Postmortem chest computed tomography in COVID-19: A minimally invasive autopsy method.

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.

Assessing socioeconomic bias of exposure to urban air pollution: an autopsy-based study in São Paulo, Brazil.

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).

Allergic sensitization and exposure to ambient air pollution beginning early in life lead to a COPD-like phenotype in young adult mice.

The perinatal period and early infancy are considered critical periods for lung development. During this period, adversities such as environmental exposures, allergic sensitization, and asthma are believed to impact lung health in adulthood. Therefore, we hypothesized that concomitant exposure to allergic sensitization and urban-derived fine particulate matter (PM2.5) in the early postnatal period of mice would cause more profound alterations in lung alveolarization and growth and differently modulate lung inflammation and gene expression than either insult alone in adult life. BALB/c mice were sensitized with ovalbumin (OVA) and exposed to PM2.5 from the fifth day of life. Then, we assessed lung responsiveness, inflammation in BALF, lung tissue, and alveolarization by stereology. In addition, we performed a transcriptomic analysis of lung tissue on the 40th day of life. Our results showed that young adult mice submitted to allergic sensitization and exposure to ambient PM2.5 since early life presented decreased lung growth with impaired alveolarization, a mixed neutrophilic-eosinophilic pattern of lung inflammation, increased airway responsiveness, and increased expression of genes linked to neutrophil recruitment when compared to animals that were OVA-sensitized or PM2.5 exposed only. Both, early life allergic sensitization and PM2.5 exposure, induced inflammation and impaired lung growth, but concomitant exposure was associated with worsened inflammation parameters and caused alveolar enlargement. Our experimental data provide pathological support for the hypothesis that allergic or environmental insults in early life have permanent adverse consequences for lung growth. In addition, combined insults were associated with the development of a COPD-like phenotype in young adult mice. Together with our data, current evidence points to the urgent need for healthier environments with fewer childhood disadvantage factors during the critical windows of lung development and growth.

SARS-CoV-2 Nucleocapsid Protein is Associated With Lower Testosterone Levels: An Experimental Study.

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.

COVID-19-Associated cardiac pathology at the postmortem evaluation: a collaborative systematic review.

BACKGROUND: Many postmortem studies address the cardiovascular effects of COVID-19 and provide valuable information, but are limited by their small sample size. OBJECTIVES: The aim of this systematic review is to better understand the various aspects of the cardiovascular complications of COVID-19 by pooling data from a large number of autopsy studies. DATA SOURCES: We searched the online databases Ovid EBM Reviews, Ovid Embase, Ovid Medline, Scopus, and Web of Science for concepts of autopsy or histopathology combined with COVID-19, published between database inception and February 2021. We also searched for unpublished manuscripts using the medRxiv services operated by Cold Spring Harbor Laboratory. STUDY ELIGIBILITY CRITERIA: Articles were considered eligible for inclusion if they reported human postmortem cardiovascular findings among individuals with a confirmed SARS coronavirus type 2 (CoV-2) infection. PARTICIPANTS: Confirmed COVID-19 patients with post-mortem cardiovascular findings. INTERVENTIONS: None. METHODS: Studies were individually assessed for risk of selection, detection, and reporting biases. The median prevalence of different autopsy findings with associated interquartile ranges (IQRs). RESULTS: This review cohort contained 50 studies including 548 hearts. The median age of the deceased was 69 years. The most prevalent acute cardiovascular findings were myocardial necrosis (median: 100.0%; IQR, 20%-100%; number of studies = 9; number of patients = 64) and myocardial oedema (median: 55.5%; IQR, 19.5%-92.5%; number of studies = 4; number of patients = 46). The median reported prevalence of extensive, focal active, and multifocal myocarditis were all 0.0%. The most prevalent chronic changes were myocyte hypertrophy (median: 69.0%; IQR, 46.8%-92.1%) and fibrosis (median: 35.0%; IQR, 35.0%-90.5%). SARS-CoV-2 was detected in the myocardium with median prevalence of 60.8% (IQR 40.4-95.6%). CONCLUSIONS: Our systematic review confirmed the high prevalence of acute and chronic cardiac pathologies in COVID-19 and SARS-CoV-2 cardiac tropism, as well as the low prevalence of myocarditis in COVID-19.

Fluctuating temperature modifies heat-mortality association around the globe.

Studies have investigated the effects of heat and temperature variability (TV) on mortality. However, few assessed whether TV modifies the heat-mortality association. Data on daily temperature and mortality in the warm season were collected from 717 locations across 36 countries. TV was calculated as the standard deviation of the average of the same and previous days' minimum and maximum temperatures. We used location-specific quasi-Poisson regression models with an interaction term between the cross-basis term for mean temperature and quartiles of TV to obtain heat-mortality associations under each quartile of TV, and then pooled estimates at the country, regional, and global levels. Results show the increased risk in heat-related mortality with increments in TV, accounting for 0.70% (95% confidence interval [CI]: -0.33 to 1.69), 1.34% (95% CI: -0.14 to 2.73), 1.99% (95% CI: 0.29-3.57), and 2.73% (95% CI: 0.76-4.50) of total deaths for Q1-Q4 (first quartile-fourth quartile) of TV. The modification effects of TV varied geographically. Central Europe had the highest attributable fractions (AFs), corresponding to 7.68% (95% CI: 5.25-9.89) of total deaths for Q4 of TV, while the lowest AFs were observed in North America, with the values for Q4 of 1.74% (95% CI: -0.09 to 3.39). TV had a significant modification effect on the heat-mortality association, causing a higher heat-related mortality burden with increments of TV. Implementing targeted strategies against heat exposure and fluctuant temperatures simultaneously would benefit public health.

Mortality risk attributable to wildfire-related PM2·5 pollution: a global time series study in 749 locations.

BACKGROUND: Many regions of the world are now facing more frequent and unprecedentedly large wildfires. However, the association between wildfire-related PM2·5 and mortality has not been well characterised. We aimed to comprehensively assess the association between short-term exposure to wildfire-related PM2·5 and mortality across various regions of the world. METHODS: For this time series study, data on daily counts of deaths for all causes, cardiovascular causes, and respiratory causes were collected from 749 cities in 43 countries and regions during 2000-16. Daily concentrations of wildfire-related PM2·5 were estimated using the three-dimensional chemical transport model GEOS-Chem at a 0·25°â€ˆ× 0·25° resolution. The association between wildfire-related PM2·5 exposure and mortality was examined using a quasi-Poisson time series model in each city considering both the current-day and lag effects, and the effect estimates were then pooled using a random-effects meta-analysis. Based on these pooled effect estimates, the population attributable fraction and relative risk (RR) of annual mortality due to acute wildfire-related PM2·5 exposure was calculated. FINDINGS: 65·6 million all-cause deaths, 15·1 million cardiovascular deaths, and 6·8 million respiratory deaths were included in our analyses. The pooled RRs of mortality associated with each 10 µg/m3 increase in the 3-day moving average (lag 0-2 days) of wildfire-related PM2·5 exposure were 1·019 (95% CI 1·016-1·022) for all-cause mortality, 1·017 (1·012-1·021) for cardiovascular mortality, and 1·019 (1·013-1·025) for respiratory mortality. Overall, 0·62% (95% CI 0·48-0·75) of all-cause deaths, 0·55% (0·43-0·67) of cardiovascular deaths, and 0·64% (0·50-0·78) of respiratory deaths were annually attributable to the acute impacts of wildfire-related PM2·5 exposure during the study period. INTERPRETATION: Short-term exposure to wildfire-related PM2·5 was associated with increased risk of mortality. Urgent action is needed to reduce health risks from the increasing wildfires. FUNDING: Australian Research Council, Australian National Health & Medical Research Council.

Tracking the time course of pathological patterns of lung injury in severe COVID-19.

BACKGROUND: Pulmonary involvement in COVID-19 is characterized pathologically by diffuse alveolar damage (DAD) and thrombosis, leading to the clinical picture of Acute Respiratory Distress Syndrome. The direct action of SARS-CoV-2 in lung cells and the dysregulated immuno-coagulative pathways activated in ARDS influence pulmonary involvement in severe COVID, that might be modulated by disease duration and individual factors. In this study we assessed the proportions of different lung pathology patterns in severe COVID-19 patients along the disease evolution and individual characteristics. METHODS: We analysed lung tissue from 41 COVID-19 patients that died in the period March-June 2020 and were submitted to a minimally invasive autopsy. Eight pulmonary regions were sampled. Pulmonary pathologists analysed the H&E stained slides, performing semiquantitative scores on the following parameters: exudative, intermediate or advanced DAD, bronchopneumonia, alveolar haemorrhage, infarct (%), arteriolar (number) or capillary thrombosis (yes/no). Histopathological data were correlated with demographic-clinical variables and periods of symptoms-hospital stay. RESULTS: Patient´s age varied from 22 to 88 years (18f/23 m), with hospital admission varying from 0 to 40 days. All patients had different proportions of DAD in their biopsies. Ninety percent of the patients presented pulmonary microthrombosis. The proportion of exudative DAD was higher in the period 0-8 days of hospital admission till death, whereas advanced DAD was higher after 17 days of hospital admission. In the group of patients that died within eight days of hospital admission, elderly patients had less proportion of the exudative pattern and increased proportions of the intermediate patterns. Obese patients had lower proportion of advanced DAD pattern in their biopsies, and lower than patients with overweight. Clustering analysis showed that patterns of vascular lesions (microthrombosis, infarction) clustered together, but not the other patterns. The vascular pattern was not influenced by demographic or clinical parameters, including time of disease progression. CONCLUSION: Patients with severe COVID-19 present different proportions of DAD patterns over time, with advanced DAD being more prevalent after 17 days, which seems to be influenced by age and weight. Vascular involvement is present in a large proportion of patients, occurs early in disease progression, and does not change over time.

Projections of excess mortality related to diurnal temperature range under climate change scenarios: a multi-country modelling study.

BACKGROUND: Various retrospective studies have reported on the increase of mortality risk due to higher diurnal temperature range (DTR). This study projects the effect of DTR on future mortality across 445 communities in 20 countries and regions. METHODS: DTR-related mortality risk was estimated on the basis of the historical daily time-series of mortality and weather factors from Jan 1, 1985, to Dec 31, 2015, with data for 445 communities across 20 countries and regions, from the Multi-Country Multi-City Collaborative Research Network. We obtained daily projected temperature series associated with four climate change scenarios, using the four representative concentration pathways (RCPs) described by the Intergovernmental Panel on Climate Change, from the lowest to the highest emission scenarios (RCP 2.6, RCP 4.5, RCP 6.0, and RCP 8.5). Excess deaths attributable to the DTR during the current (1985-2015) and future (2020-99) periods were projected using daily DTR series under the four scenarios. Future excess deaths were calculated on the basis of assumptions that warmer long-term average temperatures affect or do not affect the DTR-related mortality risk. FINDINGS: The time-series analyses results showed that DTR was associated with excess mortality. Under the unmitigated climate change scenario (RCP 8.5), the future average DTR is projected to increase in most countries and regions (by -0·4 to 1·6°C), particularly in the USA, south-central Europe, Mexico, and South Africa. The excess deaths currently attributable to DTR were estimated to be 0·2-7·4%. Furthermore, the DTR-related mortality risk increased as the long-term average temperature increased; in the linear mixed model with the assumption of an interactive effect with long-term average temperature, we estimated 0·05% additional DTR mortality risk per 1°C increase in average temperature. Based on the interaction with long-term average temperature, the DTR-related excess deaths are projected to increase in all countries or regions by 1·4-10·3% in 2090-99. INTERPRETATION: This study suggests that globally, DTR-related excess mortality might increase under climate change, and this increasing pattern is likely to vary between countries and regions. Considering climatic changes, our findings could contribute to public health interventions aimed at reducing the impact of DTR on human health. FUNDING: Korea Ministry of Environment.

Concentrated ambient fine particulate matter (PM2.5) exposure induce brain damage in pre and postnatal exposed mice.

Air pollution is a public health concern that has been associated with adverse effects on the development and functions of the central nervous system (CNS). However, studies on the effects of exposure to pollutants on the CNS across the entire developmental period still remain scarce. In this study, we investigated the impacts of prenatal and/or postnatal exposure to fine particulate matter (PM2.5) from São Paulo city, on the brain structure and behavior of juvenile male mice. BALB/c mice were exposed to PM2.5 concentrated ambient particles (CAP) at a daily concentration of 600 µg/m³ during the gestational [gestational day (GD) 1.5-18.5] and the postnatal periods [postnatal day (PND) 22-90] to filtered air (FA) in both periods (FA/FA), to CAP only in the postnatal period (FA/CAP), to CAP only in the gestational period (CAP/FA), and to CAP in both periods (CAP/CAP). Behavioral tests were performed when animals were at PND 30 and PND 90. Glial activation, brain volume, cortical neuron number, serotonergic and GABAergic receptors, as well as oxidative stress, were measured. Mice at PND 90 presented greater behavioral changes in the form of greater locomotor activity in the FA-CAP and CAP-CAP groups. In general, these same groups explored objects longer and the CAP-FA group presented anxiolytic behavior. There was no difference in total brain volume among groups, but a lower corpus callosum (CC) volume was observed in the CAP-FA group. Also, the CAP-CAP group presented an increase in microglia in the cortex and an increased in astrocytes in the cortex, CC, and C1A and dentate gyrus of hippocampus regions. Gene expression analysis showed a decrease in BDNF in the hippocampus of CAP-CAP group. Treatment of immortalized glial cells with non-cytotoxic doses of ambient PM2.5 increased micronuclei frequencies, indicating genomic instability. These findings highlight the potential for negative neurodevelopmental outcomes induced by exposure to moderate levels of PM2.5 in Sao Paulo city.

Exposure to fine particles increases blood pressure of hypertensive outdoor workers: A panel study.

BACKGROUND: Hypertension and air pollution are two important risk factors for cardiovascular morbidity and mortality. Although several studies suggest that air pollution has a significant impact on blood pressure, studies on long-term effects are sparse and still controversial. OBJECTIVE: To evaluate the effects of exposure of outdoor workers to different levels of traffic-generated PM2.5 on blood pressure. DESIGN: This is an observational panel study. PARTICIPANTS: 88 non-smoking workers exposed to different concentrations of air pollution were evaluated weekly along four successive weeks. MEASUREMENTS: In each week, personal monitoring of 24-h PM2.5 concentration and 24-h ambulatory blood pressure were measured. The association between blood pressure variables and PM2.5, adjusted for age, body mass index, time in job, daily work hours, diabetes, hypertension and cholesterol was assessed by means of multiple linear regression models fitted by least squares. RESULTS: Exposure to PM2.5 (ranging from 8.5 to 89.7 µg/m3) is significantly and consistently associated with an increase in average blood pressure. An elevation of 10 µg/m3 in the concentration of PM2.5 is associated with increments of 3.9 mm Hg (CI 95% = [1.5; 6.3]) in average systolic 24-h blood pressure for hypertensive and/or diabetic workers. CONCLUSION: Exposure to fine particles, predominantly from vehicular traffic, is associated with elevated blood pressure in hypertensive and/or diabetic workers.

The role of artificial intelligence and machine learning in harmonization of high-resolution post-mortem MRI (virtopsy) with respect to brain microstructure.

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.

Diesel exhaust exposure intensifies inflammatory and structural changes associated with lung aging in mice.

Life expectancy is increasing worldwide. Lung aging is a process marked by changes in multiple morphological, physiological and age-related biomarkers (e.g., sirtuins) and is influenced by external factors, such as air pollution. Hence, the elderly are considered more vulnerable to the air pollution hazards. We hypothesized that diesel exhaust (DE) exposure intensifies changes in lung inflammatory and structural parameters in aging subjects. Two- and fifteen-month-old mice were exposed to DE for 30 days. Lung function was measured using the forced oscillation method. The inflammatory profile was evaluated in the bronchoalveolar lavage fluid (BALF) and blood, and lung volumes were estimated by stereology. Antioxidant enzyme activity was evaluated by spectrophotometry, sirtuin 1 (SIRT1), sirtuin 2 (SIRT2) and sirtuin 6 (SIRT6) expression was assessed by reverse transcription polymerase chain reaction (RT-PCR), and levels of the sirtuin proteins were evaluated by immunohistochemical staining in lung tissues. Older mice presented decreased pulmonary resistance and elastance, increased macrophage infiltration and decreased tumor necrosis factor (TNF) and interleukin 10 (IL-10) levels in the BALF, reduced activities of the antioxidant enzymes glutathione peroxidase (GPx) and glutathione reductase (GR), and increased activity glutathione S-transferase (GST); increased lung volumes with decreased elastic fiber and increased airway collagen content. SIRT1 gene expression was decreased in older animals, but protein levels were increased. DE exposure increased macrophage infiltration and oxidative stress in the lungs of animals of both ages. SIRT6 gene expression was decreased by DE exposure, with increased protein levels. In older animals, DE affected lung structure and collagen content. Lung aging features, such as decreased antioxidant reserves, lower IL-10 expression, and decreased SIRT1 levels may predispose subjects to exacerbated responses after DE exposure. Our data support the hypothesis that strategies designed to reduce ambient air pollution are an important step towards healthy aging.

Tree rings reveal the reduction of Cd, Cu, Ni and Pb pollution in the central region of São Paulo, Brazil.

The concern about environmental pollution has risen in the last decades because of its effects on human's health. However, evaluation of the exposure to certain pollutants is currently hampered by the availability of past environmental data. Tree rings are an alternative to reconstruct environmental variability of pre-instrumental periods. Nevertheless, this approach has some reported limitations including migration of chemical elements in the tree rings. The aim of this study was to evaluate the distribution of Cd, Cu, Hg, Na, Ni, Pb, Zn in the tree rings of Tipuana tipu (Fabaceae) to aid the reconstruction of past environmental pollution. We sampled trees in the central region of the city of São Paulo, Brazil, and scanned their tree rings using LA-ICP-MS. We used these data to evaluate the temporal trends of chemical elements under investigation. Results show a non-random distribution of these chemical elements within the tree rings, with higher content in the cell-walls of vessels and lower content in the fibers. Sodium was the only element intimately related to the axial parenchyma cells. Due to differences in elemental composition of xylem cells, temporal trends where evaluated using distinct quartiles of data distribution in each tree ring. The first quartile represents the lower content found in fibers and parenchyma, while the third quartile corresponds to the higher content found in vessels. Data from vessels better represent the decreasing trend of Cd, Cu, Pb, and Ni in the last three decades. This reduction is less significant for Na and Zn. Our results highlight the potential to improve the records of environmental pollution using data from different cells. Pronounced reduction in Pb may be attributed to the lead phase-out in gasoline, while the decreasing trend of Cd, Cu, Ni pollution is probably related to increasing efficiency of vehicles and the deindustrialization of São Paulo. Chemical elements are non-randomly distributed in tree rings. Chemical content of vessels cell-walls is a reliable record of metal pollution, which is decreasing in São Paulo.

Projections of temperature-related excess mortality under climate change scenarios.

BACKGROUND: Climate change can directly affect human health by varying exposure to non-optimal outdoor temperature. However, evidence on this direct impact at a global scale is limited, mainly due to issues in modelling and projecting complex and highly heterogeneous epidemiological relationships across different populations and climates. METHODS: We collected observed daily time series of mean temperature and mortality counts for all causes or non-external causes only, in periods ranging from Jan 1, 1984, to Dec 31, 2015, from various locations across the globe through the Multi-Country Multi-City Collaborative Research Network. We estimated temperature-mortality relationships through a two-stage time series design. We generated current and future daily mean temperature series under four scenarios of climate change, determined by varying trajectories of greenhouse gas emissions, using five general circulation models. We projected excess mortality for cold and heat and their net change in 1990-2099 under each scenario of climate change, assuming no adaptation or population changes. FINDINGS: Our dataset comprised 451 locations in 23 countries across nine regions of the world, including 85 879 895 deaths. Results indicate, on average, a net increase in temperature-related excess mortality under high-emission scenarios, although with important geographical differences. In temperate areas such as northern Europe, east Asia, and Australia, the less intense warming and large decrease in cold-related excess would induce a null or marginally negative net effect, with the net change in 2090-99 compared with 2010-19 ranging from -1·2% (empirical 95% CI -3·6 to 1·4) in Australia to -0·1% (-2·1 to 1·6) in east Asia under the highest emission scenario, although the decreasing trends would reverse during the course of the century. Conversely, warmer regions, such as the central and southern parts of America or Europe, and especially southeast Asia, would experience a sharp surge in heat-related impacts and extremely large net increases, with the net change at the end of the century ranging from 3·0% (-3·0 to 9·3) in Central America to 12·7% (-4·7 to 28·1) in southeast Asia under the highest emission scenario. Most of the health effects directly due to temperature increase could be avoided under scenarios involving mitigation strategies to limit emissions and further warming of the planet. INTERPRETATION: This study shows the negative health impacts of climate change that, under high-emission scenarios, would disproportionately affect warmer and poorer regions of the world. Comparison with lower emission scenarios emphasises the importance of mitigation policies for limiting global warming and reducing the associated health risks. FUNDING: UK Medical Research Council.

Early and late pulmonary effects of nebulized LPS in mice: An acute lung injury model.

BACKGROUND AND OBJECTIVE: Acute respiratory distress syndrome (ARDS) has a high mortality rate of 35-46% depending on its severity. Animal models are crucial to better understand the pathophysiology of diseases, including ARDS. This study presents a feasible animal model of acute lung injury (ALI) using nebulized lipopolysaccharide (LPS) in a non-invasive approach, focusing on its short and long-term effects. METHODS: Mice received nebulized LPS or vehicle only (control group). Blood, BALF and lung tissue were collected 24 hours (LPS 24h) or 5 weeks (LPS 5w) after the nebulized LPS-induced lung injury. Inflammatory cytokines were assessed in the blood serum, BALF and lung tissue. Stereological analyses and remodeling changes were assessed by histology and immunohistochemistry at the specified time points. RESULTS: The LPS 24h group showed increased pro-inflammatory cytokine levels, intense cell influx, increased total septal volume, septal thickening and decreased surface density of the alveolar septa. The LPS 5w group showed persistent lung inflammation, septal thickening, increased total lung volume, accentuated collagen deposition, especially of collagen type I, and decreased MMP-2 protein expression. CONCLUSION: We present a feasible, reproducible and non-invasive nebulized-LPS animal model that allows the assessment of both the acute and late phases of acute lung injury. The presence of lung remodeling with collagen deposition after 5 weeks makes it useful to study the pathophysiology, complications, and possible therapeutic intervention studies that aim to understand and reduce pulmonary fibrosis in the late phases of ALI.

Aerobic exercise in polluted urban environments: effects on airway defense mechanisms in young healthy amateur runners.

In this study, the effects of aerobic exercise on the upper airways and their defense mechanisms were investigated in athletes. The athletes ran in two different environments: the downtown streets of the city of São Paulo (Street), more polluted, and an urban forest (Forest), less polluted. Thirty-eight young healthy athletes ran for 45 min d-1 randomly during five consecutive days, with an interval of 48 h before changing environment. Clinical parameters and respiratory tract defense markers were evaluated before and after the first run on Mondays (1 d) and on Fridays (5 d). Street presented higher mean PM2.5 concentrations (65.1 ± 39.1 µg m-3, p < 0.001) and lower temperature (22.0 °C, p = 0.010) than Forest (22.6 ± 15.3 µg m-3 and 22.8 °C). After 1 d Street running, subjects showed an increment in heart rate (p < 0.001). At day 5, there was twice the number of athletes with impaired nasal mucociliary clearance (MCC) in the Street runners group when compared to the Forest runners group. Exhaled breath condensate pH values increased in the Forest group, with significant differences between groups in day 1 (p = 0.006) and day 5 (p < 0.001), despite the fact that both groups showed values within the normal range. After exposure to both environments, the number of cells in the nasal lavage fluid was reduced after exercise (p = 0.014), without alterations in cell type and IL-8 and IL-10 concentrations. Aerobic exercise can either maintain or acutely enhance MCC and it may help to regulate inflammatory responses in the airways. Here we show that exercise practice in polluted outdoor environment, over a 5 d period, impairs MCC. In contrast, athletes running in the less polluted environment (Forest) show higher exhaled breath condensate pH values when compared to those who exercised in a more polluted environment (Street).

An approach to using heart rate monitoring to estimate the ventilation and load of air pollution exposure.

BACKGROUND: The effects of air pollution on health are associated with the amount of pollutants inhaled which depends on the environmental concentration and the inhaled air volume. It has not been clear whether statistical models of the relationship between heart rate and ventilation obtained using laboratory cardiopulmonary exercise test (CPET) can be applied to an external group to estimate ventilation. OBJECTIVES: To develop and evaluate a model to estimate respiratory ventilation based on heart rate for inhaled load of pollutant assessment in field studies. METHODS: Sixty non-smoking men; 43 public street workers (public street group) and 17 employees of the Forest Institute (park group) performed a maximum cardiopulmonary exercise test (CPET). Regression equation models were constructed with the heart rate and natural logarithmic of minute ventilation data obtained on CPET. Ten individuals were chosen randomly (public street group) and were used for external validation of the models (test group). All subjects also underwent heart rate register, and particulate matter (PM2.5) monitoring for a 24-hour period. RESULTS: For the public street group, the median difference between estimated and observed data was 0.5 (CI 95% -0.2 to 1.4) l/min and for the park group was 0.2 (CI 95% -0.2 to 1.2) l/min. In the test group, estimated values were smaller than the ones observed in the CPET, with a median difference of -2.4 (CI 95% -4.2 to -1.8) l/min. The mixed model estimated values suggest that this model is suitable for situations in which heart rate is around 120-140bpm. CONCLUSION: The mixed effect model is suitable for ventilation estimate, with good accuracy when applied to homogeneous groups, suggesting that, in this case, the model could be used in field studies to estimate ventilation. A small but significant difference in the median of external validation estimates was observed, suggesting that the applicability of the model to external groups needs further evaluation.