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Background This study aimed to assess the long-term effects of size-specific particulate matter (PM) on frailty transitions in middle-aged and older Chinese adults. Methods We included 13 910 participants ≥45 y of age from the China Health and Retirement Longitudinal Study (CHARLS) for 2015 and 2018 who were classified into three categories in 2015 according to their frailty states: robust, prefrail and frail. Air quality data were obtained from the National Urban Air Quality Real-time Publishing Platform. A two-level logistic regression model was used to examine the association between concentrations of PM and frailty transitions. Results At baseline, the total number of robust, prefrail and frail participants were 7516 (54.0%), 4324 (31.1%) and 2070 (14.9%), respectively. Significant associations were found between PM concentrations and frailty transitions. For each 10 μg/m3 increase in the 3-y averaged 2.5-μm PM (PM2.5) concentrations, the risk of worsening in frailty increased in robust (odds ratio [OR] 1.06 [95% confidence interval {CI} 1.01 to 1.12]) and prefrail (OR 1.07 [95% CI 1.01 to 1.13]) participants, while the probability of improvement in frailty in prefrail (OR 0.91 [95% CI 0.84 to 0.98]) participants decreased. In addition, the associations of PM10 and coarse fraction of PM with frailty transitions showed similar patterns. Conclusions Long-term exposure to PM was associated with higher risks of worsening and lower risks of improvement in frailty among middle-aged and older adults in China.

Background: High sodium intake is an important risk factor for hypertension and cardiovascular disease. However, the association between gut microbiota composition and metabolomic profiles with dietary sodium intake and blood pressure (BP) is not well-understood. The metabolome, microbiome, and dietary salt intervention (MetaSalt) study aimed to investigate microbial and metabolomic profiles related to dietary sodium intake and BP regulation. Methods: This family-based intervention study was conducted in four communities across three provinces in rural northern China in 2019. Probands with untreated prehypertension or stage-1 hypertension were identified through community-based BP screening, and family members including siblings, offspring, spouses, and parents were subsequently included. All participants participated in a 3-day baseline examination with usual diet consumption, followed by a 10-day low-salt diet (3 g/d of salt or 51.3 mmol/d of sodium) and a 10-day high-salt diet (18 g/d of salt or 307.8 mmol/d of sodium). Differences in mean BP levels were compared according to the intervention phases using a paired Student's t-test. Results: A total of 528 participants were included in this study, with a mean age of 48.1 years, 36.7% of whom were male, 76.8% had a middle school (69.7%) or higher (7.1%) diploma, 23.4% had a history of smoking, and 24.4% were current drinkers. The mean arterial pressure at baseline was 97.2 ± 10.5 mm Hg for all participants, and significantly decreased during the low-salt intervention (93.8 ± 9.3, P

China, with its growing population and economic development, faces increasing risks to health from climate change, but also opportunities to address these risks and protect health for generations to come. Without a timely and adequate response, climate change will impact lives and livelihoods at an accelerated rate. In 2020, the Lancet Countdown Regional Centre in Asia, led by Tsinghua University, built on the work of the global Lancet Countdown and began its assessment of the health profile of climate change in China with the aim of triggering rapid and health-responsive actions. This 2021 report is the first annual update, presenting 25 indicators within five domains: climate change impacts, exposures, and vulnerability; adaptation, planning, and resilience for health; mitigation actions and health co-benefits; economics and finance; and public and political engagement. The report represents the contributions of 88 experts from 25 leading institutions in, and outside of, China. From 2020 to 2021, five new indicators have been added and methods have been improved for many indicators. Where possible, the indicator results are presented at national and provincial levels to facilitate local understanding and policy making. In a year marked by COVID-19, this report also endeavours to reflect on China's pathway for a green recovery, ensuring it aligns with the carbon neutrality goal, for the health of the current and future generations.

Left unmitigated, climate change poses a catastrophic risk to human health, demanding an urgent and concerted response from every country. The 2015 Lancet Commission on Health and Climate Change and The Lancet Countdown: Tracking Progress on Health and Climate Change have been initiated to map out the impacts of climate change and the necessary policy responses. To meet these challenges, Tsinghua University, partnering with the University College London and 17 Chinese and international institutions, has prepared the Chinese Lancet Countdown report, which has a national focus and builds on the work of the global Lancet Countdown: Tracking Progress on Health and Climate Change. Drawing on international methodologies and frameworks, this report aims to deepen the understanding of the links between public health and climate change at the national level and track them with 23 indicators. This work is part of the Lancet's Countdown broader efforts to develop regional expertise on this topic, and coincides with the launch of the Lancet Countdown Regional Centre in Asia, based at Tsinghua University. The data and results of this report are presented at the provincial level, where possible, to facilitate targeted response strategies for local decision-makers. Based on the data and findings of the 2020 Chinese Lancet Countdown report, five recommendations are proposed to key stakeholders in health and climate change in China: (1) Enhance inter-departmental cooperation. Climate change is a challenge that demands an integrated response from all sectors, urgently requiring substantial inter-departmental cooperation among health, environment, energy, economic, financial, and education authorities. (2) Strengthen health emergency preparedness. Knowledge and findings on current and future climate-related health threats still lack the required attention and should be fully integrated into the emergency preparedness and response system. (3) Support research and raise awareness. Additional financial support should be allocated to health and climate change research in China to enhance health system adaptation, mitigation measures, and their health benefits. At the same time, media and academia should be fully motivated to raise the public and politicians' awareness of this topic. (4) Increase climate change mitigation. Speeding up the phasing out of coal is necessary to be consistent with China's pledge to be carbon neutral by 2060 and to continue to reduce air pollution. Fossil fuel subsidies must also be phased out. (5) Ensure the recovery from COVID-19 to protect health now and in the future. China's efforts to recover from COVID-19 will shape public health for years to come. Climate change should be a priority in these interventions.

Background: Air pollution nowadays has seriously threatened the health of the Chinese population, especially in the vulnerable groups of fetuses, infants and toddlers. In particular, the effects of air pollution on children’s neurobehavioral development have attracted widespread attention. Moreover, the early detection of a sensitive period is very important for the precise intervention of the disease. However, such studies focusing on hyperactive behaviors and susceptible window identification are currently lacking in China. Objectives: The study aims to explore the correlation between air pollution exposure and hyperactive behaviors during the early life stage and attempt to identify whether a susceptible exposure window exists that is crucial for further precise intervention. Methods: Based on the Longhua Child Cohort Study, we collected the basic information and hyperactivity index of 26,052 children using a questionnaire conducted from 2015 to 2017, and the Conners’ Parent Rating Scale-revised (CPRS-48) was used to assess hyperactive behaviors. Moreover, the data of air pollution concentration (PM10, PM2.5, NO2, CO, O3 and SO2) were collected from the monitoring station between 2011 to 2017, and a land-use random forest model was used to evaluate the exposure level of each subject. Furthermore, Distributed lag non-linear models (DLNMs) were applied for statistic analysis. Results: The risk of child hyperactivity was found to be positively associated with early life exposure to PM10, PM2.5 and NO2. In particular, for an increase of per 10 µg/m3 in PM10, PM2.5 and NO2 exposure concentration during early life, the risk of child hyperactivity increased significantly during the seventh month of pregnancy to the fourth month after birth, with the strongest association in the ninth month of pregnancy (PM10: OR = 1.043, 95% CI: 1.016–1.071; PM2.5: OR = 1.062, 95% CI: 1.024–1.102; NO2: OR = 1.043, 95% CI: 1.016–1.071). However, no significant associations among early life exposure to CO, O3 and SO2 and child hyperactive behaviors were observed. Conclusions: Early life exposure to PM10, PM2.5 and NO2 is associated with an increased risk of child ADHD-like behaviors at the age around 3 years, and the late-prenatal and early postnatal periods might be the susceptible exposure windows.

Plastic packaging material is widely used to package high-temperature soup food in China, but this combination might lead to increased exposure to phthalates. The health effects and potential biological mechanisms have not been well studied. This study aimed to examine urinary phthalate metabolites and the expression of inflammatory cytokines in the blood before, during, and after a "plastic-packaged high-temperature soup food" dietary intervention in healthy adults. The results showed that compared with those in the preintervention period, urinary creatinine-adjusted levels of monomethyl phthalate (MMP), mono

Currently, there is no evidence of fine particulate matter pollution (PMBased on the UK Biobank study, we included 308,507 participants aged 40-69 years at baseline (2006 to 2010) and prospectively followed up for conjunctivitis diagnosis till 2020. Annual concentrations of PMDuring the 11.6 years of follow up, we identified 4002 incident conjunctivitis cases. High-PA (≥3000 metabolic equivalent of task [MET]-mins/week) was associated with lower risk of conjunctivitis (hazard ratio [HR]: 0.79, 95% confidence interval [CI]: 0.73-0.86) compared to low-PA (0 to600 MET-mins/week), while every 1 μg/mHabitual PA and PM

We identified and characterized a novel superoxide dismutase (SOD), designated as CcSOD1, from the cDNA library from the tentacle tissue of the jellyfish Cyanea capillata. The full-length cDNA sequence of CcSOD1 consists of 745 nucleotides with an open reading frame encoding a mature protein of 154 amino acids, sharing a predicted structure similar to the typical Cu/Zn-SODs. The CcSOD1 coding sequence was cloned into the expression vector pET-24a and successfully expressed in Escherichia coli Rosetta (DE3) pLysS. The recombinant protein rCcSOD1 was purified by HisTrap High Performance chelating column chromatography and analyzed for its biological function. Our results showed that the purified rCcSOD1 could inhibit superoxide anion and keep active in a pH interval of 4.5–9 and a temperature interval of 10–70°C. Even when heated at 70°C for 60 min, rCcSOD1 retained 100% activity, indicating a relatively high thermostability. These results suggest that CcSOD1 protein may play an important role in protecting jellyfish from oxidative damage and can serve as a new resource for antioxidant products.

Background: There was lack of data on the burdens and trends of upper and lower respiratory infections (URIs and LRIs) over the past three decades in China. Methods: We estimated the incidence, mortality, and disability-adjusted life years (DALYs) due to upper and lower respiratory infections (URIs and LRIs) and attributable risk factors in China by a systematic analysis of the Global Burden of Disease 2019 study. Incidence, mortality, and DALYs were stratified by sex, age, and province. Risk factors for respiratory infections were analyzed from exposure data. Findings: The age-standardized incidence rates of URIs and LRIs were 179,077 and 3926 per 100,000 persons in 2019, with a 7•52% and 35•07% decrease from 1990, respectively. Moreover, 2801 and 185,264 persons died of URIs and LRIs in 2019, respectively. DALYs for URIs and LRIs also decreased from 1,516,727 in 1990 to 928,617 in 2019 and from 38,278,504 in 1990 to 4,020,676 in 2019. The burden of URIs and LRIs were generally similar in males and females, but relatively higher in the new-borns and the elderly. Child malnutrition and low birth weight were the most important cause of age-standardized DALYs of LRIs and URIs, respectively. Interpretation: Future URI and LRI prevention strategies should focus on the maternal and child health, air pollution, and tobacco control, especially in young children and the elderly population. Funding: National Key R&D Program of China (2018YFA0606200); National Natural Science Foundation of China (82041021); Fundamental Research Funds for the Central Universities (20ykpy86) and Guangdong Basic and Applied Basic Research Foundation (2019A1515110003); Bill & Melinda Gates Foundation (No.: INV-006371).

Background Studies have reported that exposure to air pollution during pregnancy was associated with preterm birth (PTB). However, it remains unknown whether this association differs between local residents and migrants. Objective This study aimed to differentiate the associations between maternal air pollution exposure and PTB between local residents and migrants. Methods We established a retrospective birth cohort in seven Chinese cities in Pearl River Delta (PRD) region during 2015–2017. The mothers were included in the cohort at their first time of hospital visit for pregnancy, and the endpoint events were identified using the birth registry. The air pollution exposure was estimated based on the daily air pollution concentrations in the nearby air monitoring stations during different pregnancy periods. Cox proportional hazards models were utilized to estimate the associations between each air pollutant and PTB for different pregnancy periods. Results Our cohort included a total of 628,439 mother-and-live-birth pairs. Among them, 308,201 women were local residents, and 320,238 were migrants. We observed stronger effects of air pollutants among the migrants than the local residents. For the exposure during the entire pregnancy, the hazard ratio (HR) among the migrants and local residents were 1.56 (95% CI: 1.50, 1.63) and 0.98 (95% CI: 0.93, 1.02) for each 10 μg/m3 increase in PM2.5, 1.32 (95% CI: 1.27, 1.39) and 1.18 (95% CI: 1.12, 1.23) for each 10 ppb increase in O3, and 1.48 (95% CI: 1.40, 1.57) and 0.99 (95% CI: 0.93, 1.05) for each 10 μg/m3 increase in SO2, respectively. Similarly higher effects were observed among the migrants for the exposures in different trimesters of pregnancy. However, the effects of NO2 were comparable between the two groups. Conclusion Our study suggests that maternal PM2.5, O3 and SO2 exposures might be important risk factors of preterm birth, particularly among the migrants. More specific protective and education measures should be considered for the migrant pregnant women.

The World Health Organization sets up the Ambient Air Quality Guidelines mainly based on short-term and long-term health effects of air pollution. Previous studies, however, have generally revealed a non-threshold concentration-response relationship between air pollution and health, making it difficult to determine a concentration, below which no obvious health effects can be observed. Here we proposed a novel approach based on the concept of “number needed to treat”, specifically, we calculated the reduction in air pollution concentrations needed to avoid one death corresponding to different hypothetical concentration standards; the one with the smallest value would be the most practical concentration standard. As an example, we applied this approach to the daily standard of ambient PM2.5 (particulate matter with aerodynamic diameter ≤2.5 μm) in four Chinese cities. The calculation was based on the association between daily mortality and ambient PM2.5, which was examined by a generalized additive model with adjustment of important covariates. Significant associations were observed between PM2.5 and mortality. Our analyses suggested that it is appropriate to have 50 μg/m3 as the daily standard of ambient PM2.5 for the study area, compared to the current standard of which were directly adopted from the national standard of 75 μg/m3. This novel approach should be considered when planning and/or revising the ambient air quality guidelines/standards.

Background: Previous studies have reported that maternal exposure to particles with aerodynamic diameter

Background Fine particulate matter (Particulate matter with diameter ≤ 2.5 μm) is associated with multiple health outcomes, with varying effects across seasons and locations. It remains largely unknown that which components of PM2.5 are most harmful to human health. Methods We systematically searched all the relevent studies published before August 1, 2018, on the associations of fine particulate matter constituents with mortality and morbidity, using Web of Science, MEDLINE, PubMed and EMBASE. Studies were included if they explored the associations between short term or long term exposure of fine particulate matter constituents and natural, cardiovascular or respiratory health endpoints. The criteria for the risk of bias was adapted from OHAT and New Castle Ottawa. We applied a random-effects model to derive the risk estimates for each constituent. We performed main analyses restricted to studies which adjusted the PM2.5 mass in their models. Results Significant associations were observed between several PM2.5 constituents and different health endpoints. Among them, black carbon and organic carbon were most robustly and consistently associated with all natural, cardiovascular mortality and morbidity. Other potential toxic constituents including nitrate, sulfate, Zinc, silicon, iron, nickel, vanadium, and potassium were associated with adverse cardiovascular health, while nitrate, sulfate and vanadium were relevant for adverse respiratory health outcomes. Conclusions Our analysis suggests that black carbon and organic carbon are important detrimental components of PM2.5, while other constituents are probably hazardous to human health. However, more studies are needed to further confirm our results.

Background Ambient air pollutant directly contacts with the eyes, however, the effect of ambient fine particulate matter (PM2.5) and ozone (O3) on vision impairment, such as presbyopia, has been kept largely unknown. Methods We surveyed a total of 36,620 participants aged 50 years and above in six low- and middle-income countries. Ambient annual concentrations of PM2.5 and O3 for the residential community were estimated using satellite data and chemical transport model. A mixed effects model was utilized to assess the effects of ambient PM2.5 and O3 on presbyopia, as well as their combined effects. Results A total of 13,841 presbyopia cases were identified among the participants with a prevalence rate of 41.17%. For both PM2.5 and O3, we found a J-shaped exposure-response relationship with the threshold being identified at 15 μg/m3 for PM2.5 and 55 μg/m3 for O3. The odds ratio (OR) of presbyopia was 1.15 (95% CI: 1.09, 1.21) for each 10 μg/m3 increase in PM2.5 above 15 μg/m3 and 1.37 (95% CI: 1.23, 1.54) for O3 above 55 μg/m3 after adjusting for various potential confounding factors. There appeared to be a synergistic interaction between ambient PM2.5 and O3 on presbyopia in the additive model, the combined effect was significantly larger than the sum of their individual effects, with a synergistic index of 2.39. Conclusion This study supports that exposures to ambient PM2.5 and O3 might be important risk factors of presbyopia among old adults, and simultaneously exposure to high level of the two pollutants could intensify their individual effects.

The linkage between ambient air pollution exposure and occurrence of diabetes mellitus is not well defined. This study examined the association between exposure to fine particles (PM2.5) and the prevalence of diabetes among Chinese elderly people. We surveyed 11,504 adults aged ≥50 years in China, estimated the annual concentrations of ambient PM2.5 using a satellite-based model of aerosol optical depth information. We employed a generalized mixed effects model to examine the association between PM2.5 and the prevalence of diabetes and explored potential effect modifiers. We estimated diabetes burden attributable to ambient PM2.5 if the observed association is indeed causal. The diabetes prevalence among the participants was 6.5% (n = 745). Our analysis found a statistically significant association between PM2.5 and diabetes. The adjusted odds ratio was 1.27 (95% confidence interval (CI), 1.12, 1.43) for each 10 μg/m3 increment in ambient PM2.5. Stratified analyses found a lower association among the participants with higher consumption of fruit. We estimated that 22.02% (95% CI: 8.59%, 43.29%) of the diabetes cases could be ascribable to ambient PM2.5. Our finding suggests that PM2.5 exposures could increase the risk of diabetes, and if causal, could be responsible for substantial burden of diabetes among the Chinese elderly; and higher intakes of fruit might reduce the harmful effects of PM2.5, however, due to the limitation of the cross-sectional study design, more studies are warranted to confirm this observation.

Objective Rapid urbanization has led to reduced greenness in many areas, this has been linked to adverse health outcomes. The aim was to determine the association between residential greenness experienced during very early childhood with preschool myopia and astigmatism and to explore the potential mediating role of screen time on any associations. Method Information regarding socio-demographic characteristics, home address, screen time during early childhood, and refraction data from vision screenings of 53,575 preschoolers from Longhua Child Cohort Study were collected via questionnaires. Residential greenness was calculated as the average of satellite-derived Normalized Difference Vegetation Index in buffers of 100, 250, and 500 m around each child's home address. Logistic and linear regression models were used to examine the relationships between residential greenness, screen time, and preschool myopia and astigmatism. Result The mean (SD) age of the 53,575 preschoolers was 5.0 (0.7) years, and 24,849 (46.4%) were girls. A total of 1236 (2.3%) preschoolers had myopia and 5347 (10.0%) had astigmatism. In the adjusted model, a higher neighborhood greenness level within 100 m buffers around the home address was associated with decreased risk of myopia (adjusted odds ratios (AOR): 0.62, 95% confidence interval (CI): 0.38–0.99), and higher neighborhood greenness levels within 100, 250, and 500 m decreased the risk of astigmatism, and their AORs (95% CIs) were 0.55 (0.43–0.70) for 100 m, 0.59 (0.41–0.83) for 250 m, 0.61 (0.42–0.90) for 500 m, respectively. Greater screen time during early childhood increased the risk of myopia (AOR = 1.33) and astigmatism (AOR = 1.23). Reduction in screen time fully mediated the benefits of greater residential greenness on preschool myopia, but partially mediated that on preschool astigmatism (p Conclusion Higher residential greenness reduces the risk of preschool myopia and astigmatism; the benefits of residential greenness were mediated through reduced daily screen time.

Background Both inhalable particles (PM10) and fine particles (PM2.5) are regulated in various countries mainly due to their adverse health effects. However, there is increasing evidence that PM2.5 might be responsible for these effects and coarse particles (PMc) plays little role in adverse health effects, if so, it might be not necessary to monitor PM10. Methods In this study, we conducted a time-series analysis using a generalized additive model to explore the effects of PM2.5, PMc, and PM10 on mortality from ischemic heart disease (IHD) and chronic obstructive pulmonary disease (COPD) in 96 Chinese cities during 2013–2016. The mortality number and attributable fraction were further estimated using the national air quality standard and WHO’s guideline as the reference. Results We observed significant effects of PM2.5 on IHD and COPD mortality; each 10 ug/m3 increase in lag01 PM2.5 was associated with a 0.26% (95% CI: 0.17%, 0.34%) increase in IHD mortality and a 0.19% (95% CI: 0.09%, 0.29%) increase in COPD mortality. We also found significant effects of PMc and PM10 on mortality from IHD and COPD, but the magnitudes of effects were weaker than those of PM2.5. The results were robust when adjusting for co-pollutants and altering model parameters. We further estimated that about 1.27% (95% CI: 0.29%, 2.30%) of IHD mortality and 1.25% (95% CI: 0.08%, 2.46%) of COPD mortality could be attributable to PM2.5 exposure using WHO’s guideline (25 ug/m3) as a reference, corresponding to 15,337 (95% CI: 3,375, 27,842) mortalities from IHD and 5,653 (95% CI: 379, 11,152) COPD mortalities in the 96 cities. Across all of China, almost fifty thousand cases of IHD mortality and twenty thousand cases of COPD mortality might be avoidable if the PM2.5 concentration declined to the WHO guideline. Conclusions Our study indicates that short-term exposure to PM2.5 could be an important risk factor of mortality from IHD and COPD, and substantial cardiopulmonary mortality could be avoidable by reducing daily PM2.5 concentrations. It is nonnegligible to consider the role of PMc in triggering in cardiopulmonary mortality. And it could be necessary to continue monitoring PM10 in the study regions due to the adverse effects of PMc.

The novel coronavirus disease 2019 (COVID-19) has been the biggest public health problem of the present world. As the number of people suffering from the pandemic is rising, it is likely to claim more life and worsen the global health and economy. Nepal, one of the developing countries in the south Asia has been strongly influenced by the pandemic and struggling to contain it with multiple interventions, however, spatiotemporal dynamics of the epidemic and its linkage with various intervention strategies has not been studied yet. Here, we employed the prospective spatial-temporal analysis with SaTScan assessing dynamics of the COVID-19 cases from 23 January to 31 August 2020 at district level in Nepal. The results revealed that COVID-19 dynamics in the early stage of transmission was slower and confined in certain districts. However, from the third week of April, transmission spread rapidly across districts of Province No. 2 and Sudoorpaschim Province, primarily introduced by Nepalese citizens returning from India. Despite nationwide lockdown, nine statistically significant active and emerging clusters were detected between 23 January and 21 July 2020, whereas ten emerging clusters were observed for extended period to 31 August. The population density and population inflow from India crossing the sealed border had significant effects on the elevated risk of the epidemic. The capital city Kathmandu has become the highest-risk active cluster since August when travel restriction has been suspended. Movement restriction appears to be the most effective non-pharmaceutical intervention against the COVID-19 for resource-scarce countries with limited health care facilities. Our findings could be valuable to the health authorities within Nepal and beyond to better allocate resources and improve interventions on the pandemic for containing it efficiently.

The potential impacts of daily ambient fine particulate pollution (PMThis study was based on daily mortality data covering 96 Chinese cities from 2013 to 2016. Regional- and national-associations between IHD-related YLLs and daily PMOur study provides a nationwide picture of the life expectancy improvements by reaching the daily PM

This time‐series study collects data on stroke‐related mortality, years of life lost (YLL), air pollution, and meteorological conditions in 96 Chinese cities from 2013 to 2016 and proposes a three‐stage strategy to generate the national and regional estimations of avoidable YLL, gains in life expectancy and stroke‐related population attributable fraction by postulating that the daily fine particulate matter (PM2.5) has been kept under certain standards. A total of 1 318 911 stroke deaths are analyzed. Each 10 µg m−3 increment in PM2.5 at lag03 is associated with a city‐mean increase of 0.31 (95% CI: 0.19, 0.44) years of life lost from stroke. A number of 914.11 (95% CI: 538.28, 1288.94) years of city‐mean life lost from stoke could be avoided by attaining the WHO's Air Quality Guidelines (AQG) (25 µg m−3). Moreover, by applying the AQG standard, 0.11 (0.08, 0.15) years of life lost might be prevented for each death, and about 0.91% (95% CI: 0.62%, 1.19%) of the total years of life lost from stroke might be explained by the daily excess PM2.5 exposure. This study indicates that stroke patients can have a longer life expectancy if stricter PM2.5 standards are put in place, especially ischemic stroke patients., This study aims to examine the relationships between daily fine particulate matter PM2.5 pollution and stroke‐related years of life lost YLL and potential gains in life expectancy by achieving different PM2.5 standards in 96 Chinese cities from 2013 to 2016. The results show that daily PM2.5 exposure is associated with YLL due to stroke, and that life expectancy can be longer by adopting stricter PM2.5 standards.

Summary Although exposure to air pollution increases the risk of premature mortality and years of life lost (YLL), the effects of daily air quality improvement to the life expectancy of respiratory diseases remained unclear. We applied a generalized additive model (GAM) to assess the associations between daily PM2.5 exposure and YLL from respiratory diseases in 96 Chinese cities during 2013–2016. We further estimated the avoidable YLL, potential gains in life expectancy, and the attributable fraction by assuming daily PM2.5 concentration decrease to the air quality standards of China and World Health Organization. Regional and national results were generated by random-effects meta-analysis. A total of 861,494 total respiratory diseases and 586,962 chronic obstructive pulmonary disease (COPD) caused death from 96 Chinese cities were recorded during study period. Each 10 μg/m3 increase of PM2.5 in 3-day moving average (lag02) was associated with 0.16 (95% CI: 0.08, 0.24) years increment in life expectancy from total respiratory diseases. The highest effect was observed in Southwest region with 0.42 (95% CI: 0.22, 0.62) years increase in life expectancy. By attaining the WHO's Air Quality Guidelines, we estimated that an average of 782.09 (95% CI: 438.29, 1125.89) YLLs caused by total respiratory death in each city could be avoided, which corresponded to 1.15% (95% CI: 0.67%, 1.64%) of the overall YLLs, and 0.12 (95% CI: 0.07, 0.17) years increment in life expectancy. The results of COPD were generally consistent with total respiratory diseases. Our findings indicate that reduction in daily PM2.5 concentrations might lead to longer life expectancy from respiratory death., Graphical Abstract, Public Summary • This is a nationwide time-series study in 96 Chinese cities • PM2.5 level was associated with increased risk of respiratory death • PM2.5 level was associated with increased years of life lost of respiratory death • Daily PM2.5 reduction might lead to longer life expectancy from respiratory death

BACKGROUND: Air pollution has been associated with various health outcomes. Its effect on hand-grip strength, a measurement of the construct of muscle strength and health status, remains largely unknown. METHODS: We used the survey data from 31,209 adults ≥ 50 years of age within Wave 1 of the Study on Global AGEing and Adult Health in six low- and middle-income countries. The outdoor concentration of fine particulate matter pollution (PM2.5) was estimated using satellite data. Domestic fuel type and ventilation were used as indicators of indoor air pollution. We used multilevel linear regression models to examine the association between indoor and outdoor air pollution and hand-grip strength, as well as the potential effect modifiers. RESULTS: We found inverse associations between both indoor and outdoor air pollution and hand-grip strength. Each 10 μg/m3 increase in 3 years' averaged concentrations of outdoor PM2.5 corresponded to 0.70 kg (95% CI: -1.26, -0.14) lower hand-grip strength; and compared with electricity/liquid/gas fuel users, those using solid fuels had lower hand-grip strength (β = -1.25, 95% CI: -1.74, -0.75). However, we did not observe a statistically significant association between ventilation and hand-grip strength. We further observed that urban residents and those having a higher education level had a higher association between ambient PM2.5 and hand-grip strength, and men, young participants, smokers, rural participants, and those with lower household income had higher associations between indoor air pollution and hand-grip strength. CONCLUSION: This study suggests that both indoor and outdoor air pollution might be important risk factors of poorer health and functional status as indicated by hand-grip strength.

Maternal blood glucose level is associated with fetal growth, therefore, its role in the associations between air pollution and birth weight deserves investigation. We examined the mediation effect of maternal blood glucose on the associations between maternal air pollution exposure and birth weight. A total of 10,904 pregnant women in Foshan, China during 2015–2019 were recruited. Oral glucose tolerance test (OGTT) was administered to each participant after late trimester 2. Air pollution data at the monitoring stations in residential districts was used to estimate exposures of each participant during trimester 1 and trimester 2. Mixed-effects linear models were used to estimate the associations between air pollution and birth weight. After controlling for ten covariates, the direct effect of PM2.5 and SO2 (each 10 μg/m3 increment) on birth weight was −15.7 g (95% CI: −29.4, −4.8 g) and −83.6 g (95% CI: −134.8, −33.0 g) during trimester 1. The indirect effect of PM2.5 and SO2 (each 10 μg/m3 increment) on birth weight by increasing maternal fasting glucose level was 6.6 g (95% CI: 4.6, 9.1 g) and 22.0 g (95% CI: 4.1, 44.0 g) during trimester 1. Our findings suggest that air pollution might affect the birth weight through direct and indirect pathway, and the indirect effect might be mediated by maternal blood glucose.

Being a globally emerging mite-borne zoonotic disease, scrub typhus is a serious public health concern in Nepal. Mapping environmental suitability and quantifying the human population under risk of the disease is important for prevention and control efforts. In this study, we model and map the environmental suitability of scrub typhus using the ecological niche approach, machine learning modeling techniques, and report locations of scrub typhus along with several climatic, topographic, Normalized Difference Vegetation Index (NDVI), and proximity explanatory variables and estimated population under the risk of disease at a national level. Both MaxEnt and RF technique results reveal robust predictive power with test The area under curve (AUC) and true skill statistics (TSS) of above 0.8 and 0.6, respectively. Spatial prediction reveals that environmentally suitable areas of scrub typhus are widely distributed across the country particularly in the low-land Tarai and less elevated river valleys. We found that areas close to agricultural land with gentle slopes have higher suitability of scrub typhus occurrence. Despite several speculations on the association between scrub typhus and proximity to earthquake epicenters, we did not find a significant role of proximity to earthquake epicenters in the distribution of scrub typhus in Nepal. About 43% of the population living in highly suitable areas for scrub typhus are at higher risk of infection, followed by 29% living in suitable areas of moderate-risk, and about 22% living in moderately suitable areas of lower risk. These findings could be useful in selecting priority areas for surveillance and control strategies effectively.

This study aimed to investigate the association between environmental exposure to tobacco smoke (ETS) during early life and astigmatism in Chinese preschool children. In this cross-sectional study, information concerning prenatal and postnatal ETS exposure at three stages of early life (during pregnancy, from birth to one year and from one to three years), visual problems of children and parents (including a confirmed diagnosis of astigmatism), socio-demographics and perinatal characteristics were obtained from 27,890 parent-reported questionnaires. Logistic regression analyses were undertaken to yield adjusted odds ratios (OR) for assessing their associations. After adjusting for the potential confounders, children were more likely to exhibit astigmatism when they were exposed to ETS during pregnancy + from one to three years [OR (95% CI) = 1.37 (1.02, 1.84)], or from birth to one year + from one to three years [OR (95% CI) = 1.36 (1.11, 1.66)], or during pregnancy + from birth to one year + from one to three years old [OR (95% CI) = 1.29 (1.16, 1.45)], compared to children without ETS exposure at any stage of early life. In Chinese preschool children, prenatal and postnatal astigmatism was associated with ETS exposure, the greater the ETS dose, the greater the astigmatism risk.

Background Ambient fine particulate matter pollution (PM2.5) is one leading cause of disease burden, but no study has quantified the association between daily PM2.5 exposure and life expectancy. We aimed to assess the potential benefits in life expectancy by attaining the daily PM2.5 standards in 72 cities of China during 2013–2016. Methods and findings We applied a two-stage approach for the analysis. At the first stage, we used a generalized additive model (GAM) with a Gaussian link to examine the city-specific short-term association between daily PM2.5 and years of life lost (YLL); at the second stage, a random-effects meta-analysis was used to generate the regional and national estimations. We further estimated the potential gains in life expectancy (PGLE) by assuming that ambient PM2.5 has met the Chinese National Ambient Air Quality Standard (NAAQS, 75 μg/m3) or the ambient air quality guideline (AQG) of the World Health Organization (WHO) (25 μg/m3). We also calculated the attributable fraction (AF), which denoted the proportion of YLL attributable to a higher-than-standards daily mean PM2.5 concentration. During the period from January 18, 2013 to December 31, 2016, we recorded 1,226,849 nonaccidental deaths in the study area. We observed significant associations between daily PM2.5 and YLL: each 10 μg/m3 increase in three-day–averaged (lag02) PM2.5 concentrations corresponded to an increment of 0.43 years of life lost (95% CI: 0.29–0.57). We estimated that 168,065.18 (95% CI: 114,144.91–221,985.45) and 68,684.95 (95% CI: 46,648.79–90,721.11) years of life lost can be avoided by achieving WHO’s AQG and Chinese NAAQS in the study area, which corresponded to 0.14 (95% CI: 0.09–0.18) and 0.06 (95% CI: 0.04–0.07) years of gain in life expectancy for each death in these cities. We observed differential regional estimates across the 7 regions, with the highest gains in the Northwest region (0.28 years of gain [95% CI: 0.06–0.49]) and the lowest in the North region (0.08 [95% CI: 0.02–0.15]). Furthermore, using WHO’s AQG and Chinese NAAQS as the references, we estimated that 1.00% (95% CI: 0.68%–1.32%) and 0.41% (95% CI: 0.28%–0.54%) of YLL could be attributable to the PM2.5 exposure at the national level. Findings from this study were mainly limited by the unavailability of data on individual PM2.5 exposure. Conclusions This study indicates that significantly longer life expectancy could be achieved by a reduction in the ambient PM2.5 concentrations. It also highlights the need to formulate a stricter ambient PM2.5 standard at both national and regional levels of China to protect the population’s health., Jinlei Qi and colleagues reveal the potential gains in life expectancy in China by reducing ambient PM2.5 concentrations., Author summary Why was this study done? Ambient fine particulate matter (PM2.5) pollution is a severe environmental health concern in China. Both short-term and long-term exposure to PM2.5 have been found to be associated with increased mortality and years of life lost. A few studies have estimated the association between annual PM2.5 concentration and life expectancy, but there is no report on the effects of daily PM2.5 exposure on life expectancy. What did the researchers do and find? This nationwide time-series study collected data on more than 1 million nonaccidental deaths in 72 Chinese cities from January 18, 2013 to December 31, 2016. We used a generalized additive model to explore the city-specific association between daily PM2.5 and years of life lost and then conducted random-effects meta-analyses to generate the regional and national estimates. During the study period from January 18, 2013 to December 31, 2016, we estimated that 168,065.18 (about 1.00% of the total) years of life lost can be avoided by achieving WHO’s guideline on daily PM2.5 concentrations (25 μg/m3) in the study area, which corresponded to 0.14 years of gains in life expectancy for each death. What do these findings mean? This is the first study to report the potential gains in life expectancy by attaining the daily standards of PM2.5, which provided important and useful information of the burden caused by ambient PM2.5 pollution. In the future, there should be a policy of stricter ambient PM2.5 standards at both national and regional levels in China, which would benefit the population’s health and life expectancy.

Although myopia has been largely ignored among the elderly population, there is an increased risk of myopia with advancing age. Ambient air pollution is one potential contributor to vision impairments, but few epidemiological studies have demonstrated such an association. This cross-sectional survey collected the information of 33,626 subjects aged ≥50 years in six developing countries during 2007–2010. Myopia was identified based on questions related to symptoms of myopia. The annual concentrations of fine particulate matter (PM2.5) and ozone (O3) were estimated with the satellite data and chemical transport model. We examined the associations between the two pollutants and myopia using mixed-effect Poisson regression models with robust variance estimation (sandwich estimation). We observed J-shaped associations between the two pollutants and myopia, and identified 12 and 54 μg/m3 as the threshold concentrations. The adjusted prevalence ratio was 1.12 (95% CI: 1.05, 1.21) and 1.26 (95% CI: 1.14, 1.38) for each standard deviation (SD) increase in PM2.5 and O3 concentrations above their threshold, respectively. In addition, the interaction analysis suggested a synergistic interaction of these two pollutants on myopia in the additive model, with a synergistic index of 1.81 (Bootstrapping 95% CI: 0.92, 4.94). Our results indicate that long-term exposures to PM2.5 and O3 might be important environmental risk factors of myopia in the elderly, and suggest that more efforts should be taken to reduce airborne PM2.5 and O3 levels to protect vision health.

Numerous evidence revealed that climate change could have adverse effects on human health, while in developing countries, especially in China, less evidence covering different climatic zones is available due to data unavailability. We searched studies which investigated the association between ambient temperature and mortalities in six databases. We performed random-effects model to calculate pooled estimated for mortalities in association with per 1 °C increase (or decrease). We finally included 17 in 819 identified articles. Short-term exposures to inappropriate temperature were significantly associated with mortalities, per 1 °C increase corresponded to a 1.2% (95% CI: 1.1%, 1.3%) increase in all-cause mortality, a 2.6% (95% CI: 2.4%, 2.9%) increase in cardiovascular mortality, and a 1.2% (95% CI: 1.0%, 1.3%) increase in respiratory mortality. And each 1 °C decrease caused a 3.1% (95% CI: 2.7%, 3.5%) in all-cause mortality, a 1.5% (95% CI: 1.2%, 1.9%) increase in cardiovascular mortality, and a 3.3% (95% CI: 2.8%, 3.9%) increase in respiratory mortality. Our findings indicated that the increase and decrease in ambient temperature have relationships with mortalities among Chinese population and cold effect was more durable and pronounced than hot effect.

Previous studies have reported that maternal exposure to particles with aerodynamic diameter2.5 μm (PMWe examined associations in a birth cohort of 1,455,026 mother-and-live-birth pairs who were followed up from the first hospital visit for pregnancy until the birth of the baby during 2014-2017 in nine cites of the Pearl River Delta (PRD) region, China. The PMWe found 1% (HR = 1.01; 95% CI: 1.00, 1.02), 6% (HR = 1.06; 95% CI: 1.05, 1.07), and 7% (HR = 1.07; 95% CI: 1.06, 1.08) increases in risk of PTB and 20% (HR = 1.20; 95% CI: 1.18, 1.22), 18% (HR = 1.18; 95% CI: 1.15, 1.20), and 20% (HR = 1.20; 95% CI: 1.17, 1.23) increases in risk of LBW, with each 10 μg/mThe results indicate that maternal PM

Background The potential impacts of daily ambient fine particulate pollution (PM2.5) exposure on year of life lost (YLL) due to ischemic heart diseases (IHD) remain uncertain. We aimed to estimate the improvement in IHD-related life expectancy by attaining the daily air quality standards of ambient PM2.5 in China. Methods and results This study was based on daily mortality data covering 96 Chinese cities from 2013 to 2016. Regional- and national-associations between IHD-related YLLs and daily PM2.5 were estimated by generalized additive models. We further evaluated the IHD-related avoidable YLLs with an assumption that the daily PM2.5 was below the ambient air quality standards of World Health Organization (WHO) and China, and calculated the improvement of life expectancy by dividing the avoidable YLLs by the overall number of IHD mortality. We totally recorded 1,485,140 IHD deaths from 2013 to 2016. At the national level, we found a positive association between IHD-related YLLs and daily PM2.5. Per 10 μg/m3 increment of four-day averaged ambient PM2.5 related to an increase of 0.40 IHD-related YLLs (95% CI: 0.28, 0.51). By achieving the WHO's air quality guideline, we estimated that an averaged number of 1346.94 (95% CI: 932.61, 1761.27) YLLs can be avoided for the IHD deaths in each city. On average, the life expectancy can be improved by 0.15 years (95% CI: 0.11, 0.19) for each death. Conclusions Our study provides a nationwide picture of the life expectancy improvements by reaching the daily PM2.5 standards in China, indicating that people can live longer in an environment with higher air quality.

Background Though the conjunctiva are directly contacting with the atmospheric environment, the association between air pollution and conjunctival disease has not been well documented. Objective To explore the association between ambient nitrogen dioxide (NO2) and daily outpatient visits for cause-specific conjunctivitis in Jinan, China. Methods Daily concentrations of air pollution were obtained from the air quality sharing platform of China, and daily outpatient visits for conjunctivitis were collected from Qilu Hospital. The association between daily NO2 level and outpatient visits for conjunctivitis was examined by a generalized additive Poisson model, and stratified analyses by sex, age and season were further performed. Results A total of 42,123 outpatient visits for conjunctivitis were recorded during 2014–2019, including 8504 infective conjunctivitis, 6429 allergic conjunctivitis and 27,190 unspecified conjunctivitis. Each 10 μg/m3 increase in NO2 was associated with a 1.00% (95% CI: 0.13%, 1.87%) increment in daily outpatient visits for conjunctivitis. Significant associations between NO2 and conjunctivitis were observed in the female population [excess risk, ER = 1.09% (95% CI: 0.05%, 2.15%)], in people aged 18–65 years [ER = 1.15% (95% CI: 0.15%, 2.15%)] and in cold season [ER = 1.67% (95% CI: 0.58%, 2.77%)]. Moreover, we also found significant associations of NO2 with infective conjunctivitis [ER = 2.60% (95% CI: 0.69%, 4.54%)], but not with allergic conjunctivitis [ER = −0.43% (95% CI: −2.38%, 1.56%)]and unspecified conjunctivitis [ER = 0.16% (95% CI: −0.96%, 1.29%)]. Conclusion This study suggests that short-term exposure to NO2 might induce conjunctivitis, and air pollution control measures should be encouraged to keep ocular surface healthy.

Background To investigate the effects of air pollution exposure during pregnancy on the indicators of glucose homeostasis and gestational diabetes mellitus (GDM). Methods We conducted a birth cohort study in Foshan, China during 2015–2019. Oral glucose tolerance test (OGTT) was administered to each participant during pregnancy. GDM was defined according to the International Association of Diabetes and Pregnancy Study Groups criteria (IADPSG). Air pollutant (fine particulate matter (PM2.5), particulate matter with an aerodynamic diameter of 10 μm or less (PM10), sulfate dioxide (SO2), nitrogen dioxide (NO2) and ozone (O3)) concentrations from the air monitoring stations in Foshan were used to estimate individual air pollutant exposure during the first two trimesters. Linear and logistic regression models were employed to estimate the associations between air pollution exposure during the first two trimesters and OGTT glucose levels and GDM. Results Of 12,842 pregnant women, 3055 (23.8%) had GDM. A 10 μg/m3 increase in PM2.5, PM10 and SO2 during trimester 1, trimester 2 and two trimesters were associated with 0.07 mmol/L to 0.29 mmol/L increment in OGTT-fasting glucose levels in single-pollutant model. A 10 μg/m3 increase in NO2 and O3 during two trimesters were associated with 0.15 mmol/L and 0.12 mmol/L decrease in OGTT-fasting glucose in single-pollutant model. However, no significant or weaker effects of O3 during two trimesters on OGTT-fasting glucose were observed in two-pollutant models. Moreover, exposure to PM2.5, PM10 and SO2 were associated with increased risk of GDM in both single- and two-pollutant models. Conclusions Our study suggests PM2.5, PM10 and SO2 exposure during the first two trimesters might increase the risk of GDM.

This time-series study collects data on stroke-related mortality, years of life lost (YLL), air pollution, and meteorological conditions in 96 Chinese cities from 2013 to 2016 and proposes a three-stage strategy to generate the national and regional estimations of avoidable YLL, gains in life expectancy and stroke-related population attributable fraction by postulating that the daily fine particulate matter (PM2.5) has been kept under certain standards. A total of 1 318 911 stroke deaths are analyzed. Each 10 µg m-3 increment in PM2.5 at lag03 is associated with a city-mean increase of 0.31 (95% CI: 0.19, 0.44) years of life lost from stroke. A number of 914.11 (95% CI: 538.28, 1288.94) years of city-mean life lost from stoke could be avoided by attaining the WHO's Air Quality Guidelines (AQG) (25 µg m-3). Moreover, by applying the AQG standard, 0.11 (0.08, 0.15) years of life lost might be prevented for each death, and about 0.91% (95% CI: 0.62%, 1.19%) of the total years of life lost from stroke might be explained by the daily excess PM2.5 exposure. This study indicates that stroke patients can have a longer life expectancy if stricter PM2.5 standards are put in place, especially ischemic stroke patients.

Background Previous research has reported the effects of long-term fine particulate matter (PM2.5) pollution on years of life lost (YLL), but these effects may not represent the full impact. This study aims to estimate potential benefits in life time from adhering to daily ambient PM2.5 concentration standards/guidelines. Methods This study evaluated the relationship between daily ambient PM2.5 level and YLL using a two-stage approach with generalized additive models and meta-analysis. Potential life expectancy gains were then estimated by presuming that daily PM2.5 levels were in compliance with the Chinese and WHO standards. In addition, the attributable fraction of YLL due to excess PM2.5 exposure was also calculated. Results During 2013–2016, 459,468 non-accidental deaths were recorded in the six cities of Pearl River Delta, China. Each 10 μg/m3 increment in four-day average (lag03) level of PM2.5 was related to an increment of 13.31 [95% confidence interval (CI): 5.74, 20.87] years of life lost. Implementation of the WHO guidelines might avoid 180,980.83 YLLs (95% CI: 78,116.07, 283,845.60), which corresponded to 0.39 (95% CI: 0.17, 0.62) years of increased life time per death. Additionally, an estimated 0.15% (95% CI: 0.06%, 0.23%) or 2.04% (95% CI: 0.88%, 3.20%) of YLLs could be attributed to PM2.5 exposures higher than the Chinese or WHO guidelines, respectively. Conclusions This study suggests that people might live longer by controlling daily PM2.5 concentration and highlights the need to adopt stricter standards in China.

Objectives Prenatal exposure to air pollutant has been associated with congenital heart defect (CHD). However, no study has investigated this effect in pre-pregnancy overweighted women. This study aimed to evaluate gestational exposure to particulate pollutant (PM2.5) and gaseous air pollutants (O3 and NO2) on the risk of CHD, and explore the potential effect modifiers including maternal age, pre-pregnancy BMI and pregestational diseases. Methods In this birth cohort study, a total of 63,213 pregnant women in Foshan, China were initially recruited and followed from their first hospital visit for pregnancy to delivery during 2015–2019. CHD cases were confirmed by the records in hospital- and population- based birth defect surveillance systems. Air pollutant exposures were estimated by the daily concentrations measured in air monitoring stations in each participant's residential county. Mixed-effects regression models, adjusted for potential confounding factors were applied to estimate the associations between air pollutant and CHD during the first three months of the pregnancy. Results A total of 985 (1.6%) newborns were identified as CHD cases. For each 10 μg/m3 increase in ambient O3 during the 1st month, the OR values for CHD were 1.03 (95% CI: 0.94, 1.13) in pre-pregnancy normal weighted women and 1.24 (95% CI: 1.01, 1.53) in pre-pregnancy overweighted women. For each 10 μg/m3 increase in NO2 during the 3rd month, the OR values for CHD were 1.09 (95% CI: 1.01, 1.18) in pre-pregnancy normal weighted women and 1.27 (95% CI: 1.07, 1.51) in pre-pregnancy overweighted women. No significant associations were found between PM2.5 exposure and CHD in our analysis. Conclusions This study demonstrates that gaseous air pollutants (O3 and NO2) exposure during the cardiac embryogenesis period is associated with an increased risk of CHD, particularly for pre-pregnancy overweighted women.

Background Maternal exposure to various air pollutants is one crucial contributor to adverse birth outcomes, however, the effects of ozone (O3) exposure have remained largely unknown, especially attributable burden in different exposure windows. Methods We performed a birth cohort study in nine Chinese cities in Guangdong Province during 2014–2017. The mothers were included in this study at their first time hospital visits for pregnancy in the nine cities, and followed up till the delivery. Air pollution exposure of each participant was estimated using the daily data from air monitoring stations in the mother's residential district. The status of low birth weight (LBW) and preterm birth (PTB) was ascertained based on standard criteria and collected from the electronic medical record. We applied a Cox regression model to estimate the associations and the attributable burden. Results Among the 1,455,026 mother-and-live-birth pairs, 64,028 (4.40%) were PTB, and 57,618 (3.96%) were LBW. After adjustment for potential confounders, the hazard ratios for each 10 μg/m3 increase in O3 concentrations during trimester 1, trimester 2, one week prior and four weeks prior were 1.025 (95% CI: 1.020, 1.030), 1.033 (95% CI: 1.028, 1.039), 1.013 (95% CI: 1.010, 1.017) and 1.016 (95% CI: 1.011, 1.020) for PTB, 1.035 (95% CI: 1.030, 1.040), 1.035 (95% CI: 1.029, 1.041), 1.013 (95% CI: 1.009, 1.017) and 1.016 (95% CI: 1.012, 1.021) for LBW, respectively. The estimated attributable fractions at one week prior to delivery were 0.86% (95% CI: 0.39%, 9.26%) of PTB and 0.87% (95% CI: 0.60%, 1.14%) of LBW. Conclusions This study indicates that maternal exposure to O3 might lead to increased risk of PTB and LBW, and is responsible for non-negligible burden of PTB and LBW in the study region.