Search

Background Adoptive immunotherapy with tumour-infiltrating lymphocytes (TIL) may benefit from the use of selective markers, such as PD-1, for tumour-specific T-cell enrichment, and the identification of predictive factors that help identify those patients capable of rendering tumour-reactive TILs. We have investigated this in ovarian cancer (OC) patients as candidates for TIL therapy implementation. Methods PD-1− and PD-1+ CD8 TILs were isolated from ovarian tumours and expanded cells were tested against autologous tumour cells. Baseline tumour samples were examined using flow cytometry, multiplexed immunofluorescence and Nanostring technology, for gene expression analyses, as well as a next-generation sequencing gene panel, for tumour mutational burden (TMB) calculation. Results Tumour-reactive TILs were detected in half of patients and were exclusively present in cells derived from the PD-1+ fraction. Importantly, a high TIL density in the fresh tumour, the presence of CD137+ cells within the PD-1+CD8+ TIL subset and their location in the tumour epithelium, together with a baseline T-cell-inflamed genetic signature and/or a high TMB, are features that identify patients rendering tumour-reactive TIL products. Conclusion We have demonstrated that PD-1 identifies ovarian tumour-specific CD8 TILs and has uncovered predictive factors that identify OC patients who are likely to render tumour-specific cells from PD-1+ TILs.

BackgroundNeoantigens, new immunogenic sequences arising from tumor mutations, have been associated with response to immunotherapy and are considered potential targets for vaccination. Hepatocellular carcinoma (HCC) is a moderately mutated tumor, where the neoantigen repertoire has not been investigated. Our aim was to analyze whether tumors in HCC patients contain immunogenic neoantigens suitable for future use in therapeutic vaccination.MethodsWhole-exome sequencing and RNAseq were performed in a cohort of fourteen HCC patients submitted to surgery or liver transplant. To identify mutations, single-nucleotide variants (SNV) originating non-synonymous changes that were confirmed at the RNA level were analyzed. Immunogenicity of putative neoAgs predicted by HLA binding algorithms was confirmed by using in vitro HLA binding assays and T-cell stimulation experiments, the latter in vivo, by immunizing HLA-A*02.01/HLA-DRB1*01 (HHD-DR1) transgenic mice, and in in vitro, using human lymphocytes.ResultsSequencing led to the identification of a median of 1217 missense somatic SNV per patient, narrowed to 30 when filtering by using RNAseq data. A median of 13 and 5 peptides per patient were predicted as potential binders to HLA class I and class II molecules, respectively. Considering only HLA-A*02.01- and HLA-DRB1*01-predicted binders, 70% demonstrated HLA-binding capacity and about 50% were immunogenic when tested in HHD-DR1 mice. These peptides induced polyfunctional T cells that specifically recognized the mutated but not the wild-type sequence as well as neoantigen-expressing cells. Moreover, coimmunization experiments combining CD8 and CD4 neoantigen epitopes resulted in stronger CD8 T cell responses. Finally, responses against neoantigens were also induced in vitro using human cells.ConclusionThese results show that mutations in HCC tumors may generate immunogenic neoantigens with potential applicability for future combinatorial therapeutic strategies.

Epidemiological studies mostly focus on single environmental exposures. This study aims to systematically assess associations between a wide range of prenatal and childhood environmental exposures and cognition. The study sample included data of 1298 mother-child pairs, children were 6–11 years-old, from six European birth cohorts. We measured 87 exposures during pregnancy and 122 cross-sectionally during childhood, including air pollution, built environment, meteorology, natural spaces, traffic, noise, chemicals and life styles. The measured cognitive domains were fluid intelligence (Raven's Coloured Progressive Matrices test, CPM), attention (Attention Network Test, ANT) and working memory (N-Back task). We used two statistical approaches to assess associations between exposure and child cognition: the exposome-wide association study (ExWAS) considering each exposure independently, and the deletion-substitution-addition algorithm (DSA) considering all exposures simultaneously to build a final multiexposure model. Based on this multiexposure model that included the exposure variables selected by ExWAS and DSA models, child organic food intake was associated with higher fluid intelligence (CPM) scores (beta = 1.18; 95% CI = 0.50, 1.87) and higher working memory (N-Back) scores (0.23; 0.05, 0.41), and child fast food intake (−1.25; −2.10, −0.40), house crowding (−0.39; −0.62, −0.16), and child environmental tobacco smoke (ETS) (−0.89; −1.42, −0.35), were all associated with lower CPM scores. Indoor PM2.5 exposure was associated with lower N-Back scores (−0.09; −0.16, −0.02). Additional associations in the unexpected direction were found: Higher prenatal mercury levels, maternal alcohol consumption and child higher perfluorooctane sulfonic acid (PFOS) levels were associated with better cognitive performance; and higher green exposure during pregnancy with lower cognitive performance. This first comprehensive and systematic study of many prenatal and childhood environmental risk factors suggests that unfavourable child nutrition, family crowdedness and child indoor air pollution and ETS exposures adversely and cross-sectionally associate with cognitive function. Unexpected associations were also observed and maybe due to confounding and reverse causality., Graphical abstract Prenatal and childhood exposome-wide associations with child fluid intelligence (CPM). The exposures selected by Deletion-substitution-addition algorithm are represented by a triangle. Child fluid intelligence is mainly associated with childhood exposome, fast-food (negative association, left sided) and organic food consumption (positive, right sided), house crowding (negative, left sided), and child environmental tobacco smoke (ETS, negative, left sided). Image 1, Highlights • Previous evidence for environmental risk factor associations with neurodevelopment is based on analyses of single exposures. • We systematically analysed multiple environmental exposures in relation to child neurodevelopment. • The findings describe a list of outcome-related exposures: Diet, house crowding, indoor air pollution and tobacco smoke. • The findings show methodological complexities of analysing multiple exposures and their associations with neurodevelopment.

The human exposome affects child development and health later in life, but its personal external levels, variability, and correlations are largely unknown. We characterized the personal external exposome of pregnant women and children in eight European cities. Panel studies included 167 pregnant women and 183 children (aged 6-11 years). A personal exposure monitoring kit composed of smartphone, accelerometer, ultraviolet (UV) dosimeter, and two air pollution monitors were used to monitor physical activity (PA), fine particulate matter (PM2.5), black carbon, traffic-related noise, UV-B radiation, and natural outdoor environments (NOE). 77% of women performed the adult recommendation of >= 150 min/week of moderate to vigorous PA (MVPA), while only 3% of children achieved the childhood recommendation of >= 60 min/day MVPA. 11% of women and 17% of children were exposed to daily PM2.5 levels higher than recommended >= 25 mu g/m(3)). Mean exposure to noise ranged from Lden 51.1 dB in Kaunas to Lden 65.2 dB in Barcelona. 4% of women and 23% of children exceeded the recommended maximum of 2 Standard-Erythemal-Dose of UV-B at least once a week. 33% of women and 43% of children never reached the minimum NOE contact recommendation of >= 30 min/week. The variations in air and noise pollution exposure were dominated by between-city variability, while most of the variation observed for NOE contact and PA was between-participants. The correlations between all personal exposures ranged from very low to low (Rho

Background: tobacco is the main risk factor for developing lung cancer. Yet, some heavy smokers do not develop lung cancer at advanced ages while others develop it at young ages. Here, we assess for the first time the genetic background of these clinically relevant extreme phenotypes using whole exome sequencing (WES). Methods: we performed WES of germline DNA from heavy smokers who either developed lung adenocarcinoma at an early age ( extreme cases, n=50) or did not present lung adenocarcinoma or other tumors at an advanced age (extreme controls, n=50). We selected non-synonymous variants located in exonic regions and consensus splice sites of the genes that showed significantly different allelic frequencies between both cohorts. We validated our results in all the additional extreme cases (i.e., heavy smokers who developed lung adenocarcinoma at an early age) available from The Cancer Genome Atlas (TCGA). Results: the mean age for the extreme cases and controls was respectively 49.7 and 77.5 years. Mean tobacco consumption was 43.6 and 56.8 pack-years. We identified 619 significantly different variants between both cohorts, and we validated 108 of these in extreme cases selected from TCGA. Nine validated variants, located in relevant cancer related genes, such as PARP4, HLA-A or NQO1, among others, achieved statistical significance in the False Discovery Rate test. The most significant validated variant (P=4.48x10(-5)) was located in the tumor-suppressor gene ALPK2. Conclusions: we describe genetic variants associated with extreme phenotypes of high and low risk for the development of tobacco-induced lung adenocarcinoma. Our results and our strategy may help to identify high-risk subjects and to develop new therapeutic strategies. This work was supported by the Spanish Society of Medical Oncology; Fundación SEOM and Fundación Salud 2000; and Government of Navarra. LMM research work is supported by Foundation for Applied Medical Research (FIMA), Fundación Científica de la Asociación Espanola Contra el Cáncer, Fundación Ramón Areces, and Fondo de Investigación Sanitaria-Fondo Europeo de Desarrollo Regional 'Una manera de hacer Europa' (PI19/00098).

Introduction: Early onset and high prevalence of allergic diseases result in high individual and socio-economic burdens. Several studies provide evidence for possible effects of environmental factors on allergic diseases, but these are mainly single-exposure studies. The exposome provides a novel holistic approach by simultaneously studying a large set of exposures. The aim of the study was to evaluate the association between a broad range of prenatal and childhood environmental exposures and allergy-related outcomes in children. Material and methods: Analyses of associations between 90 prenatal and 107 childhood exposures and allergy-related outcomes (last 12 months: rhinitis and itchy rash; ever: doctor-diagnosed eczema and food allergy) in 6-11 years old children (n = 1270) from the European Human Early-Life Exposome cohort were performed. Initially, we used an exposome-wide association study (ExWAS) considering the exposures independently, followed by a deletion-substitution-addition selection (DSA) algorithm considering all exposures simultaneously. All the exposure variables selected in the DSA were included in a final multi-exposure model using binomial general linear model (GLM). Results: In ExWAS, no exposures were associated with the outcomes after correction for multiple comparison. In multi-exposure models for prenatal exposures, lower distance of residence to nearest road and higher di-iso-nonyl phthalate level were associated with increased risk of rhinitis, and particulate matter absorbance (PMabs) was associated with a decreased risk. Furthermore, traffic density on nearest road was associated with increased risk of itchy rash and diethyl phthalate with a reduced risk. DSA selected no associations of childhood exposures, or between prenatal exposures and eczema or food allergy. Discussion: This first comprehensive and systematic analysis of many environmental exposures suggests that prenatal exposure to traffic-related variables, PMabs and phthalates are associated with rhinitis and itchy rash. This work was supported by the European Community’s Seventh Framework Programme [grant agreement no 308333—the HELIX project]; Instituto de Salud Carlos III; CIBERESP; Conselleria de Sanitat; Generalitat Valenciana; Department of Health of the Basque Government; Provincial Government of Gipuzkoa; Generalitat de Catalunya-CIRIT; Lithuanian Agency for Science Innovation and Technology [grant number 6-04-2014_31V-66]; Norwegian Ministry of Health and Care Services; Norwegian Ministry of Education and Research; Greek Ministry of Health; Ministerio de Ciencia Innovacion y Universidades [grant number MTM2015-68140-R]; Centro Nacional de Genotipado-CEGEN-PRB2-ISCIII; Fondation de France.

Background: Chemical and nonchemical environmental exposures are increasingly suspected to influence the development of obesity, especially during early life, but studies mostly consider single exposure groups. Objectives: Our study aimed to systematically assess the association between a wide array of early-life environmental exposures and childhood obesity, using an exposome-wide approach. Methods: The HELIX (Human Early Life Exposome) study measured child body mass index (BMI), waist circumference, skinfold thickness, and body fat mass in 1,301 children from six European birth cohorts age 6-11 y. We estimated 77 prenatal exposures and 96 childhood exposures (cross-sectionally), including indoor and outdoor air pollutants, built environment, green spaces, tobacco smoking, and biomarkers of chemical pollutants (persistent organic pollutants, metals, phthalates, phenols, and pesticides). We used an exposure-wide association study (ExWAS) to screen all exposure-outcome associations independently and used the deletion-substitution-addition (DSA) variable selection algorithm to build a final multiexposure model. Results: The prevalence of overweight and obesity combined was 28.8%. Maternal smoking was the only prenatal exposure variable associated with higher child BMI (z-score increase of 0.28, 95% confidence interval: 0.09, 0.48, for active vs. no smoking). For childhood exposures, the multiexposure model identified particulate and nitrogen dioxide air pollution inside the home, urine cotinine levels indicative of secondhand smoke exposure, and residence in more densely populated areas and in areas with fewer facilities to be associated with increased child BMI. Child blood levels of copper and cesium were associated with higher BMI, and levels of organochlorine pollutants, cobalt, and molybdenum were associated with lower BMI. Similar results were found for the other adiposity outcomes. Discussion: This first comprehensive and systematic analysis of many suspected environmental obesogens strengthens evidence for an association of smoking, air pollution exposure, and characteristics of the built environment with childhood obesity risk. Cross-sectional biomarker results may suffer from reverse causality bias, whereby obesity status influenced the biomarker concentration. https://doi.org/10.1289/EHP5975. This study received funding from the European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 308333 – the HELIX project for data collection and analyses. The HELIX program built on six existing cohorts that received previous funding, including the major ones listed below. INMA data collections were supported by grants from the Instituto de Salud Carlos III, CIBERESP, and the Generalitat de Catalunya-CIRIT. KANC was funded by the grant of the Lithuanian Agency for Science Innovation and Technology (6-04-2014_31V-66). The Norwegian Mother and Child Cohort Study (MoBa) is supported by the Norwegian Ministry of Health and the Ministry of Education and Research, National Institutes of Health (NIH)/ National Institute of Environmental Health Sciences (NIEHS) (contract no. N01-ES-75558), and NIH/NINDS (grants 1 UO1 NS 047537-01 and 2 UO1 NS 047537-06A1). The Rhea project was financially supported by European projects and the Greek Ministry of Health (Program of Prevention of Obesity and Neurodevelopmental Disorders in Preschool Children in Heraklion district, Crete, Greece: 2011–2014; “Rhea Plus,” Primary Prevention Program of Environmental Risk Factors for Reproductive Health, and Child Health: 2012–2015). M.C. received funding from Instituto de Salud Carlos III (Ministry of Economy and Competitiveness) (MS16/00128). L.C. was supported by the NIH/NIEHS grants R21ES029681, R01ES030691, R01ES029944, R01 ES030364, R21ES028903, and P30ES007048.

Background: Adoptive immunotherapy with tumor-infiltrating lymphocytes (TIL) may benefit from the use of selective markers, such as programmed cell death protein 1 (PD-1), for tumor-specific T-cell enrichment, as well as predictive biomarkers that help identify those patients capable of rendering tumor-reactive TIL products. We have investigated this in ovarian cancer (OC) patients as candidate for TIL therapy implementation. Methods: PD-1- and PD-1+ CD8 TILs were isolated from resected ovarian tumors and, after polyclonal expansion, TIL products were tested against autologous tumor cells. Reactivity was assessed by IFNg production (ELISPOT) and upregulation of CD137. Baseline tumor samples were examined using flow cytometry, multiplexed quantitative immunofluorescence, Nanostring technology, for gene expression profile (GEP) analyses, as well as a next generation sequencing gene panel, for tumor mutational burden (TMB) calculation, to identify those features that distinguished patients with tumor-reactive and non-tumor-reactive TIL products.Results: Tumor-reactive TILs were detected in half of patients and were exclusively present in cells derived from the PD-1+ fraction. Flow-cytometric studies revealed that fresh tumors from patients rendering tumor-reactive TILs presented a significantly higher frequency of CD137+ cells within the PD1+CD8+ subset. Multiplexed immunofluorescence supported this finding, which was particularly striking in intraepithelial CD8 TILs. Baseline GEP analysis showed that patients rendering tumor-reactive TILs exhibited a significantly higher T-cell inflamed signature. Despite no correlation between TMB and GEP, both parameters stratified tumors, with patients with higher TMB and/or T-cell inflamed signature score rendering tumor-reactive TILs. Conclusion: We have demonstrated that PD-1 identifies autologous-tumor specific CD8 T cells infiltrating ovarian tumors and have uncovered predictive factors that identify OC patients who are likely to render tumor-reactive cells from PD-1+ TILs. These findings have important implications for improving the efficacy of TIL therapy in OC.

From 1992 to 2018, cytogenetic analyses were successfully performed to explore the chromosomal abnormalities of 729 patients, who utilised a pioneering counselling service in the city of Passo Fundo in the northern part of the Brazilian state of Rio Grande do Sul. This city is characterised by a large conglomerate of private and public hospitals. A classical cytogenetic analysis and G-banding were performed using the patient samples. Although normal karyotypes were observed for 562 of the cases, 167 individuals evidenced chromosomal alterations. Among those, 110 exhibited numerical alterations (65.86%), 41 demonstrated structural modifications (24.55%) and 16 showed both numerical and structural chromosomal changes (9.58%). This study describes the diversity of the chromosomal alterations in this region, which have not been previously examined. After 26 years of study, the findings are discussed herein in a self-critical form.

Characterization of the "exposome", the set of all environmental factors that one is exposed to from conception onwards, has been advocated to better understand the role of environmental factors on chronic diseases. Here, we aimed to describe the early-life exposome. Specifically, we focused on the correlations between multiple environmental exposures, their patterns and their variability across European regions and across time (pregnancy and childhood periods). We relied on the Human Early-Life Exposome (HELIX) project, in which 87 environmental exposures during pregnancy and 122 during the childhood period (grouped in 19 exposure groups) were assessed in 1301 pregnant mothers and their children at 6-11 years in 6 European birth cohorts. Some correlations between exposures in the same exposure group reached high values above 0.8. The median correlation within exposure groups was >0.3 for many exposure groups, reaching 0.69 for water disinfection by products in pregnancy and 0.67 for the meteorological group in childhood. Median correlations between different exposure groups rarely reached 0.3. Some correlations were driven by cohort-level associations (e.g. air pollution and chemicals). Ten principal components explained 45% and 39% of the total variance in the pregnancy and childhood exposome, respectively, while 65 and 90 components were required to explain 95% of the exposome variability. Correlations between maternal (pregnancy) and childhood exposures were high (>0.6) for most exposures modeled at the residential address (e.g. air pollution), but were much lower and even close to zero for some chemical exposures. In conclusion, the early life exposome was high dimensional, meaning that it cannot easily be measured by or reduced to fewer components. Correlations between exposures from different exposure groups were much lower than within exposure groups, which have important implications for co-exposure confounding in multiple exposure studies. Also, we observed the early life exposome to be variable over time and to vary by cohort, so measurements at one time point or one place will not capture its complexities. This work was supported by the European Commission Seventh Framework Programme (FP7/2007–2013) [grant number: 308333–the HELIX project]. INMA data collections were supported by grants from the Instituto de Salud Carlos III, CIBERESP, and the Generalitat de Catalunya-CIRIT. KANC was funded by the grant of the Lithuanian Agency for Science Innovation and Technology (6-04-2014_31V-66). The Norwegian Mother and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research, NIH/NIEHS (contract no N01-ES-75558), NIH/NINDS (grant no.1 UO1 NS 047537-01 and grant no.2 UO1 NS 047537-06A1). The Rhea project was financially supported by European projects (EU FP6-2003-Food-3-NewGeneris, EU FP6. STREP Hiwate, EU FP7 ENV.2007.1.2.2.2. Project No 211250 Escape, EU FP7-2008-ENV-1.2.1.4 Envirogenomarkers, EU FP7-HEALTH-2009-single stage CHICOS, EU FP7 ENV.2008.1.2.1.6. Proposal No 226285 ENRIECO, EUFP7-HEALTH-2012 Proposal No 308333 HELIX, FP7 European Union project, No. 264357 MeDALL), and the Greek Ministry of Health (Program of Prevention of obesity and neurodevelopmental disorders in preschool children, in Heraklion district, Crete, Greece: 2011–2014; “Rhea Plus”: Primary Prevention Program of Environmental Risk Factors for Reproductive Health, and Child Health: 2012–15).

FI=3.835 (año 2016), Q1 Background: Few risk factors for childhood renal tumors are well established. While a small fraction of cases might be attributable to susceptibility genes and congenital anomalies, the role of environmental factors needs to be assessed. Objectives: To explore the possible association between residential proximity to environmental pollution sources (industrial and urban areas, and agricultural crops) and childhood renal cancer, taking into account industrial groups and toxic substances released. Methods: We conducted a population-based case-control study of childhood renal cancer in Spain, including 213 incident cases gathered from the Spanish Registry of Childhood Tumors (period 1996-2011), and 1278 controls individually matched by year of birth, sex, and region of residence. Distances were computed from the respective subject's residences to the 1271 industries, the 30 urban areas with ≥75,000 inhabitants, and the agricultural crops located in the study area. Using logistic regression, odds ratios (ORs) and 95% confidence intervals (95%CIs) for categories of distance to pollution sources were calculated, with adjustment for matching variables and socioeconomic confounders. Results: Excess risk (OR; 95%CI) of childhood renal tumors was observed for children living near (≤2.5km) industrial installations as a whole (1.97; 1.13-3.42) - particularly glass and mineral fibers (2.69; 1.19-6.08), galvanization (2.66; 1.14-6.22), hazardous waste (2.59; 1.25-5.37), ceramic (2.35; 1.06-5.21), surface treatment of metals (2.25; 1.24-4.08), organic chemical industry (2.22; 1.15-4.26), food and beverage sector (2.19; 1.18-4.07), urban and waste-water treatment plants (2.14; 1.07-4.30), and production and processing of metals (1.98; 1.03-3.82) -, and in the proximity of agricultural crops (3.16; 1.54-8.89 for children with percentage of crop surface ≥24.35% in a 1-km buffer around their residences). Conclusions: Our study provides some epidemiological evidence that living near certain industrial areas and agricultural crops may be a risk factor for childhood renal cancer. This study was funded by Spain's Health Research Fund (Fondo de Investigación Sanitaria - FIS 12/01416 and FIS CP11/00112). No

BACKGROUND: Environmental exposures are related to the risk of some types of cancer, and children are the most vulnerable group of people. This study seeks to present the methodological approaches used in the papers of our group about risk of childhood cancers in the vicinity of pollution sources (industrial and urban sites). A population-based case-control study of incident childhood cancers in Spain and their relationship with residential proximity to industrial and urban areas was designed. Two methodological approaches using mixed multiple unconditional logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) were developed: (a) "near vs. far" analysis, where possible excess risks of cancers in children living near ("near") versus those living far ("far") from industrial and urban areas were assessed; and (b) "risk gradient" analysis, where the risk gradient in the vicinity of industries was assessed. For each one of the two approaches, three strategies of analysis were implemented: "joint", "stratified", and "individualized" analysis. Incident cases were obtained from the Spanish Registry of Childhood Cancer (between 1996 and 2011). RESULTS: Applying this methodology, associations between proximity (≤ 2 km) to specific industrial and urban zones and risk (OR; 95% CI) of leukemias (1.31; 1.04-1.65 for industrial areas, and 1.28; 1.00-1.53 for urban areas), neuroblastoma (2.12; 1.18-3.83 for both industrial and urban areas), and renal (2.02; 1.16-3.52 for industrial areas) and bone (4.02; 1.73-9.34 for urban areas) tumors have been suggested. CONCLUSIONS: The two methodological approaches were used as a very useful and flexible tool to analyze the excess risk of childhood cancers in the vicinity of industrial and urban areas, which can be extrapolated and generalized to other cancers and chronic diseases, and adapted to other types of pollution sources. This study was funded by Carlos III Institute of Health, Spain Grand EPY1344/16, Spain’s Health Research Fund (Fondo de Investigación Sanitaria—FIS 12/01416), and Scientific Foundation of the Spanish Association Against Cancer, Spain (Fundación Científica de la Asociación Española Contra el Cáncer (AECC)—EVP-1178/14). This article presents independent research. The views expressed are those of the authors and not necessarily those of the Carlos III Institute of Health. Sí

Background: The exposome is defined as the totality of environmental exposures from conception onwards. It calls for providing a holistic view of environmental exposures and their effects on human health by evaluating multiple environmental exposures simultaneously during critical periods of life. Objective: We evaluated the association of the urban exposome with birth weight. Methods: We estimated exposure to the urban exposome, including the built environment, air pollution, road traffic noise, meteorology, natural space, and road traffic (corresponding to 24 environmental indicators and 60 exposures) for nearly 32,000 pregnant women from six European birth cohorts. To evaluate associations with either continuous birth weight or term low birth weight (TLBW) risk, we primarily relied on the Deletion-Substitution-Addition (DSA) algorithm, which is an extension of the stepwise variable selection method. Second, we used an exposure-by-exposure exposome-wide association studies (ExWAS) method accounting for multiple hypotheses testing to report associations not adjusted for coexposures. Results: The most consistent statistically significant associations were observed between increasing green space exposure estimated as Normalized Difference Vegetation Index (NDVI) and increased birth weight and decreased TLBW risk. Furthermore, we observed statistically significant associations among presence of public bus line, land use Shannon's Evenness Index, and traffic density and birth weight in our DSA analysis. Conclusion: This investigation is the first large urban exposome study of birth weight that tests many environmental urban exposures. It confirmed previously reported associations for NDVI and generated new hypotheses for a number of built-environment exposures. The study has received funding from the European Community’s Seventh Framework Programme (FP7/2007–2013) under Grant Agreement No. 308333—the HELIX project—for data collection and analyses. The HELIX program built on six existing cohorts that received previous funding, including the major cohorts listed here. INMA data collections were supported by grants from the Instituto de Salud Carlos III, CIBERESP, the Conselleria de Sanitat, Generalitat Valenciana, Department of Health of the Basque Government; the Provincial Government of Gipuzkoa, and the Generalitat de Catalunya-CIRIT. KANC was funded by the grant of the Lithuanian Agency for Science Innovation and Technology (6-04-2014_31V-66). MoBa (Norwegian Mother and Child Cohort Study) is supported by the Norwegian Ministry of Health and the Ministry of Education and Research, NIH/NIEHS (Contract No. N01-ES-75558), and the U.S. National Institutes of Health (NIH) National Institute of Environmental Health Sciences (NIEHS; Contract No. N01-ES-75558), and National Institute of Neurological Disorders and Stroke (Grant No. 1 UO1 NS 047537-01 and Grant No. 2 UO1 NS 047537-06A1). The Rhea project was financially supported by European projects (EU FP6–2003-Food-3-NewGeneris, EU FP6.STREP Hiwate, EU FP7 ENV.2007·1.2.2.2, Project No. 211250 Escape, EU FP7–2008-ENV-1·2.1·4 Envirogenomarkers, EU FP7-HEALTH-2009-single stage CHICOS, EU FP7 ENV.2008.1.2.1.6, Proposal No. 226285 ENRIECO, EUFP7-HEALTH-2012 Proposal No. 308333 HELIX, FP7 European Union Project No. 264357 MeDALL), and the Greek Ministry of Health (Program of Prevention of Obesity and Neurodevelopmental Disorders in Preschool Children, in Heraklion district, Crete, Greece: 2011–2014; “Rhea Plus”: Primary Prevention Program of Environmental Risk Factors for Reproductive Health, and Child Health: 2012–15). L.C. received additional funding from the Southern California Environmental Health Sciences Center (Grant No. P30ES007048) funded by NIEHS. We acknowledge the support of the program for international scientific collaborations of Région Rhône-Alpes-Auvergne.

BACKGROUND Growing evidence exists about the fetal and environmental origins of hypertension, but mainly limited to single-exposure studies. The exposome has been proposed as a more holistic approach by studying many exposures simultaneously.OBJECTIVES This study aims to evaluate the association between a wide range of prenatal and postnatal exposures and blood pressure (BP) in children.METHODS Systolic and diastolic BP were measured among 1,277 children from the European HELIX (Human Early-Life Exposome) cohort aged 6 to 11 years. Prenatal (n = 89) and postnatal (n = 128) exposures include air pollution, built environment, meteorology, natural spaces, traffic, noise, chemicals, and lifestyles. Two methods adjusted for confounders were applied: an exposome-wide association study considering the exposures independently, and the deletion-substitution-addition algorithm considering all the exposures simultaneously.RESULTS Decreases in systolic BP were observed with facility density (beta change for an interquartile-range increase in exposure: -1.7 mm Hg [95% confidence interval (CI): -2.5 to -0.8 mm Hg]), maternal concentrations of polychlorinated biphenyl 118 (-1.4 mm Hg [95% CI: -2.6 to -0.2 mm Hg]) and child concentrations of dichlorodiphenyldichloroethylene (DDE: -1.6 mm Hg [95% CI: -2.4 to -0.7 mm Hg]), hexachlorobenzene (-1.5 mm Hg [95% CI: -2.4 to -0.6 mm Hg]), and mono -benzyl phthalate (-0.7 mm Hg [95% CI: -1.3 to -0.1 mm Hg]), whereas increases in systolic BP were observed with outdoor temperature during pregnancy (1.6 mm Hg [95% CI: 0.2 to 2.9 mm Hg]), high fish intake during pregnancy (2.0 mm Hg [95% CI: 0.4 to 3.5 mm Hg]), maternal cotinine concentrations (1.2 mm Hg [95% CI: -0.3 to 2.8 mm Hg]), and child perfluorooctanoate concentrations (0.9 mm Hg [95% CI: 0.1 to 1.6 mm Hg]). Decreases in diastolic BP were observed with outdoor temperature at examination (-1.4 mm Hg [95% CI: -2.3 to -0.5 mm Hg]) and child DDE concentrations (-1.1 mm Hg [95% CI: -1.9 to -0.3 mm Hg]), whereas increases in diastolic BP were observed with maternal bisphenol-A concentrations (0.7 mm Hg [95% CI: 0.1 to 1.4 mm Hg]), high fish intake during pregnancy (1.2 mm Hg [95% CI: -0.2 to 2.7 mm Hg]), and child copper concentrations (0.9 mm Hg [95% CI: 0.3 to 1.6 mm Hg]).CONCLUSIONS This study suggests that early-life exposure to several chemicals, as well as built environment and meteorological factors, may affect BP in children. (C) 2019 by the American College of Cardiology Foundation.

Background: Several environmental contaminants were reported to possibly influence fetal growth, generally from single exposure family studies, which are prone to publication bias. The exposome paradigm offers perspectives to avoid selective reporting of findings and to control for confounding by co-exposures. Objectives: We aimed to assess the association of the pregnancy chemical and external exposomes with fetal growth. Methods: Within HELIX project, 131 prenatal exposures were assessed using biomarkers and environmental models in 1,287 mother-child pairs from six European cohorts. We investigated their associations with fetal growth using a deletion-substitution-addition (DSA) algorithm considering all exposures simultaneously, and an exposome-wide association study (ExWAS) considering each exposure independently. We corrected for exposure misclassification, and tested for exposure-exposure and sex-exposure interactions. Findings: Lead blood level was the only exposure associated with fetal growth in the DSA model (97g weight decrease for each doubling in lead concentration). No exposure passed the multiple testing-corrected significance threshold of ExWAS; without multiple testing correction, this model was in favor of a negative association of fine particulate matter concentration with birth weight; and of a positive sex-specific association of parabens with birth weight in boys only. No two-way interaction between exposure variables was identified. Interpretation: This first large-scale exposome study of fetal growth simultaneously considered over 100 environmental exposures. Compared to single exposure studies, our approach allowed making all tests (usually reported in successive publications) explicit. Lead exposure is still a health concern in Europe and parabens health effects warrant further investigation. Funding Statement: FP7/2007-2013, HELIX project (no 308333). Declaration of Interests: The authors declare no conflict of interest. Ethics Approval Statement: The study was approved by the relevant ethical committees from each country and an informed consent form was assigned from all participants, or the parents of the children.

BACKGROUND: Current evidence suggests that childhood leukaemia can be associated with residential traffic exposure; nevertheless, more results are needed to support this conclusion. OBJECTIVES: To ascertain the possible effects of residential proximity to road traffic on childhood leukaemia, taking into account traffic density, road proximity and the type of leukaemia (acute lymphoid leukaemia or acute myeloid leukaemia). METHODS: We conducted a population-based case-control study of childhood leukaemia in Spain, covering the period 1990-2011. It included 1061 incidence cases gathered from the Spanish National Childhood Cancer Registry and those Autonomous Regions with 100% coverage, and 6447 controls, individually matched by year of birth, sex and autonomous region of residence. Distances were computed from the respective participant's residential locations to the different types of roads and four different buffers. Using logistic regression, odds ratios (ORs) and 95% confidence intervals (95%CIs), were calculated for four different categories of distance to roads. RESULTS: Cases of childhood leukaemia had more than three-fold increased odds of living at

BACKGROUND: Epidemiological evidence on the association between ambient air pollution and breast cancer risk is inconsistent. OBJECTIVE: We examined the association between long-term exposure to ambient air pollution and incidence of postmenopausal breast cancer in European women. METHODS: In 15 cohorts from nine European countries, individual estimates of air pollution levels at the residence were estimated by standardized land-use regression models developed within the European Study of Cohorts for Air Pollution Effects (ESCAPE) and Transport related Air Pollution and Health impacts - Integrated Methodologies for Assessing Particulate Matter (TRANSPHORM) projects: particulate matter (PM) ≤2:5 μm, ≤10 μm, and 2:5–10 μm in diameter (PM2:5, PM10, and PMcoarse, respectively); PM2:5 absorbance; nitrogen oxides (NO2 and NOx); traffic intensity; and elemental composition of PM. We estimated cohort-specific associations between breast cancer and air pollutants using Cox regression models, adjusting for major lifestyle risk factors, and pooled cohort-specific estimates using random-effects meta-analyses. RESULTS: Of 74,750 postmenopausal women included in the study, 3,612 developed breast cancer during 991,353 person-years of follow-up. We found positive and statistically insignificant associations between breast cancer and PM2:5 {hazard ratio (HR) =1:08 [95% confidence interval (CI): 0.77, 1.51] per 5 μg/m3 }, PM10 [1.07 (95% CI: 0.89, 1.30) per 10 μg/m3 ], PMcoarse [1.20 (95% CI: 0.96, 1.49 per 5 μg/m3 ], and NO2 [1.02 (95% CI: 0.98, 1.07 per 10 μg/m3 ], and a statistically significant association with NOx [1.04 (95% CI: 1.00, 1.08) per 20 μg/m3, p =0:04]. CONCLUSIONS: We found suggestive evidence of an association between ambient air pollution and incidence of postmenopausal breast cancer in European women. © 2017, Public Health Services, US Dept of Health and Human Services. All rights reserved. Chemicals/CAS: copper, 15158-11-9, 7440-50-8; iron, 14093-02-8, 53858-86-9, 7439-89-6; nickel, 7440-02-0; nitrogen oxide, 11104-93-1; potassium, 7440-09-7; silicon, 7440-21-3; sulfur, 13981-57-2, 7704-34-9; vanadium, 7440-62-2; zinc, 7440-66-6, 14378-32-6

The brown rat lives with man in a wide variety of environmental contexts and adversely affects public health by transmission of diseases, bites, and allergies. Understanding behavioural aspects of pest species can contribute to their effective management and control. We report an analysis of the spatio-temporal distribution of rat sightings, which are directly related to rat infestation, in a district of Madrid (Spain). We first consider an empirical analysis of the first-order for the first and second order properties of the spatio-temporal point process of rat sightings, in which we model the first-order intensity function as a product of two intensity functions, one spatial and the other temporal, and use the inhomogeneous spatio-temporal K -function to estimate second order properties. We then formulate a more mechanistic model in which the conditional intensity of the point process depends explicitly on its past history. We have found that the sightings show strong seasonal variation and are strongly influenced by environmental factors related to human behaviour. We have also identified spatio-temporal clustering and interaction over and above the separate temporal and spatial components of variation in risk, and have estimated the spatial scale on which the interaction operates.

Spatial behaviour and habitat selection at stopover sites have a strong influence on the foraging and fuelling performance of migrating birds and hence are important aspects of stopover ecology. The aim of this study was to analyse the spatial behaviour and habitat use of reed warblers Acrocephalus scirpaceus during the autumn migration. We used radio tracking data from reed warblers surveyed at a stopover site in northern Iberia and assigned to three different groups: (1) local adult birds which were still at their breeding site, (2) migrating first-year birds (originating from beyond Iberian peninsula) and (3) migrating adult birds. Overall, migrating first-year birds tended to have larger home ranges than both local and migrating adults and to move more widely in the study area. They also showed lower fat deposition rates than adults. The proportion of habitats in home ranges (reed-beds and tidal flats being the most abundant habitats) was similar amongst groups. The spatial distribution and habitat use of organisms have been theorised to follow an ideal-free or ideal-despotic distribution. However, according to our results, other complex underlying mechanisms may play an important role in shaping the spatial behaviour of birds at stopover sites.

Urban rat infestations have multifactorial causes and may result in severe public health and environmental problems, as well as heavy economic losses. The identification of putative environmental determinants of urban rat infestations and the mapping of areas prone to experiencing such infestations (hot spots) are crucial for effectively addressing intervention efforts. We investigated the associations between a selection of environmental factors and the occurrence of rat infestations in the city of Madrid, Spain. This was done by modelling 10,956 citizen-reported rat sightings from 2002 to 2008 using generalized additive models, both at municipality (Madrid) and district (Latina) levels. Increased age and density of housing, and decreased distance to vegetated areas, markets and cat feeding stations were factors associated with an increased risk of rat infestations. Risk maps for rat infestations were also developed and recurrent hot spots of rat activity were identified. Although a better fit to the data was obtained in the model for the smaller scale and possibly more environmentally homogenous study area of Latina, modelling the spatial distribution of rat sightings was useful for identifying factors associated with an increased risk of urban rat infestations, as well as for identifying hot spots of rat activity, providing local authorities with a practical tool for effectively targeting intervention efforts to high-risk situations based on the local environmental contexts.

La gestión de avisos por plagas es un componente habitual de los programas de control de plagas en una ciudad por lo que los gestores municipales de estas actividades normalmente desarrollan procedimientos para la captación, la atención y la explotación de los datos resultantes, lo que ayuda con otras actuaciones en paralelo, a mejorar la calidad de la Salud Pública.El estudio que aquí presentamos aborda la metodología diseñada y puesta en funcionamiento por el Ayuntamiento de Madrid para controlar y gestionar la presencia de plagas en la ciudad. La larga experiencia (más de 100 años) del Ayuntamiento y su apuesta por la incorporación de tecnologías novedosas en el control y gestión de plagas, ha permitido extraer una serie de lecciones aprendidas que pretende servir de guía y modelo para ciudades en donde los servicios de salud pública no hayan aun incorporado estos métodos.Citizens’ reports of sightings of undesirable animals are a common component of pest control programmes in a city. For this reason, local authorities tend to develop procedures for the capture and analysis of the resulting data sets based on these reported sightings. These procedures in turn contribute to the development of other initiatives aimed at improving public health conditions. The study presented here focuses on the methodology designed and implemented by the Madrid City Council for controlling and managing the presence of urban pests.The long experience (over 100 years) of the City Council and its commitment to the incorporation of new technologies have allowed a number of important lessons to be learnt in pest control and management, which may be useful as a guide and model for cities where public health services have not yet incorporated these methods.Os anúncios para a gestão de pragas é um componente comum nos programas de controlo de pragas nas cidades, por isso, os gestores municipais dessas atividades costumam desenvolver procedimentos para a coleta, cuidado e exploração dos dados obtidos, o que ajuda com outras ações em paralelo, a melhorar a qualidade da saúde pública.No presente estudo apresentamos a metodologia desenvolvida e posta em operação pela Câmara Municipal de Madrid para o controlo e gestão da presença de pragas na cidade. A Câmara Municipal de Madrid com a incorporação de novas tecnologias para o controlo e gestão de pragas, permitiu chegar a uma série de lições aprendidas que poderão ser de guia e modelo para as cidades onde os serviços de saúde pública ainda não incorporaram esses métodos de gestão de pragas.

Urban Norway rats are challenging pests, posing significant health and economic threats. Implementing ecologically based integrated rodent management (EBIRM) programmes relies primarily on the understanding of ecological relationships between rodents and their environments, with emphasis on the processes influencing rodent populations in the target ecosystem. We investigated the temporal distribution of urban Norway rat infestations in Madrid, Spain, and tested for the association of such infestations with temperature, relative humidity and precipitation by fitting a multivariate Poisson generalized linear model to a 3-year (2006–2008) daily time series of 4,689 Norway rat sightings. Norway rat infestations showed a marked seasonality, peaking in the summer. Most Norway rat sightings were reported on Mondays. Minimum temperature and relative humidity were positively associated with Norway rat infestation, whereas the association with precipitation was negative. The time series was adequately explained by the model. We identified previously unrecognized time periods that are more prone to Norway rat infestation than others and generated hypotheses about the association between weather, human outdoor activity, resource availability, rodent activity and population size. This provided local authorities engaged in preserving urban ecosystem health with basic research information to predict future rodent outbreaks and support the implementation of EBIRM programmes in urban areas.

Few epidemiologic studies have explored risk factors for bone tumors in children, and the role of environmental factors needs to be analyzed. Our objective was to ascertain the association between residential proximity to industrial plants and urban areas and risk of bone tumors in children, taking into account industrial groups and toxic pollutants released. A population-based case-control study of childhood bone cancer in Spain was carried out, covering 114 incident cases obtained from the Spanish Registry of Childhood Tumors (between 1996 and 2011), and 684 controls individually matched by sex, year of birth, and autonomous region of residence. Distances from the subject's residences to the 1271 industries and the 30 urban areas (towns) with ≥75,000 inhabitants located in the study area were computed. Unconditional logistic regression models were fitted to estimate odds ratios (ORs) and 95% confidence intervals (95%CIs) for categories of distance (from 1km to 3km) to industrial and urban areas, with adjustment for matching variables and sociodemographic indicators. Excess risk (OR; 95%CI) of bone tumors in children was detected for children close to industrial facilities as a whole (2.33; 1.17-4.63 at 3km) - particularly surface treatment of metals (OR=2.50; 95%CI=1.13-5.56 at 2km), production and processing of metals (OR=3.30; 95%CI=1.41-7.77 at 2.5km), urban waste-water treatment plants (OR=4.41; 95%CI=1.62-11.98 at 2km), hazardous waste (OR=4.63; 95%CI=1.37-15.61 at 2km), disposal or recycling of animal waste (OR=4.73; 95%CI=1.40-15.97 at 2km), cement and lime (OR=3.89; 95%CI=1.19-12.77 at 2.5km), and combustion installations (OR=3.85; 95%CI=1.39-10.66 at 3km)-, and urban areas (4.43; 1.80-10.92). These findings support the need for more detailed exposure assessment of certain toxics released by these facilities. Fondo de Investigación Sanitaria y Asociación Española Contra el Cáncer (AECC) Sí

Introduction Indoor air pollution by nitrogen dioxide (NO2) and BTEX compounds (benzene, toluene, ethylbenzene, meta-, ortho- and paraxylenes) in European children’s homes may adversely affect chil...

Background: We define the 'Outdoor Exposome' as the complex mixture of environmental factors that individuals are exposed to in the outdoor environment, which may be determined by socio-demographic...

Chronic obstructive pulmonary disease (COPD) is a prevalent condition in adults aged ≥40 years characterized by progressive airflow limitation associated with chronic inflammatory response to noxious particles in the airways and lungs. Smoking, genetics, air pollution, nutrition and other factors may influence COPD development. Most hospitalizations and deaths for COPD are caused by its acute exacerbations, which greatly affect the health and quality of life of COPD patients and pose a high burden on health services. The aims of this project were to identify trends, geographic patterns and risk factors for COPD exacerbations, as revealed by hospitalizations and deaths, in the Basque Country, Spain, over a period of 12 years (2000–2011). Hospitalization and mortality rates for COPD were 262 and 18 per 100,000 population, respectively, with clusters around the biggest cities. Hospital mortality was 7.4%. Most hospitalized patients were male (77.4%) and accounted for 72.1% of hospital mortality. Hospitalizations decreased during the study period, except for 50–64 year-old women, peaking significantly. Using a multivariate modeling approach it was shown that hospitalizations were positively correlated with increased atmospheric concentrations of NO2, CO, PM10, and SO2, and increased influenza incidence, but were negatively associated with increased temperatures and atmospheric O3 concentration. COPD exacerbations decreased in the Basque Country during 2000–2011, but not among 50–64-year-old women, reflecting the high smoking prevalence among Spanish women during the 1970–1990s. The main metropolitan areas were those with the highest risk for COPD exacerbations, calling attention to the role of heavy car traffic. Influenza virus, cold temperatures, and increased atmospheric NO2, CO, PM10, and SO2 (but decreased O3) concentrations were identified as potential contributors to the burden of COPD exacerbations in the community. These findings are important for both the understanding of the disease process and in providing potential targets for COPD-reducing initiatives and new avenues for research.

Background: Few epidemiologic studies have explored risk factors for rare tumors in children, and the role of environmental factors needs to be assessed. Objectives: To ascertain the effect of residential proximity to both industrial and urban areas on childhood cancer risk, taking industrial groups into account. Methods: We conducted a population-based case-control study of five childhood cancers in Spain (retinoblastoma, hepatic tumors, soft tissue sarcomas, germ cell tumors, and other epithelial neoplasms/melanomas), including 557 incident cases from the Spanish Registry of Childhood Tumors (period 1996-2011), and 3342 controls individually matched by year of birth, sex, and region of residence. Distances were computed from the residences to the 1271 industries and the 30 urban areas with ≥75,000 inhabitants located in the study area. Using logistic regression, odds ratios (ORs) and 95% confidence intervals (95%CIs) for categories of distance to industrial and urban pollution sources were calculated, with adjustment for matching variables and socioeconomic confounders. Results: Children living near industrial and urban areas as a whole showed no excess risk for any of the tumors analyzed. However, isolated statistical associations (OR; 95%CI) were found between retinoblastoma and proximity to industries involved in glass and mineral fibers (2.49; 1.01-6.12 at 3km) and organic chemical industries (2.54; 1.10-5.90 at 2km). Moreover, soft tissue sarcomas registered the lower risks in the environs of industries as a whole (0.59; 0.38-0.93 at 4km). Conclusions: We have found isolated statistical associations between retinoblastoma and proximity to industries involved in glass and mineral fibers and organic chemical industries. This study was funded by Spain's Health Research Fund (Fondo de Investigación Sanitaria - FIS 12/01416) and Scientific Foundation of the Spanish Association Against Cancer (Fundación Científica de la Asociación Española Contra el Cáncer (AECC) – EVP-1178/14). No

Background: Neuroblastoma is the most common extracranial solid tumor in children but its etiology is not clearly understood. While a small fraction of cases might be attributable to genetic factors, the role of environmental pollution factors needs to be assessed. Objectives: To ascertain the effect of residential proximity to both industrial and urban areas on neuroblastoma risk, taking into account industrial groups and toxic substances released. Methods: We conducted a population-based case-control study of neuroblastoma in Spain, including 398 incident cases gathered from the Spanish Registry of Childhood Tumors (period 1996–2011), and 2388 controls individually matched by year of birth, sex, and region of residence. Distances were computed from the respective subject's residences to the 1271 industries and the 30 urban areas with ≥75,000 inhabitants located in the study area. Using logistic regression, odds ratios (ORs) and 95% confidence intervals (95%CIs) for categories of distance (from 1 km to 5 km) to industrial and urban pollution sources were calculated, with adjustment for matching variables and socioeconomic confounders. Results: Excess risk (OR; 95%CI) of neuroblastoma was detected for the intersection between industrial and urban areas: (2.52; 1.20–5.30) for industrial distance of 1 km, and (1.99; 1.17–3.37) for industrial distance of 2 km. By industrial groups, excess risks were observed near ‘Production of metals’ (OR = 2.05; 95%CI = 1.16–3.64 at 1.5 km), ‘Surface treatment of metals’ (OR = 1.89; 95%CI = 1.10–3.28 at 1 km), ‘Mines’ (OR = 5.82; 95%CI = 1.04–32.43 at 1.5 km), ‘Explosives/pyrotechnics’ (OR = 4.04; 95%CI = 1.31–12.42 at 4 km), and ‘Urban waste-water treatment plants’ (OR = 2.14; 95%CI = 1.08–4.27 at 1.5 km). Conclusions: These findings support the need for more detailed exposure assessment of certain substances released by these industries. Keywords: Neuroblastoma, Industrial pollution, Urban pollution, Case-control study, Residential proximity, Pollutant release and transfer register

This study aimed to describe the degree of annoyance among pregnant women in a Spanish cohort and to examine associations with proximity to traffic, NO2 and benzene exposure. We included 2457 participants from the Spanish Childhood and Environment study. Individual exposures to outdoor NO2 and benzene were estimated, temporally adjusted for pregnancy. Interviews about sociodemographic variables, noise and air pollution were carried out. Levels of annoyance were assessed using a scale from 0 (none) to 10 (strong and unbearable), a level of 8 to 10 was considered high. The reported prevalence of high annoyance levels from air pollution was 11.2% and 15.0% from noise, the two variables were moderately correlated (0.606). Significant correlations between NO2 and annoyance from air pollution (0.154) and that from noise (0.181) were observed. Annoyance owing to noise and air pollution had a low prevalence in our Spanish population compared with other European populations. Both factors were associated with proximity to traffic. In multivariate models, annoyance from air pollution was related to NO2, building age, and country of birth, annoyance from noise was only related to the first two. The health burden of these exposures can be increased by stress caused by the perception of pollution sources.

Objectives: We examined the use of low (= 1000 mu g/day) among pregnant women in Spain, and explored factors associated with the use of these non-recommended dosages. Design: Population-based cohort study. Setting: Spain. Participants: We analysed data from 2332 pregnant women of the INMA study, a prospective mother-child cohort study in Spain. Main outcome measures: We assessed usual dietary folate and the use of FAS from preconception to the 3rd month (first period) and from the 4th to the 7th month (second period), using a validated food frequency questionnaire. We used multinomial logistic regression to estimate relative risk ratios (RRRs). Results: Over a half of the women used low dosages of FAS in the first and second period while 29% and 17% took high dosages of FAS, respectively. In the first period, tobacco smoking (RRR=1.63), alcohol intake (RRR=1.40), multiparous (RRR=1.44), unplanned pregnancy (RRR=4.20) and previous spontaneous abortion (RRR=0.58, lower use of high FAS dosages among those with previous abortions) were significantly associated with low FAS dosages. Alcohol consumption (RRR=1.42), unplanned pregnancy (RRR=2.66) and previous spontaneous abortion (RRR=0.68) were associated with high dosage use. In the second period, only tobacco smoking was significantly associated with high FAS dosage use (RRR=0.67). Conclusions: A high proportion of pregnant women did not reach the recommended dosages of FAS in periconception and a considerable proportion also used FAS dosages >= 1000 mu g/day. Action should be planned by the Health Care System and health professionals to improve the appropriate periconceptional use of FAS, taking into consideration the associated factors., This study was funded by grants from Instituto de Salud Carlos III and Spanish Ministry of Health (Red INMA G03/176; CB06/02/0041; FIS 97/0588; 00/0021-2, PI061756; PS0901958; FIS-FEDER 03/1615, 04/1509, 04/1112, 04/1931, 05/1079, 05/1052, 06/1213, 07/0314; 09/02647; FIS-PI041436, FIS-PI081151, FIS-PI06/0867; FIS-PS09/00090, FIS-PI042018, FIS-PI09 02311, FIS PI11/01007, FISPI13/02429) Universidad de Oviedo, Conselleria de Sanitat Generalitat Valenciana, Generalitat de Catalunya-CIRIT 1999SGR 00241, Department of Health of the Basque Government (2005111093 and 2009111069) and the Provincial Government of Guipuzcoa (DFG06/004 and DFG08/001).

With the aim of providing a deeper insight into the potential risks derived from the close cohabitation of people and rats in cities, the objectives of the present study focused on the identification and mapping of factors contributing to the proliferation of urban pests.The methodology was supported by an extensive literature review about causal factors, the experience of officials and experts working in the field, and analysis of the spatial distribution of the previously identified factors.Brainstorming sessions, together with a survey among experts and officials, provided the basis for weighting factors. Data about these factors were implemented on a GIS, which in turn constituted the basis for the spatial analysis and mapping of such factors. Con el objetivo de proporcionar una visión más profunda de los riesgos potenciales derivados de la interrelación de las propias personas y de las ratas en las ciudades, los objetivos del estudio que se presenta se centran en la identificación y cartografíado de los factores que contribuyen a la proliferación de plagas urbanas.La metodología se basó en una extensa revisión bibliográfica acerca de los factores predisponentes/causales, en la experiencia de los profesionales y expertos involucrados en la gestión de plagas y en el análisis de la distribución espacial de los factores previamente identificados.Sesiones de tormenta de ideas, así como una encuesta entre expertos y profesionales constituyeron la base para la ponderación de los factores. Estos factores fueron georreferenciados e integrados en un sistema de información geográfica (SIG), que a su vez constituyó la base para el análisis espacial y cartografía de tales factores. Com intuito de proporcionar uma visão mais profunda sobre os riscos potenciais decorrentes na coexistência das próprias pessoas e dos ratos nas cidades, os objetivos do presente estudo incidem na identificação e mapeamento dos fatores que contribuem para a proliferação das pragas urbanas.A metodologia foi baseada numa extensa revisão da literatura sobre os fatores predisponentes/causais, na experiência dos profissionais e especialistas na gestão de pragas e na análise da distribuição espacial dos fatores identificados.Sessões de brainstorming, bem como uma pesquisa entre os especialistas e profissionais formaram a base para a ponderação dos fatores. Esses fatores foram georreferenciados e integrados num SIG, que serviu de base para a análise espacial e mapeamento dos mesmos.

Citizens’ reports of sightings of undesirable animals are a common component of pest control programmes in a city. For this reason, local authorities tend to develop procedures for the capture and analysis of the resulting data sets based on these reported sightings. These procedures in turn contribute to the development of other initiatives aimed at improving public health conditions. The study presented here focuses on the methodology designed and implemented by the Madrid City Council for controlling and managing the presence of urban pests.The long experience (over 100 years) of the City Council and its commitment to the incorporation of new technologies have allowed a number of important lessons to be learnt in pest control and management, which may be useful as a guide and model for cities where public health services have not yet incorporated these methods. La gestión de avisos por plagas es un componente habitual de los programas de control de plagas en una ciudad por lo que los gestores municipales de estas actividades normalmente desarrollan procedimientos para la captación, la atención y la explotación de los datos resultantes, lo que ayuda con otras actuaciones en paralelo, a mejorar la calidad de la Salud Pública.El estudio que aquí presentamos aborda la metodología diseñada y puesta en funcionamiento por el Ayuntamiento de Madrid para controlar y gestionar la presencia de plagas en la ciudad. La larga experiencia (más de 100 años) del Ayuntamiento y su apuesta por la incorporación de tecnologías novedosas en el control y gestión de plagas, ha permitido extraer una serie de lecciones aprendidas que pretende servir de guía y modelo para ciudades en donde los servicios de salud pública no hayan aun incorporado estos métodos. Os anúncios para a gestão de pragas é um componente comum nos programas de controlo de pragas nas cidades, por isso, os gestores municipais dessas atividades costumam desenvolver procedimentos para a coleta, cuidado e exploração dos dados obtidos, o que ajuda com outras ações em paralelo, a melhorar a qualidade da saúde pública.No presente estudo apresentamos a metodologia desenvolvida e posta em operação pela Câmara Municipal de Madrid para o controlo e gestão da presença de pragas na cidade. A Câmara Municipal de Madrid com a incorporação de novas tecnologias para o controlo e gestão de pragas, permitiu chegar a uma série de lições aprendidas que poderão ser de guia e modelo para as cidades onde os serviços de saúde pública ainda não incorporaram esses métodos de gestão de pragas.

Background Childhood cancer is the main cause of disease-related death in children in Spain. Although little is known about the etiology, environmental factors are potential explanations for a fraction of the cases. Previous studies have shown pesticides to be associated with childhood cancer. The difficulty of collecting personal environmental exposure data is an important limitation; this lack of information about pesticides motivates the development of new methods to subrogate this exposure. We developed a crop exposure index based on geographic information to study the relationship between exposure to different types of crops and risk of childhood tumors. Methods We conducted a population-based case–control study of childhood cancer covering 3350 cases and 20,365 controls in two Spanish regions. We used CORINE Land Cover to obtain data about agricultural land use. We created a 1 km buffer around every child and calculated the percentage of crop surface within the buffer (Global Crop Index) for total crops and for individual types of crops. We fitted mixed multiple unconditional logistic regression models by diagnostic group. Results We found excess of risk among children living in the proximity of crops. For total crops our results showed excesses of risk for almost all diagnostic groups and increasing risk with increasing crop index value. Analyses by region and individual type of crop also showed excess of risk. Conclusion The results suggest that living in the proximity of cultivated land could be a risk factor for several types of cancer in children. This study was funded by Spain’s Health Research Fund (Fondo de Investigación Sanitaria—FIS 12/01416) and Scientific Foundation of the Spanish Association Against Cancer (Fundación Científica de la Asociación Española Contra el Cáncer (AECC)—EVP-1178/14). Sí

BACKGROUND: Central nervous system tumors (CNS) are the most frequent solid tumor in children. Causes of CNS tumors are mainly unknown and only 5% of the cases can be explained by genetic predisposition. We studied the effects of environmental exposure on the incidence of CNS tumors in children by subtype, according to exposure to industrial and/or urban environment, exposure to crops and according to socio-economic status of the child. METHODS: We carried out a population-based case-control study of CNS tumors in Spain, covering 714 incident cases collected from the Spanish Registry of Childhood Tumors (period 1996-2011) and 4284 controls, individually matched by year of birth, sex, and autonomous region of residence. We built a covariate to approximate the exposure to industrial and/or urban environment and a covariate for the exposure to crops (GCI) using the coordinates of the home addresses of the children. We used the 2001 Census to obtain information about socio-economic status (SES). We fitted logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (95%CIs). RESULTS: The results for all CNS tumors showed an excess risk (OR = 1.37; 95%CI = 1.09-1.73) for SES, i.e., children living in the least deprived areas had 37% more risk of CNS tumor than children living in the most deprived areas. For GCI, an increase of 10% in crop surface in the 1-km buffer around the residence implied an increase of 22% in the OR (OR = 1.22; 95%CI = 1.15-1.29). Children living in the intersection of industrial and urban areas could have a greater risk of CNS tumors than children who live outside these areas (OR = 1.20; 95%CI = 0.82-1.77). Living in urban areas (OR = 0.90; 95%CI = 0.65-1.24) or industrial areas (OR = 0.96; 95%CI = 0.81-1.77) did not seem to increase the risk for all CNS tumors together. By subtype, Astrocytomas, Intracranial and intraspinal embryonal tumors, and other gliomas showed similar results. CONCLUSION: Our results suggest that higher socioeconomic status and exposure to crops could increase the risk of CNS tumors in children. This study was funded by Spain's Health Research Fund (Fondo de Investigación Sanitaria - FIS 12/01416) and Scientific Foundation of the Spanish Association Against Cancer (Fundación Científica de la Asociación Española Contra el Cáncer (AECC) – EVP-1178/14). Sí

Graphical abstract, Highlights • A wide range of pre- and postnatal environmental exposures affects child behavior. • The exposome includes outdoor, indoor, chemical, lifestyle and social exposures. • Maternal tobacco smoke and car traffic increased behavioural problems in children. • Child sleep, healthy diet and higher family social capital reduced symptoms. • Child exposure to lead, copper, indoor air pollution, increased symptoms., Background Environmental exposures in early life influence the development of behavioral outcomes in children, but research has not considered multiple exposures. We therefore aimed to investigate the impact of a broad spectrum of pre- and postnatal environmental exposures on child behavior. Methods and findings We used data from the HELIX (Human Early Life Exposome) project, which was based on six longitudinal population-based birth cohorts in Europe. At 6–11 years, children underwent a follow-up to characterize their exposures and assess behavioral problems. We measured 88 prenatal and 123 childhood environmental factors, including outdoor, indoor, chemical, lifestyle and social exposures. Parent-reported behavioral problems included (1) internalizing, (2) externalizing scores, using the child behavior checklist (CBCL), and (3) the Conner’s Attention Deficit Hyperactivity Disorder (ADHD) index, all outcomes being discrete raw counts. We applied LASSO penalized negative binomial regression models to identify which exposures were associated with the outcomes, while adjusting for co-exposures. In the 1287 children (mean age 8.0 years), 7.3% had a neuropsychiatric medical diagnosis according to parent’s reports. During pregnancy, smoking and car traffic showing the strongest associations (e.g. smoking with ADHD index, aMR:1.31 [1.09; 1.59]) among the 13 exposures selected by LASSO, for at least one of the outcomes. During childhood, longer sleep duration, healthy diet and higher family social capital were associated with reduced scores whereas higher exposure to lead, copper, indoor air pollution, unhealthy diet were associated with increased scores. Unexpected decreases in behavioral scores were found with polychlorinated biphenyls (PCBs) and organophosphate (OP) pesticides. Conclusions Our systematic exposome approach identified several environmental contaminants and healthy lifestyle habits that may influence behavioral problems in children. Modifying environmental exposures early in life may limit lifetime mental health risk.