well-being at work is stronger than that of organization-directed organizational citizenship behaviors (OCBO). Contrary to expectations, the relationship between leadership styles and well-being was not statistically significant, offering possibilities for discussion regarding the central importance usually attributed to leadership in the organizational context. However, leadership styles have a moderating effect between OCB and well-being at work, except when the employee adopts OCBO and the leadership style is people-oriented. The present study is innovative because it positions OCB as an antecedent in the relationship with well-being at work and investigates the moderating role of leadership styles in the relationship between organizational citizenship behavior and well-being.

High-risk spatial clusters for Zika, dengue, and chikungunya in Rio de Janeiro, Brazil.

OBJECTIVE: To analyze the spatial distribution and identify high-risk spatial clusters of Zika, dengue, and chikungunya (ZDC), in the city of Rio de Janeiro, Brazil, and their socioeconomic status. METHODS: An ecological study based on data from a seroprevalence survey. Using a rapid diagnostic test to detect the arboviruses, 2,114 individuals were tested in 2018. The spatial distribution was analyzed using kernel estimation. To detect high-risk spatial clusters of arboviruses, we used multivariate scan statistics. The Social Development Index (SDI) was considered in the analysis of socioeconomic status. RESULTS: Among the 2,114 individuals, 1,714 (81.1%) were positive for at least one arbovirus investigated. The kernel estimation showed positive individuals for at least one arbovirus in all regions of the city, with hot spots in the North, coincident with regions with very low or low SDI. The scan statistic detected three significant (p<0.05) high-risk spatial clusters for Zika, dengue, and chikungunya viruses. These clusters correspond to 35.7% (n=613) of all positive individuals of the sample. The most likely cluster was in the North (cluster 1) and overlapped regions with very low and low SDI. Clusters 2 and 3 were in the West and overlapping regions with low and very low SDI, respectively. The highest values of relative risks were in cluster 1 for CHIKV (1.97), in cluster 2 for ZIKV (1.58), and in cluster 3 for CHIKV (1.44). Regarding outcomes in the clusters, the Flavivirus had the highest frequency in clusters 1, 2, and 3 (42.83%, 54.46%, and 52.08%, respectively). CONCLUSION: We found an over-risk for arboviruses in areas with the worst socioeconomic conditions in Rio de Janeiro. Moreover, the highest concentration of people negative for arboviruses occurred in areas considered to have better living conditions.

BCL-XL Overexpression Protects Pancreatic ß-Cells against Cytokine- and Palmitate-Induced Apoptosis.

Diabetes is a chronic disease that affects glucose metabolism, either by autoimmune-driven ß-cell loss or by the progressive loss of ß-cell function, due to continued metabolic stresses. Although both α- and ß-cells are exposed to the same stressors, such as proinflammatory cytokines and saturated free fatty acids (e.g., palmitate), only α-cells survive. We previously reported that the abundant expression of BCL-XL, an anti-apoptotic member of the BCL-2 family of proteins, is part of the α-cell defense mechanism against palmitate-induced cell death. Here, we investigated whether BCL-XL overexpression could protect ß-cells against the apoptosis induced by proinflammatory and metabolic insults. For this purpose, BCL-XL was overexpressed in two ß-cell lines-namely, rat insulinoma-derived INS-1E and human insulin-producing EndoC-ßH1 cells-using adenoviral vectors. We observed that the BCL-XL overexpression in INS-1E cells was slightly reduced in intracellular Ca2+ responses and glucose-stimulated insulin secretion, whereas these effects were not observed in the human EndoC-ßH1 cells. In INS-1E cells, BCL-XL overexpression partially decreased cytokine- and palmitate-induced ß-cell apoptosis (around 40% protection). On the other hand, the overexpression of BCL-XL markedly protected EndoC-ßH1 cells against the apoptosis triggered by these insults (>80% protection). Analysis of the expression of endoplasmic reticulum (ER) stress markers suggests that resistance to the cytokine and palmitate conferred by BCL-XL overexpression might be, at least in part, due to the alleviation of ER stress. Altogether, our data indicate that BCL-XL plays a dual role in ß-cells, participating both in cellular processes related to ß-cell physiology and in fostering survival against pro-apoptotic insults.

A study on social contact rates relevant for the spread of infectious diseases in a Brazilian slum / Um estudo sobre as taxas de contatos sociais relevantes para a difusão de doenças infecciosas em um aglomerado brasileiro / Un estudio sobre las tasas de contactos sociales relevantes para la propagación de enfermedades infecciosas en un barrio popular del Brasil

Abstract Inspired by the POLYMOD study, an epidemiological survey was conducted in June 2021 in one of the most densely populated and socially vulnerable sectors of Belo Horizonte (Brazil). A sample of 1000 individuals allowed us to identify, within a 24-hour period, the rates of social contacts by age groups, the size and frequency of clique in which respondents participated, as well as other associated sociodemographic factors (number of household residents, location of contact, use of public transportation, among others). Data were analyzed in two phases. In the first one, results between two SIR models that simulated an eight-day pandemic process were compared. One included parameters adjusted from observed contact rates, the other operated with parameters adjusted from projected rates for Brazil. In the second phase, by means of a log-lin regression, we modeled the main social determinants of contact rates, using clique density as a proxy variable. The data analysis showed that family size, age, and social circles are the main covariates influencing the formation of cliques. It also demonstrated that compartmentalized epidemiological models, combined with social contact rates, have a better capacity to describe the epidemiological dynamics, providing a better basis for mitigation and control measures for diseases that cause acute respiratory syndromes.

Resumo Inspirado no estudo POLYMOD, foi realizado, em junho de 2021, um survey epidemiológico num dos setores de maior densidade populacional e vulnerabilidade social de Belo Horizonte (Brasil). Uma amostra de 1.000 domicílios permitiu identificar, num período de 24 horas, as taxas de contatos sociais por faixas etárias, o tamanho e a frequência de cliques do qual participou o respondente, assim como outros fatores sociodemográficos associados (número de moradores do domicílio, local do contato, uso do transporte público, entre outros). Os dados foram analisados em duas fases. Na primeira, foram comparados os resultados entre dois modelos SIR que simularam um processo pandêmico de oito dias. Um incluiu parâmetros ajustados a partir das taxas de contatos observadas. O outro operou com parâmetros ajustados a partir de taxas projetadas para o Brasil. Na segunda fase, mediante uma regressão log-lin, modelamos os principais determinantes sociais das taxas de contato, utilizando o adensamento de cliques como uma variável proxy. A análise dos dados mostrou que o tamanho da família, a idade e os círculos sociais são as principais covariáveis que influenciam a formação dos cliques. Também demonstrou que modelos epidemiológicos compartimentais, combinados com taxas de contato social, têm melhor capacidade de descrever a dinâmica epidemiológica, fornecendo uma melhor base para medidas de mitigação e controle de doenças que causam síndromes respiratórias agudas.

Resumen Con inspiración en el estudio POLYMOD, se hizo una encuesta epidemiológica, en junio de 2021, en uno de los sectores más densamente poblados y socialmente vulnerables de Belo Horizonte (Brasil). Una muestra de mil hogares permitió identificar, en un período de 24 horas, el tamaño y la frecuencia de los cliques en los que participó el encuestado, las tasas de contactos sociales por grupos de edad, así como otros factores sociodemográficos asociados (número de residentes en el hogar, lugar de contacto, uso del transporte público, entre otros). Los datos se analizaron en dos fases. En la primera, se compararon los resultados entre dos modelos SIR que simularon un proceso pandémico de ocho días. Uno incluyó parámetros ajustados a partir de tasas de contacto observadas; el otro operó con parámetros ajustados a partir de tasas proyectadas para Brasil. En la segunda, mediante una regresión log-lin, se modelaron los principales determinantes sociales de las tasas de contacto, utilizando la densificación de cliques como una variable proxy. El análisis de los datos mostró que el tamaño de la familia, la edad y los círculos sociales son las principales covariables que influyen en la formación de camarillas. También demostró que los modelos epidemiológicos compartimentados, combinados con tasas de contacto social, son más capaces de describir la dinámica epidemiológica, proporcionando una mejor base para las medidas de mitigación y control de las enfermedades causantes de síndromes respiratorios agudos.

High-risk spatial clusters for Zika, dengue, and chikungunya in Rio de Janeiro, Brazil

ABSTRACT OBJECTIVE To analyze the spatial distribution and identify high-risk spatial clusters of Zika, dengue, and chikungunya (ZDC), in the city of Rio de Janeiro, Brazil, and their socioeconomic status. METHODS An ecological study based on data from a seroprevalence survey. Using a rapid diagnostic test to detect the arboviruses, 2,114 individuals were tested in 2018. The spatial distribution was analyzed using kernel estimation. To detect high-risk spatial clusters of arboviruses, we used multivariate scan statistics. The Social Development Index (SDI) was considered in the analysis of socioeconomic status. RESULTS Among the 2,114 individuals, 1,714 (81.1%) were positive for at least one arbovirus investigated. The kernel estimation showed positive individuals for at least one arbovirus in all regions of the city, with hot spots in the North, coincident with regions with very low or low SDI. The scan statistic detected three significant (p<0.05) high-risk spatial clusters for Zika, dengue, and chikungunya viruses. These clusters correspond to 35.7% (n=613) of all positive individuals of the sample. The most likely cluster was in the North (cluster 1) and overlapped regions with very low and low SDI. Clusters 2 and 3 were in the West and overlapping regions with low and very low SDI, respectively. The highest values of relative risks were in cluster 1 for CHIKV (1.97), in cluster 2 for ZIKV (1.58), and in cluster 3 for CHIKV (1.44). Regarding outcomes in the clusters, the Flavivirus had the highest frequency in clusters 1, 2, and 3 (42.83%, 54.46%, and 52.08%, respectively). CONCLUSION We found an over-risk for arboviruses in areas with the worst socioeconomic conditions in Rio de Janeiro. Moreover, the highest concentration of people negative for arboviruses occurred in areas considered to have better living conditions.

Tendência temporal da taxa de abandono e da cobertura da vacina tríplice viral no Brasil, 2014-2021 / Temporal trend of the dropout rate and vaccination coverage of the triple viral vaccine in Brazil, 2014-2021 / Tendencia temporal de tasa de abandono y cobertura de vacunación de la vacuna triple viral en Brasil, 2014-2021

Objective: to analyze the temporal trend of coverage and dropout rate for triple viral vaccine in Brazil, according to the country's Federative Units and Macro-Regions, between 2014 and 2021. Methods: this was an ecological time series study, using data from the National Immunization Program Information System and the Live Birth Information System; joinpoint regression models were used. Results: in Brazil as a whole annual vaccination coverage was below 95% and ranged from 92.3% (2015) to 54.4% (2021); the second dose of the vaccine showed a decreasing temporal trend in the period (average change over the period = -5.8; 95%CI -10.5;-0.8); the temporal trends were stationary and decreasing in the country's Federative Units; the dropout rate ranged from 22.2% (2014) to 37.4% (2021). Conclusion: there was a downward trend in vaccination coverage and an increase in the dropout rate in Brazil as a whole and in the country's Federative Units.

Objetivo: analizar la tendencia temporal de cobertura y tasa deserción de la vacuna triple viral en Brasil, y según Unidades de la Federación y Regiones, entre 2014 y 2021. Métodos: estudio de serie temporal ecológica, sobre datos de los sistemas del Inmunizaciones y Nacido Vivo; se utilizaron modelos de regresión de punto de inflexión. Resultados: la cobertura anual de vacunación estuvo por debajo del 95% y osciló entre 92,3% (2015) y 54,4% (2021), en Brasil; la segunda dosis mostró una tendencia temporal decreciente en el período (variación promedia en el periodo = -5,8; IC95% -10,5;-0,8); las tendencias temporales fueron estacionarias y decrecientes en las Unidades de la Federación; la tasa deserción de varió del 22,2% (2014) al 37,4% (2021). Conclusión: hubo una tendencia a la baja en las coberturas de vacunación y un aumento en la tasa de deserción en Brasil y en las Unidades de la Federación.

Objetivo: analisar a tendência temporal da cobertura e da taxa de abandono da vacina tríplice viral no Brasil, nas Unidades da Federação (UFs) e grandes regiões nacionais, entre 2014 e 2021. Métodos: estudo ecológico de série temporal, sobre dados do Sistema de Informações do Programa Nacional de Imunizações e do Sistema de Informações sobre Nascidos Vivos; foram utilizados modelos de regressão por pontos de inflexão. Resultados: as coberturas vacinais anuais, no Brasil como um todo, estiveram abaixo de 95%, variando de 92,3% (2015) a 54,4% (2021); a segunda dose da vacina apresentou tendência temporal decrescente no período (variação média no período = -5,8; IC95% -10,5;-0,8); as tendências temporais foram estacionárias e decrescentes nas UFs; a taxa de abandono variou de 22,2% (2014) a 37,4% (2021). Conclusão: houve tendência de queda da cobertura vacinal e aumento da taxa de abandono, no Brasil como um todo e nas UFs.

Characteristics and temporal trends of mortality rates in children and adolescents in Mato Grosso and Brazil, 2009-2020. / Características e tendência temporal das taxas de mortalidade de crianças e adolescentes em Mato Grosso e no Brasil, 2009 a 2020.

OBJECTIVE: to analyze the characteristics and temporal trend of mortality rates in the population aged 5 to 14 years in Mato Grosso state and in Brazil, from 2009 to 2020. METHODS: this was an ecological time-series study, based on data taken from the Mortality Information System. Descriptive and trend analyses were performed, using the joinpoint regression model and calculating the average annual percentage change (AAPC). RESULTS: in Brazil and in Mato Grosso state, deaths were predominantly male, preventable and due to external causes. A falling trend was identified for Brazil (5-9 years AAPC: -2.9; 95%CI -4.3;-1.6 and 10-14 years AAPC: -2.5; 95%CI -3.3;-1.8), while a stationary trend was found in Mato Grosso (5-9 years AAPC: -2.0; 95%CI -5.6;1.7 and 10-14 years AAPC: -0.1; 95%CI -5.9;6.1). CONCLUSION: the stable trend of mortality at high levels demands urgent interventions to reduce it.

[Identification of risk areas and factors associated with the 2019 measles epidemic in the State of São Paulo, Brazil]. / Identificação de áreas de risco e fatores associados à epidemia de sarampo de 2019 no Estado de São Paulo, Brasil.

This study aimed to analyze the occurrence of clusters and factors associated with the resurgence of measles cases from the largest epidemic of the post-elimination period in the State of São Paulo, Brazil, in 2019. Sociosanitary and care factors were analyzed by zero-inflated Poisson (ZIP) and ZIP models with structured and unstructured spatial effect. The SCAN statistic was used to analyze the occurrence of case clusters. Clusters of high-risk cases were identified in municipalities that make up the intermediate region of São Paulo. In the ZIP model, the following variables were observed as risk factors at the municipal level: household heads under 18 years old (adjusted RR =0 1.39; 95%CrI: 1.27-1.53), inequality in income distribution (adjusted RR = 36.67; 95%CrI: 26.36-51.15), unemployment in people over 18 years old (adjusted RR = 1.10; 95%CrI: 1.08-1.12), and non-existent street lighting (adjusted RR = 1.05; 95%CrI: 1.04-1.05). In the ZIP models with structured and unstructured spatial effect, the following variables were observed as risk factors: household heads under 18 years old (adjusted RR = 1.36; 95%CrI: 1.04-1.90) and inequality in income distribution (adjusted RR = 3.12; 95%CrI: 1.02-9.48). In both models, the coverage of health agents was presented as a protective factor. The findings reinforce the importance of intensifying measles surveillance actions articulated to the Family Health Strategy, especially in areas with greater social vulnerability, to ensure equitable and satisfactory vaccination coverage and reduce the risk of reemergence of the disease.

O objetivo foi analisar a ocorrência de clusters e fatores associados ao ressurgimento de casos de sarampo da maior epidemia do período pós-eliminação, ocorrida no Estado de São Paulo, Brasil, em 2019. Fatores sociossanitários e assistenciais foram analisados por modelos de Poisson inflacionado de zero (ZIP) e ZIP com efeito espacial estruturado e não estruturado. A estatística de varredura SCAN foi usada para analisar a ocorrência de clusters de casos. Foram identificados clusters de casos de alto risco em municípios que compõem a região intermediária de São Paulo. No modelo ZIP, foram observadas como fatores de risco no nível municipal as variáveis chefes de domicílio menores de 18 anos (RR ajustado = 1,39; ICr95%: 1,27-1,53), desigualdade na distribuição de renda (RR ajustado = 36,67; ICr95%: 26,36-51,15), desocupação em maiores de 18 anos (RR ajustado = 1,10; ICr95%: 1,08-1,12) e iluminação pública inexistente (RR ajustado = 1,05; ICr95%: 1,04-1,05). Nos modelos ZIP com efeito espacial estruturado e não estruturado, foram identificados como fatores de risco os indicadores chefes de domicílio menores de 18 anos (RR ajustado = 1,36; ICr95%: 1,04-1,90) e desigualdade na distribuição dos rendimentos do trabalho (RR ajustado = 3,12; ICr95%: 1,02-9,48). Em ambos os modelos, a cobertura de agentes de saúde se apresentou como fator de proteção. Os achados reforçam a importância de intensificar as ações de vigilância de sarampo articuladas à Estratégia Saúde da Família, especialmente em áreas de maior vulnerabilidade social, para garantir coberturas vacinais equânimes e satisfatórias e reduzir o risco de reemergência da doença.

El objetivo de este estudio fue analizar la ocurrencia de clusters y sus factores asociados al resurgimiento de los casos de sarampión teniendo por base la mayor epidemia del período poserradicación que tuvo lugar en el Estado de São Paulo, Brasil, en 2019. Los factores sociosanitarios y asistenciales se analizaron mediante modelos de Poisson zero inflated (ZIP) y ZIP con efecto espacial estructurado y no estructurado. La estadística de exploración SCAN se utilizó para analizar la ocurrencia de clusters de casos. Se identificaron clusters de casos de alto riesgo en municipios que componen la Región Intermedia de São Paulo. En el modelo ZIP se observaron como factores de riesgo a nivel municipal las variables jefes de hogar menores de 18 años (RR ajustado = 1,39; ICr95%: 1,27-1,53), desigualdad en la distribución de renta (RR ajustado = 36,67; ICr95%: 26,36-51,15), desempleo en mayores de 18 años (RR ajustado = 1,10; ICr95%: 1,08-1,12) y alumbrado público inexistente (RR ajustado = 1,05; ICr95%: 1,04-1,05). En los modelos ZIP con efecto espacial estructurado y no estructurado, se identificaron como factores de riesgo los indicadores jefe de hogar menor de 18 años (RR ajustado = 1,36; ICr95%: 1,04-1,90) y la desigualdad en la distribución de los ingresos de trabajo (RR ajustado = 3,12; ICr95%: 1,02- 9,48). En ambos modelos, la cobertura de los agentes de salud fue un factor protector. Los hallazgos evidencian la importancia de intensificar las acciones de vigilancia del sarampión vinculadas a la Estrategia de Salud Familiar, especialmente en las zonas de mayor vulnerabilidad social, para garantizar una cobertura de la vacunación de manera equitativa y satisfactoria, además de reducir el riesgo de reemergencia de la enfermedad.

[A structural method to assess the course of the SARS-CoV-2 pandemic in school environmentsMétodo estructural para examinar el curso de la pandemia por el SARS-CoV-2 en ambientes escolares]. / Método estrutural para aferir o curso pandêmico do SARS-CoV-2 em ambientes escolares.

The COVID-19 pandemic has imposed several dilemmas for managers in the public sector, with school reopening being among the most complex decisions. The present article presents a microsimulation model of the pandemic course considering various scenarios within the confines of a classroom in the city of Belo Horizonte, Brazil. For that, a susceptible-infectious-recovered (SIR) model was integrated with a random graph model, associating epidemiological characteristics with sociometric and sociodemographic factors. Social contact rates projected for Brazil in the European POLYMOD project were adapted for the city of Belo Horizonte to simulate the number of contacts among individuals considering a Poisson distribution. The simulation used as reference a group of 20 students and their families. The projected scenarios discriminated three age groups with their respective rate of daily social contacts: 0 to 5 years (0.01), 6 a 14 years (1.80), and 15 to 19 years (0.20). The simulations showed clear differences between these age groups, depending on the initial number of infected individuals and on the use or not of face masks in the school. The results confirm that the absence of adequate mitigation measures entails a considerable increase in transmission in the school setting.

La pandemia de COVID-19 ha creado una serie de dilemas para los administradores públicos, que ha hecho de la reapertura de las escuelas una de las decisiones más complejas. En el presente artículo se presenta una microsimulación del curso de la pandemia, en la cual se analizan varias situaciones hipotéticas dentro de los límites de un salón de clases en la ciudad de Belo Horizonte (Brasil). Se utilizó un modelo de personassusceptibles, infectadas y recuperadas (SIR) integrado a un modelo de gráficos aleatorios, dentro del cual se asociaron lascaracterísticas epidemiológicas a factores sociométricos y sociodemográficos. Se utilizaron las tasas de contactos sociales previstas para Brasil por el proyecto europeo POLYMOD y adaptadas a la ciudad de Belo Horizonte con el fin de simular el número de contactos entre las personas con una distribución de Poisson. Para la simulación se tomó como referencia un grupo de 20 alumnos y sus familias. En las situaciones hipotéticas proyectadas se distinguieron tres grupos etarios con sus respectivas tasas diarias de contactos sociales: de 0 a 5 años (0,01), de 6 a 14 años (1,80) y de 15 a 19 años (0,20). Las simulaciones demostraron que hay claras diferencias en los grupos etarios analizados, según el número inicial de personas infectadas y el uso o la falta de uso de mascarilla en el ambiente escolar. Los resultados confirman que la falta de medidas adecuadas de mitigación eleva de forma considerable el riesgo de contagio en la comunidad escolar.

In Vitro Assays to Identify Metabolism-Disrupting Chemicals with Diabetogenic Activity in a Human Pancreatic ß-Cell Model.

There is a need to develop identification tests for Metabolism Disrupting Chemicals (MDCs) with diabetogenic activity. Here we used the human EndoC-ßH1 ß-cell line, the rat ß-cell line INS-1E and dispersed mouse islet cells to assess the effects of endocrine disruptors on cell viability and glucose-stimulated insulin secretion (GSIS). We tested six chemicals at concentrations within human exposure (from 0.1 pM to 1 µM). Bisphenol-A (BPA) and tributyltin (TBT) were used as controls while four other chemicals, namely perfluorooctanoic acid (PFOA), triphenylphosphate (TPP), triclosan (TCS) and dichlorodiphenyldichloroethylene (DDE), were used as "unknowns". Regarding cell viability, BPA and TBT increased cell death as previously observed. Their mode of action involved the activation of estrogen receptors and PPARγ, respectively. ROS production was a consistent key event in BPA-and TBT-treated cells. None of the other MDCs tested modified viability or ROS production. Concerning GSIS, TBT increased insulin secretion while BPA produced no effects. PFOA decreased GSIS, suggesting that this chemical could be a "new" diabetogenic agent. Our results indicate that the EndoC-ßH1 cell line is a suitable human ß-cell model for testing diabetogenic MDCs. Optimization of the test methods proposed here could be incorporated into a set of protocols for the identification of MDCs.

G protein-coupled estrogen receptor activation by bisphenol-A disrupts the protection from apoptosis conferred by the estrogen receptors ERα and ERß in pancreatic beta cells.

17ß-estradiol protects pancreatic ß-cells from apoptosis via the estrogen receptors ERα, ERß and GPER. Conversely, the endocrine disruptor bisphenol-A (BPA), which exerts multiple effects in this cell type via the same estrogen receptors, increased basal apoptosis. The molecular-initiated events that trigger these opposite actions have yet to be identified. We demonstrated that combined genetic downregulation and pharmacological blockade of each estrogen receptor increased apoptosis to a different extent. The increase in apoptosis induced by BPA was diminished by the pharmacological blockade or the genetic silencing of GPER, and it was partially reproduced by the GPER agonist G1. BPA and G1-induced apoptosis were abolished upon pharmacological inhibition, silencing of ERα and ERß, or in dispersed islet cells from ERß knockout (BERKO) mice. However, the ERα and ERß agonists PPT and DPN, respectively, had no effect on beta cell viability. To exert their biological actions, ERα and ERß form homodimers and heterodimers. Molecular dynamics simulations together with proximity ligand assays and coimmunoprecipitation experiments indicated that the interaction of BPA with ERα and ERß as well as GPER activation by G1 decreased ERαß heterodimers. We propose that ERαß heterodimers play an antiapoptotic role in beta cells and that BPA- and G1-induced decreases in ERαß heterodimers lead to beta cell apoptosis. Unveiling how different estrogenic chemicals affect the crosstalk among estrogen receptors should help to identify diabetogenic endocrine disruptors.