A critical review of the epidemiological evidence of effects of air pollution on dementia, cognitive function and cognitive decline in adult population

Dementia is arguably the most pressing public health challenge of our age. Since dementia does not have a cure,identifying risk factors that can be controlled has become paramount to reduce the personal, societal and eco-nomic burden of dementia. The relationship between exposure to air pollution and effects on cognitive function,cognitive decline and dementia has stimulated increasing scientific interest in the past few years. This review ofthe literature critically examines the available epidemiological evidence of associations between exposure to am-bient air pollutants, cognitive performance, acceleration of cognitive decline, risk of developing dementia, neuro-imaging and neurological biomarker studies, following Bradford Hill guidelines for causality.The evidence reviewed has been consistent in reporting associations between chronic exposure to air pollutionand reduced global cognition, as well as impairment in specific cognitive domains including visuo-spatial abili-ties. Cognitive decline and dementia incidence have also been consistently associated with exposure to air pollu-tion. The neuro-imaging studies reviewed report associations between exposure to air pollution and whitematter volume reduction. Other reported effects include reduction in gray matter, larger ventricular volume,and smaller corpus callosum. Findings relating to ischemic (white matter hyperintensities/silent cerebralinfarcts) and hemorrhagic (cerebral microbleeds) markers of cerebral small vessel disease have been heteroge-neous, as have observations on hippocampal volume and air pollution. The few studies available on neuro-inflammation tend to report associations with exposure to air pollution. everal effect modifiers have been suggested in the literature, but more replication studies are required. Tradi-tional confounding factors have been controlled or adjusted for in most of the reviewed studies. Additional con-founding factors have also been considered, but the inclusion of these has varied among the different studies.Despite all the efforts to adjust for confounding factors, residual confounding cannot be completely ruled out, es-pecially since the factors affecting cognition and dementia are not yet fully understood.The available evidence meets many of the Bradford Hill guidelines for causality. The reported associations be-tween a range of air pollutants and effects oncognitive function in older people,including the acceleration of cog-nitive decline and the induction of dementia, are likely to be causal in nature.However, the diversity of study designs, air pollutants and endpoints examined precludes the attribution of theseadverse effects to a single class of pollutant and makes meta-analysis inappropriate

Health impact assessment for air pollution in the presence of regional variation in effect sizes: the implications of using different meta-analytic approaches

The estimated health effects of air pollution vary between studies, and this variation is caused by factors associated with the study location, hereafter termed regional heterogeneity. This heterogeneity raises a methodological question as to which studies should be used to estimate risks in a specific region in a health impact assessment. Should one use all studies across the world, or only those in the region of interest? The current study provides novel insight into this question in two ways. Firstly, it presents an up-to-date analysis examining the magnitude of continent-level regional heterogeneity in the short-term health effects of air pollution, using a database of studies collected by Orellano et al. (2020). Secondly, it provides in-depth simulation analyses examining whether existing meta-analyses are likely to be underpowered to identify statistically significant regional heterogeneity, as well as evaluating which meta-analytic technique is best for estimating region-specific estimates. The techniques considered include global and continent-specific (sub-group) random effects meta-analysis and meta-regression, with omnibus statistical tests used to quantify regional heterogeneity. We find statistically significant regional heterogeneity for 4 of the 8 pollutant-outcome pairs considered, comprising NO2, O3 and PM2.5 with all-cause mortality, and PM2.5 with cardiovascular mortality. From the simulation analysis statistically significant regional heterogeneity is more likely to be identified as the number of studies increases (between 3 and 30 in each region were considered), between region heterogeneity increases and within region heterogeneity decreases. Finally, while a sub-group analysis using Cochran's Q test has a higher median power (0.71) than a test based on the moderators' coefficients from meta-regression (0.59) to identify regional heterogeneity, it also has an inflated type-1 error leading to more false positives (median errors of 0.15 compared to 0.09)

Identification of Novel Antimalarial Chemotypes via Chemoinformatic Compound Selection Methods for a High-Throughput Screening Program against the Novel Malarial Target, PfNDH2: Increasing Hit Rate via Virtual Screening Methods

Malaria is responsible for approximately 1 million deaths annually; thus, continued efforts to discover new antimalarials are required. A HTS screen was established to identify novel inhibitors of the parasite's mitochondrial enzyme NADH:quinone oxidoreductase (PfNDH2). On the basis of only one known inhibitor of this enzyme, the challenge was to discover novel inhibitors of PfNDH2 with diverse chemical scaffolds. To this end, using a range of ligand-based chemoinformatics methods, ~17000 compounds were selected from a commercial library of ~750000 compounds. Forty-eight compounds were identified with PfNDH2 enzyme inhibition IC(50) values ranging from 100 nM to 40 μM and also displayed exciting whole cell antimalarial activity. These novel inhibitors were identified through sampling 16% of the available chemical space, while only screening 2% of the library. This study confirms the added value of using multiple ligand-based chemoinformatic approaches and has successfully identified novel distinct chemotypes primed for development as new agents against malaria

Financial considerations in the conduct of multi-centre randomised controlled trials: evidence from a qualitative study.

National Coordinating Centre for Research Methodology; Medical Research Council, UK Department of Health; Chief Scientist OfficeNot peer reviewedPublisher PD

Using epidemiology to estimate the impact and burden of exposure to air pollutants:Health effects of air pollution

This paper focuses on the use of results of epidemiological studies to quantify the effects on health, particularly on mortality, of long-term exposure to air pollutants. It introduces health impact assessment methods, used to predict the benefits that can be expected from implementation of interventions to reduce emissions of pollutants. It also explains the estimation of annual mortality burdens attributable to current levels of pollution. Burden estimates are intended to meet the need to communicate the size of the effect of air pollution on public health to policy makers and others. The implications, for the interpretation of the estimates, of the assumptions and approximations underlying the methods are discussed. The paper starts with quantification based on results obtained from studies of the association of mortality risk with long-term average concentrations of particulate air pollution. It then tackles the additional methodological considerations that need to be addressed when also considering the mortality effects of other pollutants such as nitrogen dioxide (NO(2)). Finally, approaches that could be used to integrate morbidity and mortality endpoints in the same assessment are touched upon. This article is part of a discussion meeting issue ‘Air quality, past present and future’

Description of trihalomethane levels in three UK water suppliers

Samples of drinking water are routinely analysed for four trihalomethanes (THMs), which are indicators of by-products of disinfection with chlorine, by UK water suppliers to demonstrate compliance with regulations. The THM data for 1992–1993 to 1997–1998 for three water suppliers in the north and midlands of England were made available for a UK epidemiological study of the association between disinfection by-products and adverse birth outcomes. This paper describes the THM levels in these three supply regions and discusses possible sources of variation. THM levels varied between different suppliers' water, and average THM levels were within the regulatory limits. Chloroform was the predominant THM in all water types apart from the ground water of one supplier. The supplier that distributed more ground and lowland surface water had higher dibromochloromethane (DBCM) and bromoform levels and lower chloroform levels than the other two suppliers. In the water of two suppliers, seasonal fluctuations in bromodichloromethane (BDCM) and DBCM levels were found with levels peaking in the summer and autumn. In the other water supplier, chloroform levels followed a similar seasonal trend whereas BDCM and DBCM levels did not. For all three water suppliers, chloroform levels declined throughout 1995 when there was a drought period. There was a moderate positive correlation between the THMs most similar in their structure (chloroform and BDCM, BDCM and DBCM, and DBCM and bromoform) and a slight negative correlation between chloroform and bromoform levels

A UK framework for the assessment and integration of different scientific evidence streams in chemical risk assessmentt

Background Few methods are available for transparently combining different evidence streams for chemical risk assessment to reach an integrated conclusion on the probability of causation. Hence, the UK Committees on Toxicity (COT) and on Carcinogenicity (COC) have reviewed current practice and developed guidance on how to achieve this in a transparent manner, using graphical visualisation. Methods/approach All lines of evidence, including toxicological, epidemiological, new approach methodologies, and mode of action should be considered, taking account of their strengths/weaknesses in their relative weighting towards a conclusion on the probability of causation. A qualitative estimate of the probability of causation is plotted for each line of evidence and a combined estimate provided. Discussion/conclusions Guidance is provided on integration of multiple lines of evidence for causation, based on current best practice. Qualitative estimates of probability for each line of evidence are plotted graphically. This ensures a deliberative, consensus conclusion on likelihood of causation is reached. It also ensures clear communication of the influence of the different lines of evidence on the overall conclusion on causality. Issues on which advice from the respective Committees is sought varies considerably, hence the guidance is designed to be sufficiently flexible to meet this need