Circular RNA hsa_circ_0098181 inhibits metastasis in hepatocellular carcinoma by activating the Hippo signaling pathway via interaction with eEF2.

INTRODUCTION AND OBJECTIVES: The development of hepatocellular carcinoma (HCC) is a multi-step process that accumulates genetic and epigenetic alterations, including changes in circular RNA (circRNA). This study aimed to understand the alterations in circRNA expression in HCC development and metastasis and to explore the biological functions of circRNA. MATERIALS AND METHODS: Ten pairs of adjacent chronic hepatitis tissues and HCC tissues from patients without venous metastases, and ten HCC tissues from patients with venous metastases were analyzed using human circRNA microarrays. Differentially expressed circRNAs were then validated by quantitative real-time PCR. In vitro and in vivo assays were performed to assess the roles of the circRNA in HCC progression. RNA pull-down assay, mass spectrometry analysis, and RNA-binding protein immunoprecipitation were conducted to explore the protein partners of the circRNA. RESULTS: CircRNA microarrays revealed that the expression patterns of circRNAs across the three groups were significantly different. Among these, hsa_circ_0098181 was validated to be lowly expressed and associated with poor prognosis in HCC patients. Ectopic expression of hsa_circ_0098181 delayed HCC metastasis in vitro and in vivo. Mechanistically, hsa_circ_0098181 sequestered eukaryotic translation elongation factor 2 (eEF2) and dissociated eEF2 from filamentous actin (F-actin) to prevent F-actin formation, which blocked activation of the Hippo signaling pathway. In addition, the RNA binding protein Quaking-5 bound directly to hsa_circ_0098181 and induced its biogenesis. CONCLUSIONS: Our study reveals changes in circRNA expression from chronic hepatitis, primary HCC, to metastatic HCC. Further, the QKI5-hsa_circ_0098181-eEF2-Hippo signaling pathway exerts a regulatory role in HCC.

High ambient temperature and risk of hospitalization for gastrointestinal infection in Brazil: A nationwide case-crossover study during 2000-2015.

BACKGROUND: The burden of gastrointestinal infections related to hot ambient temperature remains largely unexplored in low-to-middle income countries which have most of the cases globally and are experiencing the greatest impact from climate change. The situation is particularly true in Brazil. OBJECTIVES: Using medical records covering over 78 % of population, we quantify the association between high temperature and risk of hospitalization for gastrointestinal infection in Brazil between 2000 and 2015. METHODS: Data on hospitalization for gastrointestinal infection and weather conditions were collected from 1814 Brazilian cities during the 2000-2015 hot seasons. A time-stratified case-crossover design was used to estimate the association. Stratified analyses were performed by region, sex, age-group, type of infection and early/late study period. RESULTS: For every 5 °C increase in mean daily temperature, the cumulative odds ratio (OR) of hospitalization over 0-9 days was 1.22 [95 % confidence interval (CI): 1.21, 1.23] at the national level, reaching its maximum in the south and its minimum in the north. The strength of association tended to decline across successive age-groups, with infants < 1 year most susceptible. The effect estimates were similar for men and women. Waterborne and foodborne infections were more associated with high temperature than the 'others' and 'idiopathic' groups. There was no substantial change in the association over the 16-year study period. DISCUSSION: Our findings indicate that exposure to high temperature is associated with increased risk of hospitalization for gastrointestinal infection in the hot season, with the strength varying by region, population subgroup and infection type. There was no evidence to indicate adaptation to heat over the study duration.

Transcriptomics integrated with widely targeted metabolomics reveals the cold resistance mechanism in Hevea brasiliensis.

The rubber tree is the primary source of natural rubber and is mainly cultivated in Southeast Asian countries. Low temperature is the major abiotic stress affecting the yield of the rubber tree. Therefore, uncovering the cold resistance mechanism in the rubber tree is necessary. The present study used RNA-sequencing technology and ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) to analyze the transcriptomic and metabolomic changes in two rubber tree clones with different cold resistance capacities (temperature-sensitive Reyan 8-79 and cold-resistant Yunyan 77-4) at 0 h, 2 h, 6 h, and 20 h of exposure to 4°C. Independent analysis of the transcriptome and metabolitome showed that under prolonged low-temperature treatment, Yunyan 77-4 expressed more genes involved in regulating enzyme activity, changing cell permeability, and synthesizing significant metabolites, such as flavonoids and amino acids, than Reyan 8-79. The KEGG annotation and enrichment analysis identified arginine metabolism and biosynthesis of flavonoids as the major pathway associated with cold resistance. Integrated transcriptome and metabolome analysis showed that the increase in the expression of genes modulated flavonoid biosynthesis, arginine biosynthesis, and anthocyanins biosynthesis, resulting in higher levels of metabolites, such as naringenin chalcone, apigenin, dihydroquercetin, cyanidin 3-glucoside, L-arginosuccinate, N-acetyl-ornithine, ornithine, and N-acetyl-glutamate, in Yunyan 77-4 than in Reyan 8-79 after prolonged low-temperature treatment. Phylogenetic analysis identified the genes, such as CHS (gene356) and F3H (gene33147) of flavonoid biosynthesis and NAGS (gene16028, gene33765), ArgC (gene2487), and ASS (gene6161) of arginine biosynthesis were the key genes involved in the cold resistant of rubber tree. Thus, the present study provides novel insights into how rubber clones resist cold and is a valuable reference for cold-resistance breeding.

Risk and burden of hospital admissions associated with wildfire-related PM2·5 in Brazil, 2000-15: a nationwide time-series study.

BACKGROUND: In the context of climate change and deforestation, Brazil is facing more frequent and unprecedented wildfires. Wildfire-related PM2·5 is associated with multiple adverse health outcomes; however, the magnitude of these associations in the Brazilian context is unclear. We aimed to estimate the association between daily exposure to wildfire-related PM2·5 and cause-specific hospital admission and attributable health burden in the Brazilian population using a nationwide dataset from 2000 to 2015. METHODS: In this nationwide time-series analysis, data for daily all-cause, cardiovascular, and respiratory hospital admissions were collected through the Brazilian Unified Health System from 1814 municipalities in Brazil between Jan 1, 2000, and Dec 31, 2015. Daily concentrations of wildfire-related PM2·5 were estimated using the 3D chemical transport model GEOS-Chem at a 2·0° latitude by 2·5° longitude resolution. A time-series analysis was fitted using quasi-Poisson regression to quantify municipality-specific effect estimates, which were then pooled at the regional and national levels using random-effects meta-analyses. Analyses were stratified by sex and ten age groups. The attributable fraction and attributable cases of hospital admissions due to wildfire-related PM2·5 were also calculated. FINDINGS: At the national level, a 10 µg/m3 increase in wildfire-related PM2·5 was associated with a 1·65% (95% CI 1·51-1·80) increase in all-cause hospital admissions, a 5·09% (4·73-5·44) increase in respiratory hospital admissions, and a 1·10% (0·78-1·42) increase in cardiovascular hospital admissions, over 0-1 days after the exposure. The effect estimates for all-cause hospital admission did not vary by sex, but were particularly high in children aged 4 years or younger (4·88% [95% CI 4·47-5·28]), children aged 5-9 years (2·33% [1·77-2·90]), and people aged 80 years and older (3·70% [3·20-4·20]) compared with other age groups. We estimated that 0·53% (95% CI 0·48-0·58) of all-cause hospital admissions were attributable to wildfire-related PM2·5, corresponding to 35 cases (95% CI 32-38) per 100 000 residents annually. The attributable rate was greatest for municipalities in the north, south, and central-west regions, and lowest in the northeast region. Results were consistent for all-cause and respiratory diseases across regions, but remained inconsistent for cardiovascular diseases. INTERPRETATION: Short-term exposure to wildfire-related PM2·5 was associated with increased risks of all-cause, respiratory, and cardiovascular hospital admissions, particularly among children (0-9 years) and older people (≥80 years). Greater attention should be paid to reducing exposure to wildfire smoke, particularly for the most susceptible populations. FUNDING: Australian Research Council and Australian National Health and Medical Research Council.

The impacts of long-term exposure to PM2.5 on cancer hospitalizations in Brazil.

BACKGROUND: Long-term exposure to PM2.5 has been linked to cancer incidence and mortality. However, it was unknown whether there was an association with cancer hospitalizations. METHODS: Data on cancer hospitalizations and annual PM2.5 concentrations were collected from 1,814 Brazilian cities during 2002-2015. A difference-in-difference approach with quasi-Poisson regression was applied to examine State-specific associations. The State-specific associations were pooled at a national level using random-effect meta-analyses. PM2.5 attributable burden were estimated for cancer hospitalization admissions, inpatient days and costs. RESULTS: We included 5,102,358 cancer hospitalizations (53.8% female). The mean annual concentration of PM2.5 was 7.0 µg/m3 (standard deviation: 4.0 µg/m3). With each 1 µg/m3 increase in two-year-average (current year and previous one year) concentrations of PM2.5, the relative risks (RR) of hospitalization were 1.04 (95% confidence interval [CI]: 1.02 to 1.07) for all-site cancers from 2002 to 2015 without sex and age differences. We estimated that 33.82% (95%CI: 14.97% to 47.84%) of total cancer hospitalizations could be attributed to PM2.5 exposure in Brazil during the study time. For every 100,000 population, 1,190 (95%CI: 527 to 1,836) cancer hospitalizations, 8,191 (95%CI: 3,627 to 11,587) inpatient days and US$788,775 (95%CI: $349,272 to $1,115,825) cost were attributable to PM2.5 exposure. CONCLUSIONS: Long-term exposure to ambient PM2.5 was positively associated with hospitalization for many cancer types in Brazil. Inpatient days and cost would be saved if the annual PM2.5 exposure was reduced.

Socioeconomic inequality in vulnerability to all-cause and cause-specific hospitalisation associated with temperature variability: a time-series study in 1814 Brazilian cities.

BACKGROUND: Exposure to temperature variability has been associated with increased risk of mortality and morbidity. We aimed to evaluate whether the association between short-term temperature variability and hospitalisation was affected by local socioeconomic level in Brazil. METHODS: In this time-series study, we collected city-level socioeconomic data, and daily hospitalisation and weather data from 1814 Brazilian cities between Jan 1, 2000, and Dec 31, 2015. All-cause and cause-specific hospitalisation data was from the Hospital Information System of the Unified Health System in Brazil. City-specific daily minimum and maximum temperatures came from a 0·25° × 0·25° Brazilian meteorological dataset. We represented city-specific socioeconomic level using literacy rate, urbanisation rate, average monthly household income per capita (using the 2000 and 2010 Brazilian census), and GDP per capita (using statistics from the Brazilian Institute of Geography and Statistics for 2000-15), and cities were categorised according to the 2015 World Bank standard. We used quasi-Poisson regression to do time-series analyses and obtain city-specific associations between temperature variability and hospitalisation. We pooled city-specific estimates according to different socioeconomic quartiles or levels using random-effect meta-analyses. Meta-regressions adjusting for demographic and climatic characteristics were used to evaluate the modification effect of city-level socioeconomic indicators on the association between temperature variability and hospitalisation. FINDINGS: We included a total of 147 959 243 hospitalisations (59·0% female) during the study period. Overall, we estimated that the hospitalisation risk due to every 1°C increase in the temperature variability in the current and previous day (TV0-1) increased by 0·52% (95% CI 0·50-0·55). For lower-middle-income cities, this risk was 0·63% (95% CI 0·58-0·69), for upper-middle-income cities it was 0·50% (0·47-0·53), and for high-income cities it was 0·39% (0·33-0·46). The socioeconomic inequality in vulnerability to TV0-1 was especially evident for people aged 0-19 years (effect estimate 1·21% [1·11-1·31] for lower-middle income vs 0·52% [0·41-0·63] for high income) and people aged 60 years or older (0·60% [0·50-0·70] vs 0·43% [0·31-0·56]), and for hospitalisation due to infectious diseases (1·62% [1·46-1·78] vs 0·56% [0·30-0·82]), respiratory diseases (1·32% [1·20-1·44] vs 0·55% [0·37-0·74]), and endocrine diseases (1·21% [0·99-1·43] vs 0·32% [0·02-0·62]). INTERPRETATION: People living in less developed cities in Brazil were more vulnerable to hospitalisation related to temperature variability. This disparity could exacerbate existing health and socioeconomic inequalities in Brazil, and it suggests that more attention should be paid to less developed areas to mitigate the adverse health effects of short-term temperature fluctuations. FUNDING: None.

Socioeconomic level and associations between heat exposure and all-cause and cause-specific hospitalization in 1,814 Brazilian cities: A nationwide case-crossover study.

BACKGROUND: Heat exposure, which will increase with global warming, has been linked to increased risk of a range of types of cause-specific hospitalizations. However, little is known about socioeconomic disparities in vulnerability to heat. We aimed to evaluate whether there were socioeconomic disparities in vulnerability to heat-related all-cause and cause-specific hospitalization among Brazilian cities. METHODS AND FINDINGS: We collected daily hospitalization and weather data in the hot season (city-specific 4 adjacent hottest months each year) during 2000-2015 from 1,814 Brazilian cities covering 78.4% of the Brazilian population. A time-stratified case-crossover design modeled by quasi-Poisson regression and a distributed lag model was used to estimate city-specific heat-hospitalization association. Then meta-analysis was used to synthesize city-specific estimates according to different socioeconomic quartiles or levels. We included 49 million hospitalizations (58.5% female; median [interquartile range] age: 33.3 [19.8-55.7] years). For cities of lower middle income (LMI), upper middle income (UMI), and high income (HI) according to the World Bank's classification, every 5°C increase in daily mean temperature during the hot season was associated with a 5.1% (95% CI 4.4%-5.7%, P < 0.001), 3.7% (3.3%-4.0%, P < 0.001), and 2.6% (1.7%-3.4%, P < 0.001) increase in all-cause hospitalization, respectively. The inter-city socioeconomic disparities in the association were strongest for children and adolescents (0-19 years) (increased all-cause hospitalization risk with every 5°C increase [95% CI]: 9.9% [8.7%-11.1%], P < 0.001, in LMI cities versus 5.2% [4.1%-6.3%], P < 0.001, in HI cities). The disparities were particularly evident for hospitalization due to certain diseases, including ischemic heart disease (increase in cause-specific hospitalization risk with every 5°C increase [95% CI]: 5.6% [-0.2% to 11.8%], P = 0.060, in LMI cities versus 0.5% [-2.1% to 3.1%], P = 0.717, in HI cities), asthma (3.7% [0.3%-7.1%], P = 0.031, versus -6.4% [-12.1% to -0.3%], P = 0.041), pneumonia (8.0% [5.6%-10.4%], P < 0.001, versus 3.8% [1.1%-6.5%], P = 0.005), renal diseases (9.6% [6.2%-13.1%], P < 0.001, versus 4.9% [1.8%-8.0%], P = 0.002), mental health conditions (17.2% [8.4%-26.8%], P < 0.001, versus 5.5% [-1.4% to 13.0%], P = 0.121), and neoplasms (3.1% [0.7%-5.5%], P = 0.011, versus -0.1% [-2.1% to 2.0%], P = 0.939). The disparities were similar when stratifying the cities by other socioeconomic indicators (urbanization rate, literacy rate, and household income). The main limitations were lack of data on personal exposure to temperature, and that our city-level analysis did not assess intra-city or individual-level socioeconomic disparities and could not exclude confounding effects of some unmeasured variables. CONCLUSIONS: Less developed cities displayed stronger associations between heat exposure and all-cause hospitalizations and certain types of cause-specific hospitalizations in Brazil. This may exacerbate the existing geographical health and socioeconomic inequalities under a changing climate.

Trends in Hospital Admission Rates and Associated Direct Healthcare Costs in Brazil: A Nationwide Retrospective Study between 2000 and 2015.

BACKGROUND: In Brazil, the increase in non-fatal events presents a new, unprecedented challenge for the free and universally accessible public healthcare system (SUS), the size and nature of which has yet to be reliably quantified. We examined the change in all-cause and cause-specific SUS hospital admissions during 2000 to 2015. MATERIALS AND METHODS: Data on hospital admissions across 1,816 cities were collected from the Brazilian Unified Health System. The age-standardized rates of hospital admissions, the associated healthcare costs, and length of hospital stay were quantified. Stratum analyses were performed by age, sex, region, and cause-specific categories. RESULTS: Hospital admission rates decreased by 10.2‰ per decade to 54.2‰ in 2015. For admissions in 2015, healthcare costs per patient equaled US$353 (an increase of $23.5/year since 2000) with an average length of hospital stay of 5 days (a decline of 0.04 days/year since 2000). Circulatory diseases incurred the greatest financial costs. Children and the elderly were most susceptible, especially for pneumonia. Injury and poisoning were the primary reason for admission in adult males, whereas maternal and other female-specific conditions were the highest burden in females. The burden of hospital admission was highest in the south and lowest in the north and northeast. DISCUSSION: Although hospital admission rates and length of stay have decreased in Brazil since 2000, the decline has been offset by an increase in direct healthcare costs. Age-, sex-, and region-specific features of the disease burden should be factored into future plans for healthcare expenditure in Brazil.

Existence of myodural bridge in the trachemys scripta elegans: indication of its important physiological function / Existencia del puente miodural en trachemys scripta elegans: indicación de su importante función fisiológica

The myodural bridge (MDB) is confirmed that connecting the most of suboccipital muscles to the cervical dura mater through the posterior intervertebral spaces and widely exists in mammals and birds. In order to reveal whether the MDB is universally existing in amniota of vertebrates, we explored the existence and the morphological features of the MDB in the Trachemys scripta elegans. Twenty fresh red-eared slider specimens were observed by the gross anatomy dissection and histological analysis. In the results, three kind of muscles in the postoccipital region of the red-eared slider were found. The rectus capitis dorsum minor muscle originated from the posterior margin of the occiput (C0) and terminated at the spinous process of the atlas (C1). The transversospinales muscle was attached to the vertebral arch and the postzygapophysis of the atlas and extended to the spinous process of the axis (C2). The C2-C3 intertransversales muscle were extended from the postzygapophysis of C2 and the one of C3. The three muscles covered the dorsal interspaces among C0-C3, and meantime they were closely connected with dense connective tissues, which filled in these interspaces. Each of these thick dense connective tissue membranes sent off several short and strong fibrous bundles ventrally to merge with the cervical spinal dura mater. Furthermore the connective tissues connecting these muscles with cervical spinal dura mater directly were revealed under the microscopy and they consisted of parallel and intensive collagen fibers with orientation from dorsal to ventral. In conclusion, this study for the first time demonstrated the existence of the MDB in the testudines, in all of the dorsal atlantooccipital, atlantoaxial and C2-C3 intervertebral spaces. Based on our results and comparative anatomical evidences in recent year, it could be inferred that the MDB might be its highly conserved structure in the evolution of amniota.

Se confirma que el puente miodural (PMD) conecta la mayoría de los músculos suboccipitales con la duramadre cervical a través de los espacios intervertebrales posteriores y existe ampliamente en mamíferos y aves. Para revelar si el MDB existe universalmente en la amniota de vertebrados, exploramos la existencia y las características morfológicas del PMD en Trachemys scripta elegans. Veinte muestras se observaron mediante disección anatómica y análisis histológico. En los resultados, se encontraron tres tipos de músculos en la región occipital. El músculo recto capitis dorsum minor se originó en el margen posterior del occipital (C0) y terminó en el proceso espinoso del atlas (C1). El músculo transverso espinal se unió al arco vertebral y el proceso del atlas y se extendió al proceso espinoso del axis (C2). El músculo intertransversario C2-C3 se extendió entre los procesos transversos de C2 y el de C3. Los tres músculos cubrían los espacios intermedios dorsales entre C0-C3 y, mientras tanto, estaban estrechamente conectados con tejidos conectivos densos, que rellenaban estos espacios. Cada una de estas membranas densas de tejido conectivo envían varios haces fibrosos cortos y fuertes ventralmente para fusionarse con la duramadre espinal cervical. Además, los tejidos conectivos que conectan estos músculos con la duramadre cervical y espinal se revelaron directamente bajo microscopía y consistían en intensas fibras de colágeno, paralelas, con orientación desde dorsal a ventral. En conclusión, este estudio demostró por primera vez la existencia del PMD en los estudios de prueba, en todos los espacios dorsales atlantooccipital, atlantoaxial e intervertebral C2-C3. Sobre la base de nuestros resultados y las evidencias anatómicas comparativas de los últimos años, se podría inferir que el PMD podría ser una estructura altamente conservada en la evolución de la amniota.

Association between Heat Exposure and Hospitalization for Diabetes in Brazil during 2000-2015: A Nationwide Case-Crossover Study.

BACKGROUND: Exposure to excessive heat, which will continue to increase with climate change, is associated with increased morbidity due to a range of noncommunicable diseases (NCDs). Whether this is true for diabetes is unknown. OBJECTIVES: We aimed to quantify the relationship between heat exposure and risk of hospitalization due to diabetes in Brazil. METHODS: Data on hospitalizations and weather conditions were collected from 1,814 cities during the hot seasons from 2000 to 2015. A time-stratified case-crossover design was used to quantify the association between hospitalization for diabetes and heat exposure. Region-specific odds ratios (ORs) were used to calculate the attributable fractions (AFs). RESULTS: A total of 553,351 hospitalizations associated with diabetes were recorded during 2000-2015. Every 5°C increase in daily mean temperature was associated with 6% [OR=1.06; 95% confidence interval (CI): 1.04, 1.07] increase in hospitalization due to diabetes with lag 0-3 d. The association was greatest (OR=1.18; 95% CI: 1.13, 1.23) in those ≥80y of age, but did not vary by sex, and was generally consistent by region and type of diabetes. Assuming a causal association, we estimated that 7.3% (95% CI: 3.5, 10.9) of all hospitalizations due to diabetes in the hot season could be attributed to heat exposure during the study period. DISCUSSION: Short-term heat exposure may increase the burden of diabetes-related hospitalization, especially among the very elderly. As global temperatures continue to rise, this burden is likely to increase. https://doi.org/10.1289/EHP5688.

The association between heat exposure and hospitalization for undernutrition in Brazil during 2000-2015: A nationwide case-crossover study.

BACKGROUND: Global warming is predicted to indirectly result in more undernutrition by threatening crop production. Whether temperature rise could affect undernutrition directly is unknown. We aim to quantify the relationship between short-term heat exposure and risk of hospitalization due to undernutrition in Brazil. METHODS AND FINDINGS: We collected hospitalization and weather data for the hot season (the 4 adjacent hottest months for each city) from 1,814 Brazilian cities during 1 January 2000-31 December 2015. We used a time-stratified case-crossover design to quantify the association between heat exposure and hospitalization due to undernutrition. Region-specific odds ratios (ORs) were used to calculate the attributable fractions (AFs). A total of 238,320 hospitalizations for undernutrition were recorded during the 2000-2015 hot seasons. Every 1°C increase in daily mean temperature was associated with a 2.5% (OR 1.025, 95% CI 1.020-1.030, p < 0.001) increase in hospitalizations for undernutrition across lag 0-7 days. The association was greatest for individuals aged ≥80 years (OR 1.046, 95% CI 1.034-1.059, p < 0.001), 0-4 years (OR 1.039, 95% CI 1.024-1.055, p < 0.001), and 5-19 years (OR 1.042, 95% CI 1.015-1.069, p = 0.002). Assuming a causal relationship, we estimate that 15.6% of undernutrition hospitalizations could be attributed to heat exposure during the study period. The AF grew from 14.1% to 17.5% with a 1.1°C increase in mean temperature from 2000 to 2015. The main limitations of this study are misclassification of different types of undernutrition, lack of individual temperature exposure data, and being unable to adjust for relative humidity. CONCLUSIONS: Our study suggests that global warming might directly increase undernutrition morbidity, by a route other than by threatening food security. This short-term effect is increasingly important with global warming. Global strategies addressing the syndemic of climate change and undernutrition should focus not only on food systems, but also on the prevention of heat exposure.

Ambient heat and hospitalisation for COPD in Brazil: a nationwide case-crossover study.

BACKGROUND: Heat exposure has been related to increased morbidity and mortality for several health outcomes. There is little evidence whether this is also true for COPD. This study quantified the relationship between ambient heat and hospitalisation for COPD in the Brazilian population. METHODS: Data on hospitalisations for COPD and weather conditions were collected from 1642 cities during the 2000-2015 hot seasons. A time-stratified, case-crossover design was used for city-specific analyses, which were then pooled at the regional and national levels using random-effect meta-analyses. Stratified analyses were performed by sex, age group and early/late hot season. Annual change in the association was examined using a random-effect meta-regression model. RESULTS: The OR of hospitalisation was 1.05 (95% CI 1.04 to 1.06) for every 5℃ increase in daily mean temperature at the national level, with the effect estimate stronger in the late hot season compared with the early hot season. The effect was similar in women and in men but was greatest for those aged ≥75 years. The association was stronger in the central west and southeast regions and minimal in the northeast. Assuming a causal relationship, 7.2% of admissions were attributable to heat exposure. There was no significant temporal decline in the impact of ambient heat over the 16-year study period. CONCLUSION: In Brazil, exposure to ambient heat was positively associated with hospitalisation for COPD, particularly during the late hot season. These data add to the growing evidence base implicating global warming as being an important contributor to the future healthcare burden.

The association between heatwaves and risk of hospitalization in Brazil: A nationwide time series study between 2000 and 2015.

BACKGROUND: To our knowledge, no study has assessed the association between heatwaves and risk of hospitalization and how it may change over time in Brazil. We quantified the heatwave-hospitalization association in Brazil during 2000-2015. METHODS AND FINDINGS: Daily data on hospitalization and temperature were collected from 1,814 cities (>78% of the national population) in the hottest five consecutive months during 2000-2015. Twelve types of heatwaves were defined with daily mean temperatures of ≥90th, 92.5th, 95th, or 97.5th percentiles of year-round temperature and durations of ≥2, 3, or 4 consecutive days. The city-specific association was estimated using a quasi-Poisson regression with constrained distributed lag model and then pooled at the national level using random-effect meta-analysis. Stratified analyses were performed by five regions, sex, 10 age groups, and nine cause categories. The temporal change in the heatwave-hospitalization association was assessed using a time-varying constrained distributed lag model. Of the 58,400,682 hospitalizations (59% women), 24%, 34%, 21%, and 19% of cases were aged <20, 20-39, 40-59, and ≥60 years, respectively. The city-specific year-round daily mean temperatures were 23.5 ± 2.8 °C on average, varying from 26.8 ± 1.8 °C for the 90th percentile to 28.0 ± 1.6 °C for the 97.5th percentile. We observed that the risk of hospitalization was most pronounced for heatwaves characterized by high daily temperatures and long durations across Brazil, except for the minimal association in the north (the hottest region). After controlling for temperature, the association remained for severe heatwaves in the south and southeast (cold regions). Children 0-9 years, the elderly ≥70 years, and admissions for perinatal conditions were most strongly associated with heatwaves. Over the study period, the strength of the heatwave-hospitalization association declined substantially in the south, while an apparent increase was observed in the southeast. The main limitations of this study included the lack of data on individual temperature exposure and measured air pollution. CONCLUSIONS: There are geographic, demographic, cause-specific, and temporal variations in the heatwave-hospitalization associations across the Brazilian population. Considering the projected increase in frequency, duration, and intensity of heatwaves, future strategies should be developed, such as building early warning systems, to reduce the health risk associated with heatwaves in Brazil.

Assessment of Intraseasonal Variation in Hospitalization Associated With Heat Exposure in Brazil.

Importance: The onset of the hot season is known to be adversely associated with a range of health outcomes. However, little is known about whether the association is constant over the course of the hot season. Objective: To quantify the change in the association between heat exposure and hospitalization from the early to late hot season in the Brazilian population. Design, Setting, and Participants: This time-stratified case-crossover study used daily data on hospitalization and weather conditions during the 2000 to 2015 hot seasons in 1814 Brazilian cities. There were 49 145 997 admissions during the study period. Data analysis was conducted between May 12, 2018, and July 2, 2018. Exposures: Increase in daily mean temperature. Main Outcomes and Measures: Daily hospitalizations were recorded. Conditional quasi-Poisson regression with time-varying constrained distributed lag model was used to examine the city-specific association between heat and hospitalization in the early or late hot season. City-specific estimates were then pooled at the national level using random-effect meta-analysis. Stratified analyses were conducted by 5 regions, sex, 10 age groups, and 7 cause-specific categories. Results: Of the 49 145 997 admissions (59% women), the median (interquartile range) age was 33.3 (19.8-55.7) years. At the national level, the risk of hospitalization increased by 4.6% (95% CI, 4.3%-4.9%) and 2.3% (95% CI, 1.9%-2.6%) for every 5°C increase in daily mean temperature in the early and late hot season, respectively. Exposure to early heat was associated with greater risk of hospitalization for residents in the northeast (6.4%; 95% CI, 5.5%-7.3%) and central west (7.1%; 95% CI, 6.1%-8.2%) compared with other regions. Children aged 0 to 9 years and elderly individuals (aged ≥80 years) were most susceptible. Admissions due to endocrine, nutritional, and metabolic diseases were most strongly associated with heat exposure. There was an attenuation in the heat-associated risk of hospitalization from the early to late hot season for all subgroups except young children and patients with hospitalization caused by respiratory illness. Conclusions and Relevance: In this study, the association between heat exposure and hospitalization attenuated temporally for most of the Brazilian population. Preventive strategies to mitigate the association of high temperature with population health should focus in particular on the first few days of heat exposure.

Temperature variability and hospitalization for ischaemic heart disease in Brazil: A nationwide case-crossover study during 2000-2015.

BACKGROUND: Previous studies have suggested a potential relationship between temperature variability (TV) and ischaemic heart disease (IHD) but the nature and strength differ between studies. We quantify the association between TV and risk of hospitalization for IHD across Brazilian regions and examine how the relationship varies across important population subgroups. METHODS: Data on hospitalization for IHD and meteorological parameters were collected from 1814 cities during 2000-2015. TV was defined as the standard deviation of daily minimum and maximum temperatures during exposure days. City-specific estimates were quantified using a time-stratified case-crossover approach, and then pooled at the national level using a random-effect meta-analysis. Stratified analyses were performed by region, sex and three age-groups. RESULTS: There were 2,864,904 IHD hospitalizations during 2000-2015. The estimate of TV effect was strongest on 0-1 days' exposure: odds ratio was 1.019 [95% confidence interval (CI): 1.013-1.025] per 5 °C increase in TV. The relationship was stronger in men [1.025 (95%CI: 1.017-1.033)] than in women [1.011 (95%CI: 1.002-1.019)] and in successively older age groups [1.034 (95%CI: 1.018-1.050)]. Regional differences existed, with the association only apparent in the most ageing parts of Brazil. CONCLUSIONS: Exposure to TV is associated with increased risk of hospitalization for IHD, particularly in men and in older age groups. Our findings add to the growing evidence regarding the potential impact of climatic factors on important health outcomes.

Geographic, Demographic, and Temporal Variations in the Association between Heat Exposure and Hospitalization in Brazil: A Nationwide Study between 2000 and 2015.

BACKGROUND: Limited evidence is available regarding the association between heat exposure and morbidity in Brazil and how the effect of heat exposure on health outcomes may change over time. OBJECTIVES: This study sought to quantify the geographic, demographic and temporal variations in the heat­hospitalization association in Brazil from 2000­2015. METHODS: Data on hospitalization and meteorological conditions were collected from 1,814 cities during the 2000­2015 hot seasons. Quasi-Poisson regression with constrained lag model was applied to examine city-specific estimates, which were then pooled at the regional and national levels using random-effect meta-analyses. Stratified analyses were performed by sex, 10 age groups, and 11 cause categories. Meta-regression was used to examine the temporal change in estimates of heat effect from 2000 to 2015. RESULTS: For every 5°C increase in daily mean temperature during the 2000­2015 hot seasons, the estimated risk of hospitalization over lag 0-7 d rose by 4.0% [95% confidence interval (CI): 3.7%, 4.3%] nationwide. Estimated 6.2% [95% empirical CI (eCI): 3.3%, 9.1%] of hospitalizations were attributable to heat exposure, equating to 132 cases (95% eCI: 69%, 192%) per 100,000 residents. The attributable rate was greatest in children [Formula: see text] and was highest for hospitalizations due to infectious and parasitic diseases. Women of reproductive age and those [Formula: see text] had higher heat burden than men. The attributable burden was greatest for cities in the central west and the inland of the northeast; lowest in the north and eastern coast. Over the 16-y period, the estimated heat effects declined insignificantly at the national level. CONCLUSIONS: In Brazil's hot seasons, 6% of hospitalizations were estimated to be attributed to heat exposure. As there was no evidence indicating that thermal adaptation had occurred at the national level, the burden of hospitalization associated with heat exposure in Brazil is likely to increase in the context of global warming. https://doi.org/10.1289/EHP3889.

Temperature variability and hospitalization for cardiac arrhythmia in Brazil: A nationwide case-crossover study during 2000-2015.

BACKGROUND: There is growing recognition of a potential role for environmental and climatic factors in influencing cardiovascular risk. It has been speculated that temperature variability (TV) is a risk factor for cardiac arrhythmia but evidence is limited. OBJECTIVE: To quantify the geographic and demographic variations in the association between TV and hospitalization for cardiac arrhythmia in Brazil during 2000-2015. METHODS: Data on hospitalization for arrhythmia and weather conditions were collected from 1,814 cities. TV was calculated as the standard deviation of daily maximum and minimum temperatures during exposure days. A time-stratified case-crossover approach was applied to examine the city-specific association between TV and hospitalization for arrhythmia. City-specific estimates were pooled at the national and regional levels using a random-effect meta-analysis. Stratified analyses were conducted by sex, three age-groups (0-64, 65-74 and ≥75 years), and three arrhythmia subtypes (paroxysmal tachycardia, atrial fibrillation and flutter, and other arrhythmias). RESULTS: There were 447,667 arrhythmia-related hospitalizations during 2000-2015. The odds ratio of hospitalization per 1 °C increase in TV peaked on 0-1 days' exposure [1.012 (95% confidence interval: 1.010-1.015)]. There were no substantial differences in effect estimates of TV0-1 by region, age or sex, except for the non-significant association observed in the north. However, women were more affected by prolonged TV exposure than men. For the three arrhythmias subtypes, only paroxysmal tachycardia and other arrhythmias were sensitive to TV. Assuming a causal relationship, 35,813 (95%CI: 18,302-51,665) cases were attributable to TV0-1 in Brazil during 2000-2015, accounting for 8.0% (95%CI: 4.1-11.5%) of hospitalizations for cardiac arrhythmia. CONCLUSIONS: At a population-level exposure to TV was associated with increased risk of arrhythmia-related hospitalization in Brazil, with the relationship equally distributed across most residents but varied by arrhythmia subtypes. Our findings add to the accumulating evidence-base that climatic factors can influence cardiovascular outcomes in populations.

Inhibitory effect of reduced graphene oxide-silver nanocomposite on progression of artificial enamel caries

Abstract The use of antimicrobial agents is an efficient method to prevent dental caries. Also, nanometric antibacterial agents with wide antibacterial spectrum and strong antibacterial effects can be applied for prevention of dental caries. Objectives: The aim of this study was to evaluate the inhibitory effect of reduced graphene oxide-silver nanoparticles (rGO/Ag) composite on the progression of artificial enamel caries in a Streptococcus mutans biofilm model. Material and Methods: Enamel specimens from bovine incisors were divided into eight treatment groups (n = 13), as follows: group 1 was inoculated with S. mutans grown in Brain Heart Infusion containing 1% sucrose (1% BHIS), as negative control; groups 2-4 were inoculated with S. mutans grown in the presence of different rGO/Ag concentrations (0.08, 0.12, 0.16 mg/mL) + 1% BHIS; group 5-7 were inoculated with S. mutans grown in the presence of different agents (0.16 mg/mL reduced graphene oxide, 0.16 mg/mL silver nanoparticles, 10 ppm NaF) + 1% BHIS; group 8 was mixed with 1% BHIS, without inoculation. Artificial enamel carious lesions were produced by S. mutans biofilm model for 7 days. Confocal laser scanning microscopy and atomic force microscopy were used to analyze roughness and morphology of the enamel surface. Polarized light microscopy and confocal laser scanning microscopy were employed to measure the lesion depth and the relative optical density (ROD) of the demineralized layer. Results: Compared with the control groups, the rGO/Ag groups showed: (a) reduced enamel surface roughness; (b) much smoother and less eroded surfaces; (c) shallower lesion depth and less mineral loss. Conclusion: As a novel composite material, rGO/Ag can be a promising antibacterial agent for caries prevention.

Inhibitory effect of reduced graphene oxide-silver nanocomposite on progression of artificial enamel caries.

OBJECTIVES: The use of antimicrobial agents is an efficient method to prevent dental caries. Also, nanometric antibacterial agents with wide antibacterial spectrum and strong antibacterial effects can be applied for prevention of dental caries. The aim of this study was to evaluate the inhibitory effect of reduced graphene oxide-silver nanoparticles (rGO/Ag) composite on the progression of artificial enamel caries in a Streptococcus mutans biofilm model. MATERIAL AND METHODS: Enamel specimens from bovine incisors were divided into eight treatment groups (n = 13), as follows: group 1 was inoculated with S. mutans grown in Brain Heart Infusion containing 1% sucrose (1% BHIS), as negative control; groups 2-4 were inoculated with S. mutans grown in the presence of different rGO/Ag concentrations (0.08, 0.12, 0.16 mg/mL) + 1% BHIS; group 5-7 were inoculated with S. mutans grown in the presence of different agents (0.16 mg/mL reduced graphene oxide, 0.16 mg/mL silver nanoparticles, 10 ppm NaF) + 1% BHIS; group 8 was mixed with 1% BHIS, without inoculation. Artificial enamel carious lesions were produced by S. mutans biofilm model for 7 days. Confocal laser scanning microscopy and atomic force microscopy were used to analyze roughness and morphology of the enamel surface. Polarized light microscopy and confocal laser scanning microscopy were employed to measure the lesion depth and the relative optical density (ROD) of the demineralized layer. RESULTS: Compared with the control groups, the rGO/Ag groups showed: (a) reduced enamel surface roughness; (b) much smoother and less eroded surfaces; (c) shallower lesion depth and less mineral loss. CONCLUSION: As a novel composite material, rGO/Ag can be a promising antibacterial agent for caries prevention.

Spatiotemporal and demographic variation in the association between temperature variability and hospitalizations in Brazil during 2000-2015: A nationwide time-series study.

BACKGROUND: Extreme temperature events are known to be adversely associated with a range of health outcomes, but little is known about the effect of less extreme, but more frequent fluctuation in temperature. We examined the spatiotemporal and demographic variation in the effect of temperature variability (TV) on nationwide hospitalizations in Brazil during 2000-2015. METHODS: Data on daily hospitalizations and weather variables were collected from 1814 cities, comprising 78.4% of Brazilian population. TV was defined as the standard deviation of daily minimum and maximum temperatures during exposure days. City-specific TV effect was estimated using a quasi-Poisson regression model, and then pooled at the national and regional level using meta-analysis. Stratified analyses were performed by sex, 10 age-groups, and 11 cause categories. Meta-regression was applied to city-year-specific estimates to examine the temporal change. RESULTS: The estimate of TV effect peaked on 0-1 days' exposure, contributing to 3.5% [95% confidence interval (CI): 3.1-3.8%] of hospitalizations nationwide, equalling 221 (95%CI: 200-242) cases per 100,000 population annually. The effect estimate varied across 11 cause categories, which was strongest for respiratory admissions. Males, particular those 10-49 year old were more affected than females but there was no sex difference for the attributable hospitalization rate. The attributable rate for the under-fives was twice as high as for the elderly, and five times higher than in adults. The majority of the most affected cities were located in the central west and the inland of northeast. The risk of hospitalization related to TV showed a significant increase over the 16-year period at the national level. CONCLUSIONS: In Brazil, the effect of TV on hospitalization is acute, and varies by spatial, sex, age, and cause category. Given there is no evidence regarding TV adaptation, hospitalization burden associated with TV is likely to further increase and warrants consideration when developing future public health policies in the context of climate change.