PAR4 Antagonism in Patients With Coronary Artery Disease Receiving Antiplatelet Therapies.

BACKGROUND: BMS-986141 is a novel potent highly selective antagonist of PAR (protease-activated receptor) type 4. PAR4 antagonism has been demonstrated to reduce thrombus formation in isolation and in combination with factor Xa inhibition in high shear conditions in healthy people. We sought to determine whether PAR4 antagonism had additive antithrombotic effects in patients with coronary artery disease who were receiving antiplatelet therapy. METHODS: Forty-five patients with stable coronary heart disease and 10 healthy volunteers completed a phase 2a open-label 4-arm single-center study. Patients were allocated to 1 of 3 treatment arms for 7 days: (1) ticagrelor (90 mg BID), (2) aspirin (75 mg QD), or (3) the combination of ticagrelor and aspirin. Agonist-induced platelet aggregation, platelet activation, and ex vivo thrombus formation were measured before and 2 and 24 hours after a single oral 4-mg dose of BMS-986141 on the first study visit day in all participants. RESULTS: BMS-986141 demonstrated highly selective inhibition of PAR4-AP (agonist peptide)-induced platelet aggregation, P-selectin expression, and platelet-monocyte aggregate expression (P≤0.001 for all), which were unaffected by concomitant antiplatelet therapies. PAR4 antagonism reduced ex vivo thrombus area in high shear conditions in healthy volunteers (-21%; P=0.001) and in patients receiving ticagrelor alone (-28%; P=0.001), aspirin alone (-23%; P=0.018), or both in combination (-24%; P≤0.001). Plasma concentration of BMS-986141 correlated with PAR4-AP-induced platelet responses (P≤0.001 for all) and total thrombus area under high shear stress conditions (P≤0.01 for all). CONCLUSIONS: PAR4 antagonism has additive antithrombotic effects when used in addition to ticagrelor, aspirin, or their combination, in patients with stable coronary heart disease. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05093790.

First-in-human controlled inhalation of thin graphene oxide nanosheets to study acute cardiorespiratory responses.

Graphene oxide nanomaterials are being developed for wide-ranging applications but are associated with potential safety concerns for human health. We conducted a double-blind randomized controlled study to determine how the inhalation of graphene oxide nanosheets affects acute pulmonary and cardiovascular function. Small and ultrasmall graphene oxide nanosheets at a concentration of 200 µg m-3 or filtered air were inhaled for 2 h by 14 young healthy volunteers in repeated visits. Overall, graphene oxide nanosheet exposure was well tolerated with no adverse effects. Heart rate, blood pressure, lung function and inflammatory markers were unaffected irrespective of graphene oxide particle size. Highly enriched blood proteomics analysis revealed very few differential plasma proteins and thrombus formation was mildly increased in an ex vivo model of arterial injury. Overall, acute inhalation of highly purified and thin nanometre-sized graphene oxide nanosheets was not associated with overt detrimental effects in healthy humans. These findings demonstrate the feasibility of carefully controlled human exposures at a clinical setting for risk assessment of graphene oxide, and lay the foundations for investigating the effects of other two-dimensional nanomaterials in humans. Clinicaltrials.gov ref: NCT03659864.

Cardiovascular disease in low- and middle-income countries associated with environmental factors.

There is a growing recognition that the profound environmental changes that have occurred over the past century pose threats to human health. Many of these environmental factors, including air pollution, noise pollution, as well as exposure to metals such as arsenic, cadmium, lead, and other metals, are particularly detrimental to the cardiovascular health of people living in low-to-middle income countries (LMICs). Low-to-middle income countries are likely to be disproportionally burdened by cardiovascular diseases provoked by environmental factors. Moreover, they have the least capacity to address the core drivers and consequences of this phenomenon. This review summarizes the impact of environmental factors such as climate change, air pollution, and metal exposure on the cardiovascular system, and how these specifically affect people living in LMICs. It also outlines how behaviour changes and interventions that reduce environmental pollution would have significant effects on the cardiovascular health of those from LMICs, and globally.

New insights into the association of air pollution and kidney diseases by tracing gold nanoparticles with inductively coupled plasma mass spectrometry.

Exposure to particles from air pollution has been associated with kidney disease; however, the underlying biological mechanisms are incompletely understood. Inhaled particles can gain access to the circulation and, depending on their size, pass into urine, raising the possibility that particles may also sequester in the kidney and directly alter renal function. This study optimised an inductively coupled plasma mass spectrometry (ICP-MS) method to investigate the size dependency of particle accumulation in the kidneys of mice following pulmonary instillation (0.8 mg in total over 4 weeks) to gold nanoparticles (2, 3-4, 7-8, 14 or 40 nm or saline control). Due to the smallest particle sizes being below the limit of detection in single particle mode, ICP-MS was operated in total quantification mode. Gold was detected in all matrices of interest (blood, urine and kidney) from animals treated with all sizes of gold nanoparticles, at orders of magnitude higher than the methodological limit of detection in biological matrices (0.013 ng/mL). A size-dependent effect was observed, with smaller particles leading to greater levels of accumulation in tissues. This study highlights the value of a robust and reliable method by ICP-MS to detect extremely low levels of gold in biological samples for indirect particle tracing. The finding that nano-sized particles translocate from the lung to the kidney may provide a biological explanation for the associations between air pollution and kidney disease.

Ambient air pollution and maternal cardiovascular health in pregnancy.

In this review, we summarise the current epidemiological and experimental evidence on the association of ambient (outdoor) air pollution exposure and maternal cardiovascular health during pregnancy. This topic is of utmost clinical and public health importance as pregnant women represent a potentially susceptible group due to the delicate balance of the feto-placental circulation, rapid fetal development and tremendous physiological adaptations to the maternal cardiorespiratory system during pregnancy.Several meta-analyses including up to 4 245 170 participants provide robust evidence that air pollutants, including particulate matter, nitrogen oxides and others, have adverse effects on the development of hypertensive disorders of pregnancy, gestational diabetes mellitus and cardiovascular events during labour. Potential underlying biological mechanisms include oxidative stress with subsequent endothelial dysfunction and vascular inflammation, ß-cell dysfunction and epigenetic changes. Endothelial dysfunction can lead to hypertension by impairing vasodilatation and promoting vasoconstriction. Air pollution and the consequent oxidative stress can additionally accelerate ß-cell dysfunction, which in turn triggers insulin resistance leading to gestational diabetes mellitus. Epigenetic changes in placental and mitochondrial DNA following air pollution exposures can lead to altered gene expression and contribute to placental dysfunction and induction of hypertensive disorders of pregnancy.The maternal and fetal consequences of such cardiovascular and cardiometabolic disease during pregnancy can be serious and long lasting, including preterm birth, increased risk of type 2 diabetes mellitus or cardiovascular disease later in life. Acceleration of efforts to reduce air pollution is therefore urgently needed to realise the full health benefits for pregnant mothers and their children.

Joint effect of multiple air pollutants on cardiometabolic health in normal-weight and obese adults: A novel insight into the role of circulating free fatty acids.

The cardiometabolic effects of air pollution in the context of mixtures and the underlying mechanisms remain not fully understood. This study aims to investigate the joint effect of air pollutant mixtures on a broad range of cardiometabolic parameters, examine the susceptibility of obese individuals, and determine the role of circulating fatty acids. In this panel study, metabolically healthy normal-weight (MH-NW, n = 49) and obese (MHO, n = 39) adults completed three longitudinal visits (257 person-visits in total). Personal exposure levels of PM2.5, PM10, O3, NO2, SO2, CO and BC were estimated based on fixed-site monitoring data, time-activity logs and infiltration factor method. Blood pressure, glycemic homeostasis, lipid profiles, systematic inflammation and coagulation biomarkers were measured. Targeted metabolomics was used to quantify twenty-eight plasma free fatty acids (FFAs). Bayesian kernel machine regression models were applied to establish the exposure-response relationships and identify key pollutants. Significant joint effects of measured air pollutants on systematic inflammation and coagulation biomarkers were observed in the MHO group, instead of the MH-NW group. Lipid profiles showed the most significant changes in both groups and O3 contributed the most to the total effect. Specific FFA patterns were identified, and de novo lipogenesis (DNL)-related pattern was most closely related to blood lipid profiles. In particular, interaction analysis suggested that DNL-related FFA pattern augmented the effects of O3 on triglyceride (TG, Pinteraction = 0.040), high-density lipoprotein cholesterol (HDL-C, Pinteraction = 0.106) and TG/HDL-C (Pinteraction = 0.020) in the MHO group but not MH-NW group. This modification was further confirmed by interaction analysis with estimated activity of SCD1, a key enzyme in the DNL pathway. Therefore, despite being metabolically healthy, obese subjects have a higher cardiometabolic susceptibility to air pollution, especially O3, and the DNL pathway may represent an intrinsic driver of lipid susceptibility. This study provides new insights into the cardiometabolic susceptibility of obese individuals to air pollution.

Cardiopulmonary benefits of respirator intervention against near road ambient particulate matters in healthy young adults: A randomized, blinded, crossover, multi-city study.

Wearing a respirator is generally the most convenient individual intervention against ambient particulate matter (PM), and therefore there has been considerable research into its effectiveness. However, the effects of respirator intervention under different PM concentration settings have been insufficiently elucidated. We conducted a randomized, blinded, crossover intervention study in four representative cities in China in which 128 healthy university students spent 2-h walking along a busy road wearing either a real or a sham respirator and then spent the next 5-h indoors away from traffic pollution. Lung function, blood pressure, and heart rate variability were continuously measured throughout the visit. Linear mixed-effect models were fitted to evaluate the protective effects of respirator intervention on the cardiopulmonary indicators. Results showed that the beneficial effects of respirator intervention were only occasionally significant at specific time points or in specific cities or in selected parameters. Overall, respirator intervention was associated with reduced SBP (6.2 vs. 11.5 mmHg compared to baseline, p < 0.05) and increased LF (44 vs. 35 ms2 compared to baseline, p < 0.05) over the 2-h walk, but no significant effects were found over the 7-h period. Respirators have significant effect modifications on the associations between PM2.5/PM10 and the cardiopulmonary indicators, but the directions of effects were inconsistent. The intercity difference in the effects of respirator intervention was found significant, with Taiyuan and Shanghai to be the two cities with lower personal PM concentrations but more pronounced benefits. In conclusion, reducing personal exposure to PM can have some beneficial effects in some scenarios. However, respirators may not provide sufficient protection from air pollution overall, and we should avoid over-reliance on respirators and accelerate efforts to reduce emissions of pollutants in the first place. Despite standardized procedures, we found inconsistency in results across cities, consistent with the previous literature.

A Review of Road Traffic-Derived Non-Exhaust Particles: Emissions, Physicochemical Characteristics, Health Risks, and Mitigation Measures.

Implementation of regulatory standards has reduced exhaust emissions of particulate matter from road traffic substantially in the developed world. However, nonexhaust particle emissions arising from the wear of brakes, tires, and the road surface, together with the resuspension of road dust, are unregulated and exceed exhaust emissions in many jurisdictions. While knowledge of the sources of nonexhaust particles is fairly good, source-specific measurements of airborne concentrations are few, and studies of the toxicology and epidemiology do not give a clear picture of the health risk posed. This paper reviews the current state of knowledge, with a strong focus on health-related research, highlighting areas where further research is an essential prerequisite for developing focused policy responses to nonexhaust particles.

Nitrate and nitrite contamination in drinking water and cancer risk: A systematic review with meta-analysis.

BACKGROUND: Pollution of water sources, largely from wide-scale agricultural fertilizer use has resulted in nitrate and nitrite contamination of drinking water. The effects on human health of raised nitrate and nitrite levels in drinking water are currently unclear. OBJECTIVES: We conducted a systematic review of peer-reviewed literature on the association of nitrate and nitrite in drinking water with human health with a specific focus on cancer. METHODS: We searched eight databases from 1 January 1990 until 28 February 2021. Meta-analyses were conducted when studies had the same exposure metric and outcome. RESULTS: Of 9835 studies identified in the literature search, we found 111 studies reporting health outcomes, 60 of which reported cancer outcomes (38 case-control studies; 12 cohort studies; 10 other study designs). Most studies were set in the USA (24), Europe (20) and Taiwan (14), with only 3 studies from low and middle-income countries. Nitrate exposure in water (59 studies) was more commonly investigated than nitrite exposure (4 studies). Colorectal (15 studies) and gastric (13 studies) cancers were the most reported. In meta-analyses (4 studies) we identified a positive association of nitrate exposure with gastric cancer, OR = 1.91 (95%CI = 1.09-3.33) per 10 mg/L increment in nitrate ion. We found no association of nitrate exposure with colorectal cancer (10 studies; OR = 1.02 [95%CI = 0.96-1.08]) or cancers at any other site. CONCLUSIONS: We identified an association of nitrate in drinking water with gastric cancer but with no other cancer site. There is currently a paucity of robust studies from settings with high levels nitrate pollution in drinking water. Research into this area will be valuable to ascertain the true health burden of nitrate contamination of water and the need for public policies to protect human health.

Exposure to Elevated Nitrogen Dioxide Concentrations and Cardiac Remodeling in Patients With Dilated Cardiomyopathy.

BACKGROUND: Empirical evidence suggests a strong link between exposure to air pollution and heart failure incidence, hospitalizations, and mortality, but the biological basis of this remains unclear. We sought to determine the relationship between differential air pollution levels and changes in cardiac structure and function in patients with dilated cardiomyopathy. METHODS AND RESULTS: We undertook a prospective longitudinal observational cohort study of patients in England with dilated cardiomyopathy (enrollment 2009-2015, n = 716, 66% male, 85% Caucasian) and conducted cross sectional analysis at the time of study enrollment. Annual average air pollution exposure estimates for nitrogen dioxide (NO2) and particulate matter with diameter of 2.5 µm or less (PM2.5) at enrolment were assigned to each residential postcode (on average 12 households). The relationship between air pollution and cardiac morphology was assessed using linear regression modelling. Greater ambient exposure to NO2 was associated with higher indexed left ventricular (LV) mass (4.3 g/m2 increase per interquartile range increase in NO2, 95% confidence interval 1.9-7.0 g/m2) and lower LV ejection fraction (-1.5% decrease per interquartile range increase in NO2, 95% confidence interval -2.7% to -0.2%), independent of age, sex, socioeconomic status, and clinical covariates. The associations were robust to adjustment for smoking status and geographical clustering by postcode area. The effect of air pollution on LV mass was greatest in women. These effects were specific to NO2 exposure. CONCLUSIONS: Exposure to air pollution is associated with raised LV mass and lower LV ejection fraction, with the strongest effect in women. Although epidemiological associations between air pollution and heart failure have been established and supported by preclinical studies, our findings provide novel empirical evidence of cardiac remodeling and exposure to air pollution with important clinical and public health implications.

Air pollution and cardiovascular disease: the Paul Wood Lecture, British Cardiovascular Society 2021.

Air pollution is associated with up to 8.8 million excess deaths worldwide each year and is a major contributor to the global burden of disease. Cardiovascular conditions are the predominant cause for air pollution-related deaths and there is an urgent need to address the silent pandemic of air pollution on cardiovascular health. Air pollution exposure is associated with acute events like acute coronary syndrome and stroke, and with chronic conditions, such as atherosclerosis and heart failure. Several potential mechanisms have been proposed that link particle inhalation to cardiovascular disease including oxidative stress and inflammation, changes in autonomic balance and neuroendocrine regulation and the particle translocation into the circulation itself. This, in turn, can cause endothelial, vasomotor and fibrinolytic dysfunction and increased thrombogenicity and blood pressure which are implicated in the mediation of adverse cardiovascular events. Certain interventions can help mitigate these adverse effects. At an individual level, this includes the use of a facemask and indoor air purification systems. At an environmental level, interventions reducing the generation or release of combustion-derived pollutants are key and include public health policies to facilitate active transport, cleaner sources of energy and reductions in vehicular and fossil fuel emissions. In this review, we summarise the key pathways and mechanisms that draw together how air pollution can lead to adverse cardiovascular effects, as well as explore potential interventions to reduce the burden of air pollution-induced cardiovascular morbidity and mortality.

The cardiovascular effects of air pollution: Prevention and reversal by pharmacological agents.

Air pollution is associated with staggering levels of cardiovascular morbidity and mortality. Airborne particulate matter (PM), in particular, has been associated with a wide range of detrimental cardiovascular effects, including impaired vascular function, raised blood pressure, alterations in cardiac rhythm, blood clotting disorders, coronary artery disease, and stroke. Considerable headway has been made in elucidating the biological processes underlying these associations, revealing a labyrinth of multiple interacting mechanistic pathways. Several studies have used pharmacological agents to prevent or reverse the cardiovascular effects of PM; an approach that not only has the advantages of elucidating mechanisms, but also potentially revealing therapeutic agents that could benefit individuals that are especially susceptible to the effects of air pollution. This review gathers investigations with pharmacological agents, offering insight into the biology of how PM, and other air pollutants, may cause cardiovascular morbidity.

Atmospheric conditions and composition that influence PM2.5 oxidative potential in Beijing, China.

Epidemiological studies have consistently linked exposure to PM2.5 with adverse health effects. The oxidative potential (OP) of aerosol particles has been widely suggested as a measure of their potential toxicity. Several acellular chemical assays are now readily employed to measure OP; however, uncertainty remains regarding the atmospheric conditions and specific chemical components of PM2.5 that drive OP. A limited number of studies have simultaneously utilised multiple OP assays with a wide range of concurrent measurements and investigated the seasonality of PM2.5 OP. In this work, filter samples were collected in winter 2016 and summer 2017 during the atmospheric pollution and human health in a Chinese megacity campaign (APHH-Beijing), and PM2.5 OP was analysed using four acellular methods: ascorbic acid (AA), dithiothreitol (DTT), 2,7-dichlorofluorescin/hydrogen peroxidase (DCFH) and electron paramagnetic resonance spectroscopy (EPR). Each assay reflects different oxidising properties of PM2.5, including particle-bound reactive oxygen species (DCFH), superoxide radical production (EPR) and catalytic redox chemistry (DTT/AA), and a combination of these four assays provided a detailed overall picture of the oxidising properties of PM2.5 at a central site in Beijing. Positive correlations of OP (normalised per volume of air) of all four assays with overall PM2.5 mass were observed, with stronger correlations in winter compared to summer. In contrast, when OP assay values were normalised for particle mass, days with higher PM2.5 mass concentrations (µgm-3) were found to have lower mass-normalised OP values as measured by AA and DTT. This finding supports that total PM2.5 mass concentrations alone may not always be the best indicator for particle toxicity. Univariate analysis of OP values and an extensive range of additional measurements, 107 in total, including PM2.5 composition, gas-phase composition and meteorological data, provided detailed insight into the chemical components and atmospheric processes that determine PM2.5 OP variability. Multivariate statistical analyses highlighted associations of OP assay responses with varying chemical components in PM2.5 for both mass- and volume-normalised data. AA and DTT assays were well predicted by a small set of measurements in multiple linear regression (MLR) models and indicated fossil fuel combustion, vehicle emissions and biogenic secondary organic aerosol (SOA) as influential particle sources in the assay response. Mass MLR models of OP associated with compositional source profiles predicted OP almost as well as volume MLR models, illustrating the influence of mass composition on both particle-level OP and total volume OP. Univariate and multivariate analysis showed that different assays cover different chemical spaces, and through comparison of mass- and volume-normalised data we demonstrate that mass-normalised OP provides a more nuanced picture of compositional drivers and sources of OP compared to volume-normalised analysis. This study constitutes one of the most extensive and comprehensive composition datasets currently available and provides a unique opportunity to explore chemical variations in PM2.5 and how they affect both PM2.5 OP and the concentrations of particle-bound reactive oxygen species.

Acute cardiovascular effects of controlled exposure to dilute Petrodiesel and biodiesel exhaust in healthy volunteers: a crossover study.

BACKGROUND: Air pollution derived from combustion is associated with considerable cardiorespiratory morbidity and mortality in addition to environmental effects. Replacing petrodiesel with biodiesel may have ecological benefits, but impacts on human health remain unquantified. The objective was to compare acute cardiovascular effects of blended and pure biodiesel exhaust exposure against known adverse effects of petrodiesel exhaust (PDE) exposure in human subjects. In two randomized controlled double-blind crossover studies, healthy volunteers were exposed to PDE or biodiesel exhaust for one hour. In study one, 16 subjects were exposed, on separate occasions, to PDE and 30% rapeseed methyl ester biodiesel blend (RME30) exhaust, aiming at PM10 300 µg/m3. In study two, 19 male subjects were separately exposed to PDE and exhaust from a 100% RME fuel (RME100) using similar engine load and exhaust dilution. Generated exhaust was analyzed for physicochemical composition and oxidative potential. Following exposure, vascular endothelial function was assessed using forearm venous occlusion plethysmography and ex vivo thrombus formation was assessed using a Badimon chamber model of acute arterial injury. Biomarkers of inflammation, platelet activation and fibrinolysis were measured in the blood. RESULTS: In study 1, PDE and RME30 exposures were at comparable PM levels (314 ± 27 µg/m3; (PM10 ± SD) and 309 ± 30 µg/m3 respectively), whereas in study 2, the PDE exposure concentrations remained similar (310 ± 34 µg/m3), but RME100 levels were lower in PM (165 ± 16 µg/m3) and PAHs, but higher in particle number concentration. Compared to PDE, PM from RME had less oxidative potential. Forearm infusion of the vasodilators acetylcholine, bradykinin, sodium nitroprusside and verapamil resulted in dose-dependent increases in blood flow after all exposures. Vasodilatation and ex vivo thrombus formation were similar following exposure to exhaust from petrodiesel and the two biodiesel formulations (RME30 and RME100). There were no significant differences in blood biomarkers or exhaled nitric oxide levels between exposures. CONCLUSIONS: Despite differences in PM composition and particle reactivity, controlled exposure to biodiesel exhaust was associated with similar cardiovascular effects to PDE. We suggest that the potential adverse health effects of biodiesel fuel emissions should be taken into account when evaluating future fuel policies. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01337882 /NCT01883466. Date of first enrollment March 11, 2011, registered April 19, 2011, i.e. retrospectively registered.

Exposure to fine particulate matter promotes platelet activation and thrombosis via obesity-related inflammation.

Short-term exposure to fine particulate matter (PM2.5) increases thrombotic risk particularly in obese individuals, but the underlying mechanisms remain unclear. This study aims to compare the effects of PM2.5 on inflammation and platelet activation in obese versus normal-weight adults, and investigate potential causal pathways. We conducted a panel study measuring blood markers in 44 obese and 53 normal-weight adults on 3 separate occasions in 2017-2018. Associations between PM2.5/black carbon (BC) and biomarkers were estimated using mixed-effect models. An interaction analysis compared PM2.5/BC-related effects between subgroups. Biomarker combinations and mediation analysis were performed to elucidate the biological pathways. There was a significant "low-high-low" trend of PM2.5 levels across the 3 study periods. Increases in pro-inflammatory cytokines and changes of platelet activation and aggregation markers were associated with PM2.5/BC in obese subgroup only. Among obese subjects, the combination of pro-inflammatory cytokines and that of platelet markers increased 26.8% (95% CI: 16.0%, 37.9%) and 14.7% (95% CI: 1.9%, 27.0%) per IQR increase in PM2.5 over 5-day and 7-day averages. Inflammation mediated 24.5% of the pathways through which PM2.5 promoted platelet activation. This study suggested obese people are susceptible to pro-thrombotic impacts of PM2.5 exposures. PM2.5 may aggravate thrombosis through obesity-related inflammation.

Adverse health effects associated with household air pollution: a systematic review, meta-analysis, and burden estimation study.

BACKGROUND: 3 billion people worldwide rely on polluting fuels and technologies for domestic cooking and heating. We estimate the global, regional, and national health burden associated with exposure to household air pollution. METHODS: For the systematic review and meta-analysis, we systematically searched four databases for studies published from database inception to April 2, 2020, that evaluated the risk of adverse cardiorespiratory, paediatric, and maternal outcomes from exposure to household air pollution, compared with no exposure. We used a random-effects model to calculate disease-specific relative risk (RR) meta-estimates. Household air pollution exposure was defined as use of polluting fuels (coal, wood, charcoal, agricultural wastes, animal dung, or kerosene) for household cooking or heating. Temporal trends in mortality and disease burden associated with household air pollution, as measured by disability-adjusted life-years (DALYs), were estimated from 2000 to 2017 using exposure prevalence data from 183 of 193 UN member states. 95% CIs were estimated by propagating uncertainty from the RR meta-estimates, prevalence of household air pollution exposure, and disease-specific mortality and burden estimates using a simulation-based approach. This study is registered with PROSPERO, CRD42019125060. FINDINGS: 476 studies (15·5 million participants) from 123 nations (99 [80%] of which were classified as low-income and middle-income) met the inclusion criteria. Household air pollution was positively associated with asthma (RR 1·23, 95% CI 1·11-1·36), acute respiratory infection in both adults (1·53, 1·22-1·93) and children (1·39, 1·29-1·49), chronic obstructive pulmonary disease (1·70, 1·47-1·97), lung cancer (1·69, 1·44-1·98), and tuberculosis (1·26, 1·08-1·48); cerebrovascular disease (1·09, 1·04-1·14) and ischaemic heart disease (1·10, 1·09-1·11); and low birthweight (1·36, 1·19-1·55) and stillbirth (1·22, 1·06-1·41); as well as with under-5 (1·25, 1·18-1·33), respiratory (1·19, 1·18-1·20), and cardiovascular (1·07, 1·04-1·11) mortality. Household air pollution was associated with 1·8 million (95% CI 1·1-2·7) deaths and 60·9 million (34·6-93·3) DALYs in 2017, with the burden overwhelmingly experienced in low-income and middle-income countries (LMICs; 60·8 million [34·6-92·9] DALYs) compared with high-income countries (0·09 million [0·01-0·40] DALYs). From 2000, mortality associated with household air pollution had reduced by 36% (95% CI 29-43) and disease burden by 30% (25-36), with the greatest reductions observed in higher-income nations. INTERPRETATION: The burden of cardiorespiratory, paediatric, and maternal diseases associated with household air pollution has declined worldwide but remains high in the world's poorest regions. Urgent integrated health and energy strategies are needed to reduce the adverse health impact of household air pollution, especially in LMICs. FUNDING: British Heart Foundation, Wellcome Trust.

The relationship between personal exposure and ambient PM2.5 and black carbon in Beijing.

This study is part of the "Air Polluion Impacts on Cardiopulmonary disease in Beijing: an integrated study of Exposure Science, Toxicologenomics & Environmental Epidemiology (APIC-ESTEE)" project under the UK-China joint research programme "Atmospheric Pollution and Human Health in a Chinese Megacity (APHH-China)". The aim is to capture the spatio-temporal variability in people's exposure to fine particles (PM2.5) and black carbon (BC) air pollution in Beijing, China. A total of 120 students were recruited for a panel study from ten universities in Haidian District in northwestern Beijing from December 2017 to June 2018. Real-time personal concentrations of PM2.5 and BC were measured over a 24-h period with two research-grade portable personal exposure monitors. Personal microenvironments (MEs) were determined by applying an algorithm to the handheld GPS unit data. On average, the participants spent the most time indoors (79% in Residence and 16% in Workplace), and much less time travelling by Walking, Cycling, Bus and Metro. Similar patterns were observed across participant gender and body-mass index classifications. The participants were exposed to 33.8 ± 27.8 µg m-3 PM2.5 and to 1.9 ± 1.2 µg m-3 BC over the 24-h monitoring period, on average 24.3 µg m-3 (42%) and 0.8 µg m-3 (28%) lower, respectively, than the concurrent fixed-site ambient measurements. Relative differences between personal and ambient BC concentrations showed greater variability across the MEs, highlighting significant contributions from Dining and travelling by Bus, which involve potential combustion of fuels. This study demonstrates the potential value of personal exposure monitoring in investigating air pollution related health effects, and in evaluating the effectiveness of pollution control and intervention measures.

Identification of potential markers for internal exposure to ambient ozone in oral cavity of healthy adults.

BACKGROUND: Ozone is a highly oxidative gaseous pollutant associated with adverse health outcomes, but markers for internal exposure to ambient ozone are not well-established. METHODS: We aimed to evaluate the feasibility and suitability of the markers in oral microbiome for ambient ozone exposure. Between March and May in 2018, 97 healthy adults were examined on 2 or 3 occasions for oral swab sampling. Hourly concentrations of ambient ozone 1-7 days preceding sampling were collected. Mixed-effect models were fitted to examine the associations between ambient ozone and the diversity and taxon abundances of oral microbiome. Receiver operating characteristic (ROC) curves estimated the accuracies of markers to delineate between samples exposed to different concentrations of ambient ozone. The associations between the makers and lung function were further examined by linear mixed effect models. RESULTS: The averages of daily mean concentrations of ambient ozone (O3-daily), maximum 8-h means (O3-8hmax) and 1-h maximums (O3-1hmax) were respectively 72 µg/m³, 123 µg/m³ and 144 µg/m³. O3-daily was positively associated with α-diversity of oral microbiome, but the exposure-response curves only yielded positive associations in the range of O3-daily from 60 µg/m³ to 75 µg/m³. Results of O3-8hmax and O3-1hmax were consistent with these of O3-daily. With an interquartile range increase in O3-daily at lag04, the abundance of Proteobacteria decreased by 3.1% (95% CI: -4.0%, -2.2%) and Firmicutes increased by 3.3% (95% CI: 2.3%, 4.3%), whilst the Proteobacteria:Firmicutes ratio (P/F) decreased by 0.9 (95% CI: -1.5, -0.4). The areas under ROC curves for Proteobacteria, Firmicutes and P/F were 0.8535, 0.7569 and 0.8929, respectively. Proteobacteria and P/F were associated with forced expiratory volume in the first second and fractional exhaled nitric oxide significantly. CONCLUSION: Ambient ozone disturbs oral microbial homeostasis. Proteobacteria, Firmicutes and their ratio may be potential markers for short-term ambient ozone exposure, and indicators of airway inflammation or lung function decline.