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ABSTRACT Objective: The objective of this narrative review is to discuss the current state of research funding in Brazil. Materials and Methods: This study is based on the most recent edition of the course Funding for Research and Innovation in the University of Sao Paulo School of Medicine which was a three-day course with 12 hours of instruction. The course brought together leading experts in the field to comprehensively discuss the current state of research funding in Brazil. Each speaker provided a presentation on a specific topic related to research funding. After the workshop, speakers assembled relevant topics in this manuscript. Results: collaborative research is critical for securing research funding. It optimizes proposal competitiveness, amplifies societal impact, and manages risks effectively. As such, fostering and supporting these collaborations is paramount for both researchers and funding agencies. To maintain the highest integrity in research, investigators involved in these collaborations must disclose any relationships that could potentially influence the outcomes or interpretation of their projects. Conclusions: In Brazil, the mainstay of research funding stems from public entities, with agencies such as CNPq, CAPES, and state bodies like FAPESP, FAPERJ, FAPEMIG and others at the forefront. Concurrently, industry funding offers viable pathways, especially through industry-sponsored studies, investigator-led projects, and collaborative initiatives. The Brazilian funding landscape is further enriched by innovative platforms, including crowdfunding and the contributions of institutions like the Serrapilheira Institute. Internationally, esteemed organizations such as the National Institutes of Health (NIH) and the Bill & Melinda Gates Foundation stand out as potential funders.

The Tradescantia stamen hair mutation assay (Trad-SHM) was employed for assessing the environmental mutagenesis in two areas of São Paulo City. The study sites were defined as follows: 1) Celso Garcia Avenue, an industrial area on the outskirts of the urban center (Belém neighborhood), with an average daily traffic volume of 8,750 vehicles; 2) Doutor Arnaldo Avenue, in downtown area (Pinheiros neighborhood), with a mostly residential and business offices occupation, with an average daily traffic volume of 46,125 vehicles. The negative control (background) site is located in the city of Jaguariúna, 138 km from São Paulo, in an area of low atmospheric pollution. The mutation frequency observed for Belém was similar to the background for clone 4430, whereas plants exposed in Pinheiros showed significant increases in mutation rate. Positive correlation was observed between mutation frequency and the levels of particulate matter in the atmosphere. This indicated a relationship between mutation frequency and the amount of atmospheric pollution present at the exposure sites in São Paulo City, with special reference to vehicular emissions.

Carotid bodies are chemoreceptors sensitive to a fall of partial oxygen pressure in blood (hypoxia). The morphological alterations of these organs in patients with chronic obstructive pulmonary disease (COPD) and in people living at high altitude are well known. However, it is not known whether the histological profile of human carotid bodies is changed in acute clinical conditions such as acute respiratory distress syndrome (ARDS). The objective of the present study was to perform a quantitative analysis of the histology of carotid bodies collected from patients who died of ARDS. A morphometric study of carotid bodies collected during routine autopsies was carried out on three groups: patients that died of non-respiratory diseases (controls, N = 8), patients that presented COPD and died of its complications or associated diseases (N = 7), and patients that died of ARDS (N = 7). Morphometric measurements of the volume fraction of clusters of chief cells were performed in five fields on each slide at 40X magnification. The numerical proportion of the four main histological cell types (light, dark, progenitor and sustentacular cells) was determined analyzing 10 fields on each slide at 400X magnification. The proportion of dark cells was 0.22 in ARDS patients, 0.12 in controls (P

OBJETIVO: Investigar os efeitos causados pela poluição atmosférica na morbidade por pneumonia e por gripe em idosos entre 1996 e 1998. MÉTODOS: Foram obtidos dados diários de atendimentos por pneumonia e gripe para idosos em pronto-socorro médico de um hospital-escola de referência no Município de São Paulo, SP, Brasil. Os níveis diários de CO, O3, SO2, NO2 e PM10 foram obtidos na Companhia de Tecnologia de Saneamento Ambiental, e os dados diários de temperatura e umidade relativa do ar foram obtidos no Instituto Astronômico e Geofísico da USP. Para verificar a relação existente entre pneumonia e gripe e poluição atmosférica, utilizou-se o modelo aditivo generalizado de regressão de Poisson, tendo como variável dependente o número diário de atendimentos por pneumonia e gripe e como variáveis independentes as concentrações médias diárias dos poluentes atmosféricos. A análise foi ajustada para sazonalidade de longa duração (número de dias transcorridos), sazonalidade de curta duração (dias da semana), temperatura mínima, umidade média, períodos de rodízio e os atendimentos por doenças não-respiratórias em idosos. RESULTADOS: O3 e SO2 estão diretamente associados à pneumonia e à gripe, independentemente das variáveis de controle. Porém, na análise conjunta, eles perdem sua significância estatística. Pôde-se observar que um aumento interquartil (25%-75%) para o O3 (38,80 mig/m³) e SO2 (15,05 mig/m³) levaram a um acréscimo de 8,07% e 14,51%, respectivamente, no número de atendimentos por pneumonia e gripe em idosos. CONCLUSÕES: Os resultados sugerem que a poluição atmosférica promove efeitos adversos para a saúde de idosos.

Abstract BackgroundStudies have reported the adverse effects of cold events on influenza. However, the role of critical factors, such as characteristics of cold spells, and regional variations remain unresolved. ObjectiveWe aimed to systematically evaluate the association between cold spells and influenza incidence in mainland China. MethodsThis time series analysis used surveillance data of daily influenza from 325 sites in China in the 2014‐2019 period. A total of 15 definitions of cold spells were adopted based on combinations of temperature thresholds and days of duration. A distributed lag linear model was used to estimate the short-term effects of cold spells on influenza incidence during the cool seasons (November to March), and we further explored the potential impact of cold spell characteristics (ie, intensity, duration, and timing during the season) on the estimated associations. Meta-regressions were used to evaluate the modification effect of city-level socioeconomic indicators. ResultsThe overall effect of cold spells on influenza incidence increased with the temperature threshold used to define cold spells, whereas the added effects were generally small and not statistically significant. The relative risk of influenza-associated with cold spells was 3.35 (95% CI 2.89‐3.88), and the estimated effects were stronger during the middle period of cool seasons. The health effects of cold spells varied geographically and residents in Jiangnan region were vulnerable groups (relative risk 7.36, 95% CI 5.44‐9.95). The overall effects of cold spells were positively correlated with the urban population density, population size, gross domestic product per capita, and urbanization rate, indicating a sterner response to cold spells in metropolises. ConclusionsCold spells create a substantial health burden on seasonal influenza in China. Findings on regional and socioeconomic differences in the health effects of cold spells on seasonal influenza may be useful in formulating region-specific public health policies to address the hazardous effects of cold spells.

Objectives: Performing autopsies in a pandemic scenario is challenging, as the need to understand pathophysiology must be balanced with the contamination risk. A minimally invasive autopsy might be a solution. We present a model that combines radiology and pathology to evaluate postmortem CT lung findings and their correlation with histopathology. Methods: Twenty-nine patients with fatal COVID-19 underwent postmortem chest CT, and multiple lung tissue samples were collected. The chest CT scans were analyzed and quantified according to lung involvement in five categories: normal, ground-glass opacities, crazy-paving, small consolidations, and large or lobar consolidations. The lung tissue samples were examined and quantified in three categories: normal lung, exudative diffuse alveolar damage (DAD), and fibroproliferative DAD. A linear index was used to estimate the global severity of involvement by CT and histopathological analysis. Results: There was a positive correlation between patient mean CT and histopathological severity score indexes - Pearson correlation coefficient (R) = 0.66 (p = 0.0078). When analyzing the mean lung involvement percentage of each finding, positive correlations were found between the normal lung percentage between postmortem CT and histopathology (R=0.65, p = 0.0082), as well as between ground-glass opacities in postmortem CT and normal lungs in histopathology (R=0.65, p = 0.0086), but negative correlations were observed between ground-glass opacities extension and exudative diffuse alveolar damage in histological slides (R=−0.68, p = 0.005). Additionally, it was found is a trend toward a decrease in the percentage of normal lung tissue on the histological slides as the percentage of consolidations in postmortem CT scans increased (R =−0.51, p = 0.055). The analysis of the other correlations between the percentage of each finding did not show any significant correlation or correlation trends (p ≥ 0.10). Conclusions: A minimally invasive autopsy is valid. As the severity of involvement is increased in CT, more advanced disease is seen on histopathology. However, we cannot state that one specific radiological category represents a specific pathological correspondent. Ground-glass opacities, in the postmortem stage, must be interpreted with caution, as expiratory lungs may overestimate disease.

ABSTRACT OBJECTIVE To evaluate the association between gestational age and green areas, urban built areas, and the concentration of particulate matter 2.5 (PM2.5) in the city of São Paulo, analyzing the irregular distribution of these areas and pollution levels above the recommended level. METHODS The study population consisted of a cohort of live births from 2012, and data from the Live Birth Information System (Sinasc) of the city of São Paulo were used. Using satellite images and supervised classification, the distribution and quantity of green areas and built areas in the city of São Paulo was obtained, as well as the concentrations of PM2.5. Logistic regressions were used to obtain possible associations. RESULTS The results of the study show that a lower percentage of green areas is significantly associated with a higher chance of preterm births. A higher building density was positively associated with the odds ratio for preterm birth. We did not find any significant associations between air pollution (PM2.5) and preterm births. CONCLUSIONS The results of this study show that greener areas are less associated with preterm births when compared with less green areas.

Megacities can be considered excellent laboratories for studying the effects of the urban environment on human health. Typically, exposure to pollution is estimated according to daily or annual averages of pollutant concentrations, collected at monitoring stations, using satellite data for remote sensing of pollutant levels, considering proximity to major roads, or through personal exposure monitoring with portable sensors. However, these approaches fall short in identifying individual exposure values over a lifetime. It is well established that individuals living in large urban areas inhale atmospheric particles containing carbonaceous components, resulting in the deposition of black pigments in lung tissue, known as black carbon or anthracosis. This study aims to detail the procedures for assessing the deposition of such pigments, which serve as an estimate of an individual’s exposure to atmospheric pollution particles. Data collection involves administering detailed questionnaires and capturing lung images in the autopsy room. The analysis is based on macroscopic quantification of black pigments, supplemented by an evaluation of personal habits and the clinical histories of the individuals. This method of estimating lifetime exposure to inhaled particles provides a valuable tool for understanding the correlation between urban living and its potential health effects.

Abstract Objective: To create a protocol for performing minimally invasive autopsies (MIA) in detecting deaths from arboviruses and report preliminary data from its application in Ceará state, Brazil. Methods: Training was provided to medical pathologists on MIA. Results: A protocol was established for performing MIA, defining criteria for sample collection, storage methods, and diagnoses to be carried out according to the type of biological sample; 43 MIAs were performed in three months. Of these, 21 (48.8%) arrived at the Death Verification Service (SVO) with arboviruses as a diagnostic hypothesis, and seven (16.3%) were confirmed (six chikungunya cases and one dengue case); cases of COVID-19 (n = 9), tuberculosis (n = 5), meningitis (n = 4), cryptococcosis (n = 1), Creutzfeldt-Jakob disease (n = 1), breast cancer (n = 1), and human rabies (n = 1) were also confirmed. Conclusion: The protocol implemented enabled identification of a larger number of suspected arbovirus-related deaths, as well as confirmation of other diseases of interest for surveillance.

BackgroundThe regional disparity of heatwave-related mortality over a long period has not been sufficiently assessed across the globe, impeding the localisation of adaptation planning and risk management towards climate change. We quantified the global mortality burden associated with heatwaves at a spatial resolution of 0.5°×0.5° and the temporal change from 1990 to 2019.Methods and findingsWe collected data on daily deaths and temperature from 750 locations of 43 countries or regions, and 5 meta-predictors in 0.5°×0.5° resolution across the world. Heatwaves were defined as location-specific daily mean temperature ≥95th percentiles of year-round temperature range with duration ≥2 days. We first estimated the location-specific heatwave-mortality association. Secondly, a multivariate meta-regression was fitted between location-specific associations and 5 meta-predictors, which was in the third stage used with grid cell-specific meta-predictors to predict grid cell-specific association. Heatwave-related excess deaths were calculated for each grid and aggregated. During 1990 to 2019, 0.94% (95% CI: 0.68-1.19) of deaths [i.e., 153,078 cases (95% eCI: 109,950-194,227)] per warm season were estimated to be from heatwaves, accounting for 236 (95% eCI: 170-300) deaths per 10 million residents. The ratio between heatwave-related excess deaths and all premature deaths per warm season remained relatively unchanged over the 30 years, while the number of heatwave-related excess deaths per 10 million residents per warm season declined by 7.2% per decade in comparison to the 30-year average. Locations with the highest heatwave-related death ratio and rate were in Southern and Eastern Europe or areas had polar and alpine climates, and/or their residents had high incomes. The temporal change of heatwave-related mortality burden showed geographic disparities, such that locations with tropical climate or low incomes were observed with the greatest decline. The main limitation of this study was the lack of data from certain regions, e.g., Arabian Peninsula and South Asia.ConclusionsHeatwaves were associated with substantial mortality burden that varied spatiotemporally over the globe in the past 30 years. The findings indicate the potential benefit of governmental actions to enhance health sector adaptation and resilience, accounting for inequalities across communities.

Background: Temperature variability (TV) is associated with increased mortality risk. However, it is still unknown whether intra-day or inter-day TV has different effects. Objectives: We aimed to assess the association of intra-day TV and inter-day TV with all-cause, cardiovascular, and respiratory mortality. Methods: We collected data on total, cardiovascular, and respiratory mortality and meteorology from 758 locations in 47 countries or regions from 1972 to 2020. We defined inter-day TV as the standard deviation (SD) of daily mean temperatures across the lag interval, and intra-day TV as the average SD of minimum and maximum temperatures on each day. In the first stage, inter-day and intra-day TVs were modelled simultaneously in the quasi-Poisson time-series model for each location. In the second stage, a multi-level analysis was used to pool the location-specific estimates. Results: Overall, the mortality risk due to each interquartile range [IQR] increase was higher for intra-day TV than for inter-day TV. The risk increased by 0.59% (95% confidence interval [CI]: 0.53, 0.65) for all-cause mortality, 0.64% (95% CI: 0.56, 0.73) for cardiovascular mortality, and 0.65% (95% CI: 0.49, 0.80) for respiratory mortality per IQR increase in intra-day TV0–7 (0.9 °C). An IQR increase in inter-day TV0–7 (1.6 °C) was associated with 0.22% (95% CI: 0.18, 0.26) increase in all-cause mortality, 0.44% (95% CI: 0.37, 0.50) increase in cardiovascular mortality, and 0.31% (95% CI: 0.21, 0.41) increase in respiratory mortality. The proportion of all-cause deaths attributable to intra-day TV0–7 and inter-day TV0–7 was 1.45% and 0.35%, respectively. The mortality risks varied by lag interval, climate area, season, and climate type. Conclusions: Our results indicated that intra-day TV may explain the main part of the mortality risk related to TV and suggested that comprehensive evaluations should be proposed in more countries to help protect human health.

Assessing the association between temperature frequency and mortality can provide insights into human adaptation to local ambient temperatures. We collected daily time-series data on mortality and temperature from 757 locations in 47 countries/regions during 1979–2020. We used a two-stage time series design to assess the association between temperature frequency and all-cause mortality. The results were pooled at the national, regional, and global levels. We observed a consistent decrease in the risk of mortality as the normalized frequency of temperature increases across the globe. The average increase in mortality risk comparing the 10th to 100th percentile of normalized frequency was 13.03% (95% CI: 12.17–13.91), with substantial regional differences (from 4.56% in Australia and New Zealand to 33.06% in South Europe). The highest increase in mortality was observed for high-income countries (13.58%, 95% CI: 12.56–14.61), followed by lower-middle-income countries (12.34%, 95% CI: 9.27–15.51). This study observed a declining risk of mortality associated with higher temperature frequency. Our findings suggest that populations can adapt to their local climate with frequent exposure, with the adapting ability varying geographically due to differences in climatic and socioeconomic characteristics.

Abstract Background Lung fibrosis is a major concern in severe COVID-19 patients undergoing mechanical ventilation (MV). Lung fibrosis frequency in post-COVID syndrome is highly variable and even if the risk is proportionally small, many patients could be affected. However, there is still no data on lung extracellular matrix (ECM) composition in severe COVID-19 and whether it is different from other aetiologies of ARDS. Methods We have quantified different ECM elements and TGF-β expression in lung tissue of 28 fatal COVID-19 cases and compared to 27 patients that died of other causes of ARDS, divided according to MV duration (up to six days or seven days or more). In COVID-19 cases, ECM elements were correlated with lung transcriptomics and cytokines profile. Results We observed that COVID-19 cases presented significant increased deposition of collagen, fibronectin, versican, and TGF-β, and decreased decorin density when compared to non-COVID-19 cases of similar MV duration. TGF-β was precociously increased in COVID-19 patients with MV duration up to six days. Lung collagen was higher in women with COVID-19, with a transition of upregulated genes related to fibrillogenesis to collagen production and ECM disassembly along the MV course. Conclusions Fatal COVID-19 is associated with an early TGF-β expression lung environment after the MV onset, followed by a disordered ECM assembly. This uncontrolled process resulted in a prominent collagen deposition when compared to other causes of ARDS. Our data provides pathological substrates to better understand the high prevalence of pulmonary abnormalities in patients surviving COVID-19.

RESUMO A redução das doenças infecciosas e vida mais longa favoreceram a maior prevalência das doenças crônicas como câncer, diabetes, doenças cardiovasculares e doenças respiratórias. Em geral, a escala geográfica dos estudos sobre condições socioeconômicas e problemas de saúde é o município. Nesta escala geográfica não há separação nítida entre os tipos de assentamento. Estudos intraurbanos por tipo de assentamento podem contribuir para um retrato mais fiel sobre as desigualdades nas condições de vida. Neste estudo, foram analisados dados de residentes do município de São Paulo que foram internados e os que foram a óbito, por doenças do aparelho circulatório de 2010 a 2016, para óbitos, e de 2011 a 2016, para internações. Cada internação e óbito foi atribuída ao assentamento de moradia segundo tipo: aglomerado subnormal (AGSN), precário ou regular. Foram feitos os seguintes cálculos: proporção de internações hospitalares pelo Sistema Único de Saúde (SUS) por grupos de causas, taxas padronizadas por sexo e faixa etária, Razão internação/habitante segundo sexo, faixa etária e tipo de assentamento e Taxas padronizadas por sexo e faixa etária de mortalidade por doenças do aparelho circulatório. Os resultados encontrados mostram uma situação ainda mais iníqua nos assentamentos precários para todas as faixas etárias, nos dois sexos. A diferença da saúde cardiovascular entre os três tipos de assentamentos, avaliada por meio das proporções de internações hospitalares e pelas taxas de mortalidade, evidenciam que quase 1.700 mil pessoas em São Paulo estão em grande desvantagem em relação ao grupo formado por 85% da população. Em termos de internações, as taxas são mais altas nos AGSN. Neste sentido, pode-se especular que há maior acesso ao serviço de saúde para os moradores de AGSN em relação aos de assentamentos precários. Este acesso é revertido em menor mortalidade quando as taxas dos dois grupos são comparadas. Se considerarmos apenas dois grupos (assentamentos regulares e AGSN), a situação de maior desvantagem nos assentamentos precários se dilui, tornando-se invisível. Tais resultados podem munir a vigilância em saúde para a definição de programas específicos para estes assentamentos, assim como a gestão do território, em geral, para propiciar melhores condições de moradia.

IntroductionCOVID-19 affects patients of all ages. There are few autopsy studies focusing on the younger population. We assessed an autopsy cohort aiming to understand how age influences pathological outcomes in fatal COVID-19.MethodsThis study included autopsied patients, aged 6 months to 83 years, with confirmed COVID-19 in 2020–2021. We collected tissue samples from deceased patients using a minimally invasive autopsy protocol and assessed pathological data following a systematic approach.ResultsEighty-six patients were included, with a median age of 55 years (IQR 32.3–66.0). We showed that age was significantly lower in patients with acute heart ischemia (p = 0.004), myocarditis (p = 0.03) and lung angiomatosis (p

Abstract Background Cigarette exposure increases brain oxidative stress. The literature showed that increased brain oxidative stress affects cardiovascular regulation. However, no previous study investigated the involvement of brain oxidative stress in animals exposed to cigarette and its relationship with cardiovascular regulation. We aimed to evaluate the effects of central catalase inhibition on baroreflex and cardiovascular responses in rats exposed to sidestream cigarette smoke (SSCS). Methods We evaluated males Wistar rats (320-370 g), which were implanted with a stainless steel guide cannula into the fourth cerebral ventricle (4th V). Femoral artery and vein were cannulated for mean arterial pressure (MAP) and heart rate (HR) measurement and drug infusion, respectively. Rats were exposed to SSCS during three weeks, 180 minutes, 5 days/week (CO: 100-300 ppm). Baroreflex was tested with a pressor dose of phenylephrine (PHE, 8 μg/kg, bolus) to induce bradycardic reflex and a depressor dose of sodium nitroprusside (SNP, 50 μg/kg, bolus) to induce tachycardic reflex. Cardiovascular responses were evaluated before, 5, 15, 30 and 60 minutes after 3-amino-1,2,4-triazole (ATZ, catalase inhibitor, 0.001 g/100 μL) injection into the 4th V. Results Central catalase inhibition increased basal HR in the control group during the first 5 minutes. SSCS exposure increased basal HR and attenuated bradycardic peak during the first 15 minutes. Conclusion We suggest that SSCS exposure affects cardiovascular regulation through its influence on catalase activity.

Abstract Background The Amazon represents an area of 61% of Brazilian territory and is undergoing major changes resulting from disorderly economic development, especially the advance of agribusiness. Composition of the atmosphere is controlled by several natural and anthropogenic processes, and emission from biomass burning is one with the major impact on human health. The aim of this study was to evaluate genotoxic potential of air pollutants generated by biomass burning through micronucleus assay in exfoliated buccal cells of schoolchildren in the Brazilian Amazon region. Methods The study was conducted during the dry seasons in two regions of the Brazilian Amazon. The assay was carried out on buccal epithelial cells of 574 schoolchildren between 6-16 years old. Results The results show a significant difference between micronucleus frequencies in children exposed to biomass burning compared to those in a control area. Conclusions The present study demonstrated that in situ biomonitoring using a sensitive and low cost assay (buccal micronucleus assay) may be an important tool for monitoring air quality in remote regions. It is difficult to attribute the increase in micronuclei frequency observed in our study to any specific toxic element integrated in the particulate matters. However, the contribution of the present study lies in the evidence that increased exposure to fine particulate matter generates an increased micronuclei frequency in oral epithelial cells of schoolchildren.

Abstract Background The Brazilian Amazon has suffered impacts from non-sustainable economic development, especially owing to the expansion of agricultural commodities into forest areas. The Tangará da Serra region, located in the southern of the Legal Amazon, is characterized by non-mechanized sugar cane production. In addition, it lies on the dispersion path of the pollution plume generated by biomass burning. The aim of this study was to assess the genotoxic potential of the atmosphere in the Tangará da Serra region, using Tradescantia pallida as in situ bioindicator. Methods The study was conducted during the dry and rainy seasons, where the plants were exposed to two types of exposure, active and passive. Results The results showed that in all the sampling seasons, irrespective of exposure type, there was an increase in micronucleus frequency, compared to control and that it was statistically significant in the dry season. A strong and significant relationship was also observed between the increase in micronucleus incidence and the rise in fine particulate matter, and hospital morbidity from respiratory diseases in children. Conclusions Based on the results, we demonstrated that pollutants generated by biomass burning in the Brazilian Amazon can induce genetic damage in test plants that was more prominent during dry season, and correlated with the level of particulates and elevated respiratory morbidity.

Summary: Background: The characterisation of individual exposure to air pollution in urban scenarios is a challenge in environmental epidemiological studies. We investigated if the city's pollution monitoring stations over or underestimate the exposure of individuals depending on their socioeconomic conditions and daily commuting times. Methods: The amount of black carbon accumulated in the lungs of 604 deceased who underwent autopsy in São Paulo was considered as a proxy for PM10. The concentrations of PM10 in the residence of the deceased were estimated by interpolating an ordinary kriging model. These two-exposure metrics allowed us to construct an environmental exposure misclassification index ranging from −1 to 1. The association between the index and daily commuting, socioeconomic context index (GeoSES), and street density as predictors was assessed by means of a multilevel linear regression model. Findings: With a decrease of 0.1 units in GeoSES, the index increases, on average, by 0.028 units and with an increase of 1 h in daily commuting, the index increases, on average, by 0.022 units indicating that individual exposure to air pollution is underestimated in the lower GeoSES and in people with many hours spent in daily commuting. Interpretation: Reduction of health consequences of air pollution demands not only alternative fuel and more efficient mobility strategies, but also should include profound rethink of cities. Funding: São Paulo Research Foundation (FAPESP-13/21728-2) and National Council for Scientific and Technological Development (CNPq-304126/2015-2, 401825/2020-5).

Background: The epidemiological evidence on the interaction between heat and ambient air pollution on mortality is still inconsistent. Objectives: To investigate the interaction between heat and ambient air pollution on daily mortality in a large dataset of 620 cities from 36 countries. Methods: We used daily data on all-cause mortality, air temperature, particulate matter ≤ 10 μm (PM10), PM ≤ 2.5 μm (PM2.5), nitrogen dioxide (NO2), and ozone (O3) from 620 cities in 36 countries in the period 1995–2020. We restricted the analysis to the six consecutive warmest months in each city. City-specific data were analysed with over-dispersed Poisson regression models, followed by a multilevel random-effects meta-analysis. The joint association between air temperature and air pollutants was modelled with product terms between non-linear functions for air temperature and linear functions for air pollutants. Results: We analyzed 22,630,598 deaths. An increase in mean temperature from the 75th to the 99th percentile of city-specific distributions was associated with an average 8.9 % (95 % confidence interval: 7.1 %, 10.7 %) mortality increment, ranging between 5.3 % (3.8 %, 6.9 %) and 12.8 % (8.7 %, 17.0 %), when daily PM10 was equal to 10 or 90 μg/m3, respectively. Corresponding estimates when daily O3 concentrations were 40 or 160 μg/m3 were 2.9 % (1.1 %, 4.7 %) and 12.5 % (6.9 %, 18.5 %), respectively. Similarly, a 10 μg/m3 increment in PM10 was associated with a 0.54 % (0.10 %, 0.98 %) and 1.21 % (0.69 %, 1.72 %) increase in mortality when daily air temperature was set to the 1st and 99th city-specific percentiles, respectively. Corresponding mortality estimate for O3 across these temperature percentiles were 0.00 % (-0.44 %, 0.44 %) and 0.53 % (0.38 %, 0.68 %). Similar effect modification results, although slightly weaker, were found for PM2.5 and NO2. Conclusions: Suggestive evidence of effect modification between air temperature and air pollutants on mortality during the warm period was found in a global dataset of 620 cities.

Summary: Background: Yellow fever (YF) is a viral hemorrhagic fever, endemic in parts of South America and Africa. There is scarce evidence about the pathogenesis of the myocardial injury. The objective of this study is to evaluate the cardiac pathology in fatal cases of YF. Methods: This retrospective autopsy study included cases from the São Paulo (Brazil) epidemic of 2017–2019. We reviewed medical records and performed cardiac tissue histopathological evaluation, electron microscopy, immunohistochemical assays, RT-qPCR for YF virus (YFV)-RNA, and proteomics analysis on inflammatory and endothelial biomarkers. Findings: Seventy-three confirmed YF cases with a median age of 48 (34–60) years were included. We observed myocardial fibrosis in 68 (93.2%) patients; cardiomyocyte hypertrophy in 68 (93.2%); endothelial alterations in 67 (91.8%); fiber necrosis in 50 (68.5%); viral myocarditis in 9 (12.3%); and secondary myocarditis in 5 (6.8%). Four out of five patients with 17DD vaccine-associated viscerotropic disease presented with myocarditis. The cardiac conduction system showed edema, hemorrhages and endothelial fibrinoid necrosis. Immunohistochemistry detected CD68-positive inflammatory interstitial cells and YFV antigens in endothelial and inflammatory cells. YFV-RNA was detected positive in 95.7% of the cardiac samples. The proteomics analysis demonstrated that YF patients had higher levels of multiple inflammatory and endothelial biomarkers in comparison to cardiovascular controls, and higher levels of interferon gamma-induced protein 10 (IP-10) in comparison to sepsis (p = 0.01) and cardiovascular controls (p

Abstract Heavy metals are natural and essential elements of the environment and living beings, produced from natural (e.g. volcanic activity and cosmic ray-induced spallation) and anthropogenic processes (e.g. industrial and fossil fuel combustion). High-concentrations of heavy metals and radionuclides are also originated from anthropogenic activities in urban and industrial areas. In this preliminary study, we analyzed the levels of heavy metals and Polonium-210 (210Po) in lung tissues in autopsies from residents of the city of Sao Paulo, SP, Brazil. In order to identify the link among sources of the heavy metals in lungs, factor analysis was performed. Of the first four factors, which explain 66% of the total variability, three were associated with vehicular sources. The fitting of a regression model with 210Po as the response variable and with the four factors as explanatory variables, controlling for age, sex and tobacco, showed a significant association between the concentration of polonium and the first factor that is generated by catalysts and brakes (coefficient = 0.90, standard error = 0.33, p = 0.016). Our findings suggest an association between traffic-related trace metals and 210Po in lung autopsies.

Objective: To understand whether thyroid cells can be directly infected by the SARS-CoV-2 virus and to establish a putative correlation with the expression of the host entry machinery: ACE-2, TMPRSS2, and furin. Methods: We assessed the presence of SARS-CoV-2 virus at the gene level by RT-PCR, viral RNA transcripts localization by in situ hybridization, and by detecting viral proteins by immunohistochemistry for the nucleocapsid and the spike proteins. Furthermore, we also described the immunoexpression of key host factors for virus entry in the COVID-19 thyroid samples. Results: We performed RT-PCR for SARS-CoV-2 in all autopsy specimens and detected viral genome positivity in 13 of 15 thyroid tissues and in a lung specimen. In 9 of the 14 positive samples, we were also able to confirm SARS-CoV-2 signal by in situ hybridization. Immunohistochemistry for the viral nucleocapsid and spike protein was also positive for ten and nine of the RT-PCR-positive cases, respectively, but revealed a lower sensitivity. We also described, for the first time in a COVID-19 series, the immunohistochemical expression of ACE-2, TMPRSS2, and furin in the thyroid. Conclusions: Our results obtained in thyroid specimens from deceased COVID-19 patients indicate that thyrocytes can be directly infected by SARS-CoV-2 since we detected the presence of SARS-CoV-2 genome in follicular cells. Nevertheless, we did not find a clear correlation between the presence of viral genome and the expression of the host factors for virus entry, namely ACE-2, TMPRSS2, and furin.

Enhanced resolution of 7 T magnetic resonance imaging (MRI) scanners has considerably advanced our knowledge of structure and function in human and animal brains. Post-industrialized countries are particularly prone to an ever-increasing number of ageing individuals and ageing-associated neurodegenerative diseases. Neurodegenerative diseases are associated with volume loss in the affected brain. MRI diagnoses and monitoring of subtle volume changes in the ageing/diseased brains have the potential to become standard diagnostic tools. Even with the superior resolution of 7 T MRI scanners, the microstructural changes comprising cell types, cell numbers, and cellular processes, are still undetectable. Knowledge of origin, nature, and progression for microstructural changes are necessary to understand pathogenetic stages in the relentless neurodegenerative diseases, as well as to develop therapeutic tools that delay or stop neurodegenerative processes at their earliest stage. We illustrate the gap in resolution by comparing the identical regions of the post-mortem in situ 7 T MR images (virtual autopsy or virtopsy) with the histological observations in serial sections through the same brain. We also described the protocols and limitations associated with these comparisons, as well as the necessity of supercomputers and data management for "Big data". Analysis of neuron and/or glial number by using a body of mathematical tools and guidelines (stereology) is time-consuming, cumbersome, and still restricted to trained human investigators. Development of tools based on machine learning (ML) and artificial intelligence (AI) could considerably accelerate studies on localization, onset, and progression of neuron loss. Finally, these observations could disentangle the mechanisms of volume loss into stages of reversible atrophy and/or irreversible fatal cell death. This AI- and ML-based cooperation between virtopsy and histology could bridge the present gap between virtual reality and neuropathology. It could also culminate in the creation of an imaging-associated comprehensive database. This database would include genetic, clinical, epidemiological, and technical aspects that could help to alleviate or even stop the adverse effects of neurodegenerative diseases on affected individuals, their families, and society.

To assess mortality risks and burdens associated with short-term exposure to wildfire-related PM2.5, the authors collect daily mortality data from 2000 to 2016 for 510 immediate regions in Brazil, the most wildfire-prone area.

Abstract Background Reliable mortality data are essential for the development of public health policies. In Brazil, although there is a well-consolidated universal system for mortality data, the quality of information on causes of death (CoD) is not even among Brazilian regions, with a high proportion of ill-defined CoD. Verbal autopsy (VA) is an alternative to improve mortality data. This study aimed to evaluate the performance of an adapted and reduced version of VA in identifying the underlying causes of non-forensic deaths, in São Paulo, Brazil. This is the first time that a version of the questionnaire has been validated considering the autopsy as the gold standard. Methods The performance of a physician-certified verbal autopsy (PCVA) was evaluated considering conventional autopsy (macroscopy plus microscopy) as gold standard, based on a sample of 2060 decedents that were sent to the Post-Mortem Verification Service (SVOC-USP). All CoD, from the underlying to the immediate, were listed by both parties, and ICD-10 attributed by a senior coder. For each cause, sensitivity and chance corrected concordance (CCC) were computed considering first the underlying causes attributed by the pathologist and PCVA, and then any CoD listed in the death certificate given by PCVA. Cause specific mortality fraction accuracy (CSMF-accuracy) and chance corrected CSMF-accuracy were computed to evaluate the PCVA performance at the populational level. Results There was substantial variability of the sensitivities and CCC across the causes. Well-known chronic diseases with accurate diagnoses that had been informed by physicians to family members, such as various cancers, had sensitivities above 40% or 50%. However, PCVA was not effective in attributing Pneumonia, Cardiomyopathy and Leukemia/Lymphoma as underlying CoD. At populational level, the PCVA estimated cause specific mortality fractions (CSMF) may be considered close to the fractions pointed by the gold standard. The CSMF-accuracy was 0.81 and the chance corrected CSMF-accuracy was 0.49. Conclusions The PCVA was efficient in attributing some causes individually and proved effective in estimating the CSMF, which indicates that the method is useful to establish public health priorities.

Background: Wildfire imposes a high mortality burden on Brazil. However, there is a limited assessment of the health economic losses attributable to wildfire-related fine particulate matter (PM2.5). Methods: We collected daily time-series data on all-cause, cardiovascular, and respiratory mortality from 510 immediate regions in Brazil during 2000–2016. The chemical transport model GEOS-Chem driven with Global Fire Emissions Database (GFED), in combination with ground monitored data and machine learning was used to estimate wildfire-related PM2.5 data at a resolution of 0.25° × 0.25°. A time-series design was applied in each immediate region to assess the association between economic losses due to mortality and wildfire-related PM2.5 and the estimates were pooled at the national level using a random-effect meta-analysis. We used a meta-regression model to explore the modification effect of GDP and its sectors (agriculture, industry, and service) on economic losses. Results: During 2000–2016, a total of US$81.08 billion economic losses (US$5.07 billion per year) due to mortality were attributable to wildfire-related PM2.5 in Brazil, accounting for 0.68% of economic losses and equivalent to approximately 0.14% of Brazil’s GDP. The attributable fraction (AF) of economic losses due to wildfire-related PM2.5 was positively associated with the proportion of GDP from agriculture, while negatively associated with the proportion of GDP from service. Conclusion: Substantial economic losses due to mortality were associated with wildfires, which could be influenced by the agriculture and services share of GDP per capita. Our estimates of the economic losses of mortality could be used to determine optimal levels of investment and resources to mitigate the adverse health impacts of wildfires.

IntroductionThe timing of maternal exposure to air pollution is crucial to define metabolic changes in the offspring. Here we aimed to determine the most critical period of maternal exposure to particulate matter (PM2.5) that impairs offspring's energy metabolism and gut microbiota composition.MethodsUnexposed female and male C57BL/6J mice were mated. PM2.5 or filtered air (FA) exposure occurred only in gestation (PM2.5/FA) or lactation (FA/PM2.5). We studied the offspring of both genders.ResultsPM2.5 exposure during gestation increased body weight (BW) at birth and from weaning to young in male adulthood. Leptin levels, food intake, Agrp, and Npy levels in the hypothalamus were also increased in young male offspring. Ikbke, Tnf increased in male PM2.5/FA. Males from FA/PM2.5 group were protected from these phenotypes showing higher O2 consumption and Ucp1 in the brown adipose tissue. In female offspring, we did not see changes in BW at weaning. However, adult females from PM2.5/FA displayed higher BW and leptin levels, despite increased energy expenditure and thermogenesis. This group showed a slight increase in food intake. In female offspring from FA/PM2.5, BW, and leptin levels were elevated. This group displayed higher energy expenditure and a mild increase in food intake. To determine if maternal exposure to PM2.5 could affect the offspring’s gut microbiota, we analyzed alpha diversity by Shannon and Simpson indexes and beta diversity by the Linear Discriminant Analysis (LDA) in offspring at 30 weeks. Unlike males, exposure during gestation led to higher adiposity and leptin maintenance in female offspring at this age. Gestation exposure was associated with decreased alpha diversity in the gut microbiota in both genders.DiscussionOur data support that exposure to air pollution during gestation is more harmful to metabolism than exposure during lactation. Male offspring had an unfavorable metabolic phenotype at a young age. However, at an older age, only females kept more adiposity. Ultimately, our data highlight the importance of controlling air pollution, especially during gestation.

Summary: In this Viewpoint we argue that primary care practitioners should receive professional education in how to directly respond to planetary health challenges. We reflect on the provision of a massive open online course (MOOC) on planetary health for primary care practitioners in the context of existing training programmes. We describe the construction, delivery, and certification of a Global South-originated MOOC and explain aspects of its rhizomatic learning theory. We share baseline information and preliminary findings collected on the initial cohort of participants, including their profiles and previous knowledge about planetary health. We suggest that this MOOC is an appropriate response to planetary health challenges, and argue that cost-free, accredited planetary health education for primary care practitioners should be provided as a public good that also fulfils individual professionals’ entitlement to quality education and continuing professional development.

Em fevereiro de 2020, a Organização Mundial da Saúde alertou sobre a gravidade da epidemia de Covid-19 e enfatizou que as iniciativas relacionadas ao seu combate têm sido acompanhadas por uma infodemia. O Ministério da Saúde do Brasil publicou diretrizes em relação ao manejo da doença com o “tratamento precoce”. O objetivo deste artigo foi construir uma linha do tempo visual de janeiro de 2020 até abril de 2021 por meio de pesquisa bibliográfica, documental e análise de conteúdo. Sistematizaram-se as principais notícias veiculadas no website do Ministério da Saúde sobre o “tratamento precoce”, as evidências científicas sobre os medicamentos relacionados a este e os dados das mortes e fatos relacionados à doença que aconteceram no Brasil. A linha do tempo evidencia a insistência da promoção do “tratamento precoce”, no contexto da desinfodemia, pelo Ministério da Saúde na existência de evidências contrárias a essa intervenção.

Introdução: As mortes atribuíveis à poluição do ar em longo prazo chegam a 9 milhões ao ano, concentrando-se principalmente em países de baixa e média renda como o Brasil. Classifica-se a poluição do ar em: domiciliar (indoor) ou ambiente (outdoor). A inalação de poluentes está relacionada com o aumento da incidência e desenvolvimento de condições clínicas, como doenças cardiovasculares, respiratórias e outras, que fazem parte da prática da medicina de família e comunidade. Objetivo: Verificar as evidências clínicas para a abordagem da poluição do ar relacionada à saúde humana no contexto da prática na Atenção Primária à Saúde. Métodos: Revisão de escopo do papel clínico da medicina de família e comunidade em relação à poluição do ar e saúde, voltada para questões clínicas associadas com a poluição do ar. Incluíram-se 35 artigos nesta revisão. Recomendações clínicas: Em nível individual, destacam-se a redução do uso de fogões a lenha, o uso de estratégias de proteção de fontes poluidoras (como queimadas, vias de trânsito e indústria), a filtragem do ar, o estímulo ao transporte ativo, a cessação do tabagismo. Essas recomendações devem ser complementares às políticas governamentais relacionadas à poluição do ar. Propõem-se perguntas para a entrevista clínica. Exploram-se recomendações específicas sobre uso de máscaras, atividade física e COVID-19. Sugerem-se temas de pesquisa que podem ser realizadas na Atenção Primária à Saúde e o papel da medicina de família e comunidade nesse contexto. Considerações: A inclusão na classificação internacional de atenção primária e no Código internacional de Doenças poderia melhorar a notificação e os estudos epidemiológicos sobre o assunto.

BackgroundAlthough aging correlates with a worse prognosis for Covid-19, super elderly still unvaccinated individuals presenting mild or no symptoms have been reported worldwide. Most of the reported genetic variants responsible for increased disease susceptibility are associated with immune response, involving type I IFN immunity and modulation; HLA cluster genes; inflammasome activation; genes of interleukins; and chemokines receptors. On the other hand, little is known about the resistance mechanisms against SARS-CoV-2 infection. Here, we addressed polymorphisms in the MHC region associated with Covid-19 outcome in super elderly resilient patients as compared to younger patients with a severe outcome.MethodsSARS-CoV-2 infection was confirmed by RT-PCR test. Aiming to identify candidate genes associated with host resistance, we investigated 87 individuals older than 90 years who recovered from Covid-19 with mild symptoms or who remained asymptomatic following positive test for SARS-CoV-2 as compared to 55 individuals younger than 60 years who had a severe disease or died due to Covid-19, as well as to the general elderly population from the same city. Whole-exome sequencing and an in-depth analysis of the MHC region was performed. All samples were collected in early 2020 and before the local vaccination programs started.ResultsWe found that the resilient super elderly group displayed a higher frequency of some missense variants in the MUC22 gene (a member of the mucins’ family) as one of the strongest signals in the MHC region as compared to the severe Covid-19 group and the general elderly control population. For example, the missense variant rs62399430 at MUC22 is two times more frequent among the resilient super elderly (p = 0.00002, OR = 2.24).ConclusionSince the pro-inflammatory basal state in the elderly may enhance the susceptibility to severe Covid-19, we hypothesized that MUC22 might play an important protective role against severe Covid-19, by reducing overactive immune responses in the senior population.

Abstract Background Prenatal exposure to Cannabis is a worldwide growing problem. Although retina is part of the central nervous system, the impact of maternal Cannabis use on the retinal development and its postnatal consequences remains unknown. As the prenatal period is potentially sensitive in the normal development of the retina, we hypothesized that recreational use of Cannabis during pregnancy may alter retina structure in the offspring. To test this, we developed a murine model that mimics human exposure in terms of dose and use. Methods Pregnant BalbC mice were exposed daily for 5 min to Cannabis smoke (0.2 g of Cannabis) or filtered air, from gestational day 5 to 18 (N = 10/group). After weaning period, pups were separated and examined weekly. On days 60, 120, 200, and 360 after birth, 10 pups from each group were randomly selected for Spectral Domain Optical Coherence Tomography (SD-OCT) analysis of the retina. All retina layers were measured and inner, outer, and total retina thickness were calculated. Other 37 mice from both groups were sacrificed on days 20, 60, and 360 for retinal stereology (total volume of the retina and volume fraction of each retinal layer) and light microscopy. Means and standard deviations were calculated and MANOVA was performed. Results The retina of animals which mother was exposed to Cannabis during gestation was 17% thinner on day 120 (young adult) than controls (P = 0.003) due to 21% thinning of the outer retina (P = 0.001). The offspring of mice from the exposed group presented thickening of the IS/OS in comparison to controls on day 200 (P

The ongoing COVID-19 pandemic represents an extra burden in the majority of public and private health systems worldwide beyond the most pessimistic expectations, driving an urgent rush to develop effective vaccines and effective medical treatments against the SARS-CoV-2 pandemic. The Nucleocapsid structural viral protein is remarkably immunogenic and hugely expressed during infection. High IgG antibodies against Nucleocapsid protein (N protein) levels were detected in the serum of COVID-19 patients, confirming its pivotal antigen role for a T lymphocyte response in a vaccine microenvironment. Currently, adverse events associated with immunizations have raised some degree of concern, irrespective of its huge benefits in dealing with disease severity and decreasing mortality and morbidity. This hitherto study evaluates histological changes in rats’ testes, epididymis, prostate, and seminal vesicles and analyzes hormone levels after solely N protein inoculation. Therefore, we exposed a group of Lewis rats to weekly injections of the recombinant N protein for 28 days, while a control group was inoculated with a buffer solution. The N group revealed a more significant number of spermatozoa. Spermatozoa in the seminiferous tubules were counted in twenty 400 × microscopy fields (mean of 9.2 vs. 4.6 in the control group; p < 0,01), but significantly lower testosterone levels (mean of 125.70 ng/dl vs. 309,00 ng/dl in the control group; p < 0,05) were found. No other histological and biochemical changes were displayed. Conclusively, these data suggest testicular hormonal imbalance mediated by the SARS-CoV-2 N protein that could be linked to reported post-COVID-19 syndrome hypogonadism. More relevant research might be performed to confirm this viral antigen’s deleterious mechanism in the human testicular microenvironment, particular in Leydig cell function.

Abstract Background Dengue infection is caused by an arbovirus with a wide range of presentations, varying from asymptomatic disease to unspecific febrile illness and haemorrhagic syndrome with shock, which can evolve to death. In Brazil, the virus circulates since the 1980s with many introductions of new serotypes, genotypes, and lineages since then. Here we report a fatal case of dengue associated with a Dengue virus (DENV) lineage not detected in the country until now. Case presentation The patient, a 58-year-old man arrived at the hospital complaining of fever and severe abdominal pain due to intense gallbladder edema, mimicking acute abdomen. After 48 h of hospital admission, he evolved to refractory shock and death. DENV RNA was detected in all tissues collected (heart, lung, brain, kidney, spleen, pancreas, liver, and testis). Viral sequencing has shown that the virus belongs to serotype 2, American/Asian genotype, in a new clade, which has never been identified in Brazil before. The virus was phylogenetically related to isolates from central America [Puerto Rico (2005–2007), Martinique (2005), and Guadeloupe (2006)], most likely arriving in Brazil from Puerto Rico. Conclusion In summary, this was the first fatal documented case with systemic dengue infection associated with the new introduction of Dengue type 2 virus in Brazil during the 2019 outbreak.