Monitoring the impact of desert dust outbreaks for air quality for health studies

We review the major features of desert dust outbreaks that are relevant to the assessment of dust impacts upon human health. Our ultimate goal is to provide scientific guidance for the acquisition of relevant population exposure information for epidemiological studies tackling the short and long term health effects of desert dust. We first describe the source regions and the typical levels of dust particles in regions close and far away from the source areas, along with their size, composition, and bio-aerosol load. We then describe the processes by which dust may become mixed with anthropogenic particulate matter (PM) and/or alter its load in receptor areas. Short term health effects are found during desert dust episodes in different regions of the world, but in a number of cases the results differ when it comes to associate the effects to the bulk PM, the desert dust-PM, or non-desert dust-PM. These differences are likely due to the different monitoring strategies applied in the epidemiological studies, and to the differences on atmospheric and emission (natural and anthropogenic) patterns of desert dust around the world. We finally propose methods to allow the discrimination of health effects by PM fraction during dust outbreaks, and a strategy to implement desert dust alert and monitoring systems for health studies and air quality management.The systematic review was funded by WHO with as part of a Grant Agreement with Ministry of Foreign Affairs, Norway. Thanks are also given to the Spanish Ministry for the Ecological Transition for long term support in the last 2 decades to our projects on African dust effects on air quality over Spain; to the Spanish Ministry of Science, Innovation and Universities and FEDER Funds for the HOUSE project (CGL2016-78594-R), and to the Generalitat de Catalunya (AGAUR 2017 SGR41). Carlos Pérez García-Pando acknowledges long-term support from the AXA Research Fund, as well as the support received through the Ramón y Cajal program (grant RYC-2015-18690) of the Spanish Ministry of Science, Innovation and Universities.Peer ReviewedPostprint (published version

The role of burden of disease assessment in tracking progress towards achieving WHO global air quality guidelines

OBJECTIVES: More than 90% of the global population live in areas exceeding the PM2.5 air quality guidelines (AQGs). We provide an overview of the ambient PM2.5-related burden of disease (BoD) studies along with scenario analysis in the framework of the WHO AQG update on the estimated reduction in the BoD if AQGs were achieved globally. METHODS: We reviewed the literature for large-scale studies for the BoD attributed to ambient PM2.5. Moreover, we used the latest WHO statistics to calculate the BoD at current levels and the scenarios of aligning with interim targets and AQG levels. RESULTS: The most recent BoD studies (2010 onwards) share a similar methodology, but there are differences in the input data which affect the estimates for attributable deaths (2.9-8.9 million deaths annually). Moreover, we found that if AQGs were achieved, the estimated BoD would be reduced by up to 50% in total deaths worldwide. CONCLUSIONS: Understanding the BoD across countries, especially in those that do not align with the AQGs, is essential in order to inform actions to reduce air pollution globally

Multivariate Hierarchical Modelling of Household Air Pollution

This is the author accepted manuscript. The final version is available from the Statistical Modelling Society via the link in this recordExposure to household air pollution has been attributed to an estimated 3.8 million deaths per year. A major contributor to this exposure is the reliance on various polluting fuels for cooking by almost half of all households in low and middle-income countries. We present a multivariate hierarchical model for surveys of the proportion of people relying on each fuel type, for the period 1990-2017, addressing several challenges with modelling the data including incomplete surveys and sampling bias.Natural Environment Research Council (NERC)World Health Organizatio

Global household energy model: a multivariate hierarchical approach to estimating trends in the use of polluting and clean fuels for cooking

This is the final version. Available on open access from Wiley via the DOI in this recordIn 2017 an estimated 3 billion people used polluting fuels and technologies as their primary cooking solution, with 3.8 million deaths annually attributed to household exposure to the resulting fine particulate matter air pollution. Currently, health burdens are calculated using aggregations of fuel types, e.g. solid fuels, as country-level estimates of the use of specific fuel types, e.g. wood and charcoal, are unavailable. To expand the knowledge base about impacts of household air pollution on health, we develop and implement a Bayesian hierarchical model, based on Generalized Dirichlet Multinomial distributions, that jointly estimates non-linear trends in the use of eight key fuel types, overcoming several data-specific challenges including missing or combined fuel use values. We assess model fit using within-sample predictive analysis and an out-of-sample prediction experiment to evaluate the model's forecasting performance.Natural Environment Research Council (NERC)World Health Organizatio

Cohort-based association study of germline genetic variants with acute and chronic health complications of childhood cancer and its treatment: Genetic Risks for Childhood Cancer Complications Switzerland (GECCOS) study protocol

INTRODUCTION: Childhood cancer and its treatment may lead to various health complications. Related impairment in quality of life, excess in deaths and accumulated healthcare costs are relevant. Genetic variations are suggested to contribute to the wide inter-individual variability of complications but have been used only rarely to risk-stratify treatment and follow-up care. This study aims to identify germline genetic variants associated with acute and late complications of childhood cancer. METHODS AND ANALYSIS: The Genetic Risks for Childhood Cancer Complications Switzerland (GECCOS) study is a nationwide cohort study. Eligible are patients and survivors who were diagnosed with childhood cancers or Langerhans cell histiocytosis before age 21 years, were registered in the Swiss Childhood Cancer Registry (SCCR) since 1976 and have consented to the Paediatric Biobank for Research in Haematology and Oncology, Geneva, host of the national Germline DNA Biobank Switzerland for Childhood Cancer and Blood Disorders (BISKIDS).GECCOS uses demographic and clinical data from the SCCR and the associated Swiss Childhood Cancer Survivor Study. Clinical outcome data consists of organ function testing, health conditions diagnosed by physicians, second primary neoplasms and self-reported information from participants. Germline genetic samples and sequencing data are collected in BISKIDS. We will perform association analyses using primarily whole-exome or whole-genome sequencing to identify genetic variants associated with specified health conditions. We will use clustering and machine-learning techniques and assess multiple health conditions in different models. DISCUSSION: GECCOS will improve knowledge of germline genetic variants associated with childhood cancer-associated health conditions and help to further individualise cancer treatment and follow-up care, potentially resulting in improved efficacy and reduced side effects. ETHICS AND DISSEMINATION: The Geneva Cantonal Commission for Research Ethics has approved the GECCOS study.Research findings will be disseminated through national and international conferences, publications in peer-reviewed journals and in lay language online

Data Integration Model for Air Quality: A Hierarchical Approach to the Global Estimation of Exposures to Ambient Air Pollution

This is the author accepted manuscript. Available from arXiv via the URL in this record.Air pollution is a major risk factor for global health, with both ambient and household air pollution contributing substantial components of the overall global disease burden. One of the key drivers of adverse health effects is fine particulate matter ambient pollution (PM2:5) to which an estimated 3 million deaths can be attributed annually. The primary source of information for estimating exposures has been measurements from ground monitoring networks but, although coverage is increasing, there remain regions in which monitoring is limited. Ground monitoring data therefore needs to be supplemented with information from other sources, such as satellite retrievals of aerosol optical depth and chemical transport models. A hierarchical modelling approach for integrating data from multiple sources is proposed allowing spatially-varying relationships between ground measurements and other factors that estimate air quality. Set within a Bayesian framework, the resulting Data Integration Model for Air Quality (DIMAQ) is used to estimate exposures, together with associated measures of uncertainty, on a high resolution grid covering the entire world. Bayesian analysis on this scale can be computationally challenging and here approximate Bayesian inference is performed using Integrated Nested Laplace Approximations. Model selection and assessment is performed by cross-validation with the final model offering substantial increases in predictive accuracy, particularly in regions where there is sparse ground monitoring, when compared to previous approaches: root mean square error (RMSE) reduced from 17.1 to 10.7, and population weighted RMSE from 23.1 to 12.1 gm3. Based on summaries of the posterior distributions for each grid cell, it is estimated that 92% of the world’s population reside in areas exceeding the World Health Organization’s Air Quality Guidelines.Matthew Lloyd Thomas is supported by a scholarship from the EPSRC Centre for Doctoral Training in Statistical Applied Mathematics at Bath (SAMBa), under the project EP/L015684/1. Amelia Jobling was supported for this work by WHO contracts APW 201255146 and 201255393

Neuregulin 1 Type III/ErbB Signaling Is Crucial for Schwann Cell Colonization of Sympathetic Axons

Analysis of Schwann cell (SC) development has been hampered by the lack of growing axons in many commonly used in vitro assays. As a consequence, the molecular signals and cellular dynamics of SC development along peripheral axons are still only poorly understood. Here we use a superior cervical ganglion (SCG) explant assay, in which axons elongate after treatment with nerve growth factor (NGF). Migration as well as proliferation and apoptosis of endogenous SCG-derived SCs along sympathetic axons were studied in these cultures using pharmacological interference and time-lapse imaging. Inhibition of ErbB receptor tyrosine kinases leads to reduced SC proliferation, increased apoptosis and thereby severely interfered with SC migration to distal axonal sections and colonization of axons. Furthermore we demonstrate that SC colonization of axons is also strongly impaired in a specific null mutant of an ErbB receptor ligand, Neuregulin 1 (NRG1) type III. Taken together, using a novel SC development assay, we demonstrate that NRG1 type III serves as a critical axonal signal for glial ErbB receptors that drives SC development along sympathetic axons

Dibutyltin Disrupts Glucocorticoid Receptor Function and Impairs Glucocorticoid-Induced Suppression of Cytokine Production

BACKGROUND: Organotins are highly toxic and widely distributed environmental chemicals. Dibutyltin (DBT) is used as stabilizer in the production of polyvinyl chloride plastics, and it is also the major metabolite formed from tributyltin (TBT) in vivo. DBT is immunotoxic, however, the responsible targets remain to be defined. Due to the importance of glucocorticoids in immune-modulation, we investigated whether DBT could interfere with glucocorticoid receptor (GR) function. METHODOLOGY: We used HEK-293 cells transiently transfected with human GR as well as rat H4IIE hepatoma cells and native human macrophages and human THP-1 macrophages expressing endogenous receptor to study organotin effects on GR function. Docking of organotins was used to investigate the binding mechanism. PRINCIPAL FINDINGS: We found that nanomolar concentrations of DBT, but not other organotins tested, inhibit ligand binding to GR and its transcriptional activity. Docking analysis indicated that DBT inhibits GR activation allosterically by inserting into a site close to the steroid-binding pocket, which disrupts a key interaction between the A-ring of the glucocorticoid and the GR. DBT inhibited glucocorticoid-induced expression of phosphoenolpyruvate carboxykinase (PEPCK) and tyrosine-aminotransferase (TAT) and abolished the glucocorticoid-mediated transrepression of TNF-alpha-induced NF-kappaB activity. Moreover, DBT abrogated the glucocorticoid-mediated suppression of interleukin-6 (IL-6) and TNF-alpha production in lipopolysaccharide (LPS)-stimulated native human macrophages and human THP-1 macrophages. CONCLUSIONS: DBT inhibits ligand binding to GR and subsequent activation of the receptor. By blocking GR activation, DBT may disturb metabolic functions and modulation of the immune system, providing an explanation for some of the toxic effects of this organotin

Association study of candidate DNA-repair gene variants and acute graft versus host disease in pediatric patients receiving allogeneic hematopoietic stem-cell transplantation

Acute Graft versus Host Disease (aGvHD) grades 2-4 occurs in 15-60% of pediatric patients undergoing allogeneic haematopoietic stem-cell transplantation (allo-HSCT). The collateral damage to normal tissue by conditioning regimens administered prior to allo-HSCT serve as an initial trigger for aGvHD. DNA-repair mechanisms may play an important role in mitigating this initial damage, and so the variants in corresponding DNA-repair protein-coding genes via affecting their quantity and/or function. We explored 51 variants within 17 DNA-repair genes for their association with aGvHD grades 2-4 in 60 pediatric patients. The cumulative incidence of aGvHD 2-4 was 12% (n = 7) in the exploratory cohort. MGMT rs10764881 (G>A) and EXO rs9350 (c.2270C>T) variants were associated with aGvHD 2-4 [Odds ratios = 14.8 (0 events out of 40 in rs10764881 GG group) and 11.5 (95% CI: 2.3-191.8), respectively, multiple testing corrected p A) remained significant (adjusted HR = 2.05 [95% CI: 1.06-3.94]; p = 0.03) in the presence of other clinical risk factors. Higher MGMT expression was seen in GG carriers for rs10764881 and was associated with higher IC50 of Busulfan in lymphoblastoid cells. MGMT rs10764881 carrier status could predict aGvHD occurrence in pediatric patients undergoing allo-HSCT.Transplantation and immunomodulatio

Functional Complexity of the Axonal Growth Cone: A Proteomic Analysis

The growth cone, the tip of the emerging neurite, plays a crucial role in establishing the wiring of the developing nervous system. We performed an extensive proteomic analysis of axonal growth cones isolated from the brains of fetal Sprague-Dawley rats. Approximately 2000 proteins were identified at ≥99% confidence level. Using informatics, including functional annotation cluster and KEGG pathway analysis, we found great diversity of proteins involved in axonal pathfinding, cytoskeletal remodeling, vesicular traffic and carbohydrate metabolism, as expected. We also found a large and complex array of proteins involved in translation, protein folding, posttranslational processing, and proteasome/ubiquitination-dependent degradation. Immunofluorescence studies performed on hippocampal neurons in culture confirmed the presence in the axonal growth cone of proteins representative of these processes. These analyses also provide evidence for rough endoplasmic reticulum and reveal a reticular structure equipped with Golgi-like functions in the axonal growth cone. Furthermore, Western blot revealed the growth cone enrichment, relative to fetal brain homogenate, of some of the proteins involved in protein synthesis, folding and catabolism. Our study provides a resource for further research and amplifies the relatively recently developed concept that the axonal growth cone is equipped with proteins capable of performing a highly diverse range of functions