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BACKGROUND: DNA methylation programming is sensitive to prenatal life environmental influences, but the impact of maternal exposure to green space on newborns DNA methylation has not been studied yet. METHODS: We conducted a meta-epigenome-wide association study (EWAS) of maternal exposure to green space during gestation with cord blood DNA methylation in two subsets of the ENVIRONAGE cohort (N = 538). Cord blood DNA methylation was measured by Illumina HumanMethylation 450K in one subset (N = 189) and EPICarray in another (N = 349). High (vegetation height>3 m (m)), low (vegetation height

Telomere length (TL) and telomere shortening are biological indicators of aging, and epigenetic associates have been found for TL in adults. However, the role of epigenetic signatures in setting newborn TL and early life telomere dynamics is unknown. In the present study, based on 247 participating newborns from the ENVIRONAGE birth cohort, whole-genome DNA methylation, profiled on the Illumina MethylationEPIC BeadChip microarray, and TL were measured in cord blood. In a follow-up visit at a mean age of 4.58 years, leukocyte TL was evaluated. We combined an epigenome-wide association study and a statistical learning method with re-sampling to select CpGs and their two-way interactions to model baseline (cord blood) TL and early-life telomere attrition rate, where distinct epigenetic signatures were identified for the two outcomes. In addition, a stronger epigenetic regulation was suggested in setting newborn TL than that of telomere dynamics in early life: 47 CpGs and 7 between-CpG interactions explained 76% of the variance in baseline TLs, while 72% of the total variance in telomere attrition rate was explained by 31 CpGs and 5 interactions. Functional enrichment analysis based on the selected CpGs in the two models revealed GLUT4 translocation and immune cell signaling pathways, respectively. These CpGs and interactions, as well as the cellular pathways, are potential novel targets of further investigation of telomere biology and aging. Funding The ENVIRONAGE birth cohort is supported by grants from the European Research Council (Grant No. ERC-2012-StG310898), the Flemish Scientific Fund (FWO, Grant No. G073315N) and Kom Op Tegen Kanker DSM (FWO grant 12X9620N) is postdoctoral fellows of the Flanders Research Foundation. SL is the beneficiary of a post-doctoral fellowship (12L5216N) provided by The Research Foundation-Flanders (FWO) and the Flemish Institute of Technological Research (VITO). Acknowledgments We acknowledge the cohort participants, midwives, the staff of the maternity ward and the clinical laboratory of East-Limburg Hospital in Genk.

Background Most of the literature on conflict of interest (COI) has not focused on the role of academic editors and their possible COIs, although academic editors often hold senior faculty positions at universities, which might be considered a COI if this influences towards a more favourable processing to articles submitted by institutional colleagues. The current study aims to assess whether academic editor affiliation, a potential COI, can influence academic institution ranking as top contributor in the biomedical field. Methods We conducted a cross-sectional analysis extracting publicly available data from the 2019 Clarivate InCites Journal Citation Reports for journals in the “Medicine, General & Internal” category and from each journal website. We constructed the following study outcomes: i) being a top 5 academic contributor for the peer-review journal of interest (yes/no), ii) being a top 10 academic contributor for the peer-review journal of interest (yes/no), and iii) ranking position as top 50 academic contributor for the peer-review journal of interest. Mixed-effect linear and logistic regression models were employed, as appropriate. Results We included 114 journals in our analysis, 49% were open-access only. Sharing same affiliation of any of the editorial board members was associated with a 6.7 and 5.6 greater likelihood of being top 5 and top 10 contributors, respectively (95%CI 5.07-8.73 and 4.34-7.22). Similarly, sharing same affiliation was associated with being 12.1 places higher as top contributor (95%CI 10.35-13.81). When considering the editor in chief affiliation solely, association was even stronger. Conclusions We found that academic editors sharing the same institutional affiliation with authors was strongly associated with the likelihood of that institution of being a top contributor. Shared institutional affiliations between editors and authors should be clearly stated as part of an open and transparent peer-review process. Key messages • Editors sharing same affiliation with authors was strongly associated with the likelihood for the institution the editor was affiliated with of being top contributor for academic medical journals. • Shared institutional affiliations between editors and authors should be clearly stated as part of an open and transparent peer-review process.

OBJECTIVE Maternal glycemic dysregulation during pregnancy increases the risk of adverse health outcomes in her offspring; a risk thought to be linearly related to maternal hyperglycemia. It is hypothesized that changes in offspring DNA methylation (DNAm) underline these associations. RESEARCH DESIGN AND METHODS To address this hypothesis, we conducted fixed-effect meta-analyses of epigenome-wide association study (EWAS) results from eight birth cohorts investigating relationships between cord blood DNAm and fetal exposure to maternal glucose (Nmax= 3,503), insulin (Nmax= 2,062), and the area under the curve of glucose (AUCgluc) following oral glucose tolerance tests (OGTT, Nmax= 1,505). We performed look-up analyses for identified CpG dinucleotides (CpGs) in independent observational cohorts to examine associations between DNAm and cardiometabolic traits as well as tissue-specific gene expression. RESULTS Greater maternal AUCgluc was associated with lower cord blood DNAm at neighboring CpGs cg26974062 (β= -0.013 [SE=2.1x10-3], PFDR= 5.1x10-3) and cg02988288 (β= -0.013 [SE=2.3x10-3], PFDR =0.031) in TXNIP. These associations were attenuated in women with GDM. Lower blood DNAm at these two CpGs near TXNIP was associated with multiple metabolic traits later in life, including type 2 diabetes. TXNIP DNAm in liver biopsies was associated with hepatic expression of TXNIP. We observed little evidence of associations between either maternal glucose or insulin and cord blood DNAm. CONCLUSION Maternal hyperglycemia, as reflected by AUCgluc, was associated with lower cord blood DNAm at TXNIP. Associations between DNAm at these CpGs and metabolic traits in subsequent look-up analyses suggest that these may be candidate loci to investigate in future causal and mediation analyses.

Background: The mechanisms underlying childhood overweight and obesity are poorly known. Here, we investigated the direct and indirect effects of different prenatal exposures on offspring rapid postnatal growth and overweight in childhood, mediated through cord blood metabolites. Additionally, rapid postnatal growth was considered a potential mediator on childhood overweight, alone and sequentially to each metabolite. Methods: Within four European birth-cohorts (N = 375 mother-child dyads), information on seven prenatal exposures (maternal education, pre-pregnancy BMI, weight gain and tobacco smoke during pregnancy, age at delivery, parity, and child gestational age), selected as obesogenic according to a-priori knowledge, was collected. Cord blood levels of 31 metabolites, associated with rapid postnatal growth and/or childhood overweight in a previous study, were measured via liquid-chromatography-quadrupole-time-of-flight-mass-spectrometry. Rapid growth at 12 months and childhood overweight (including obesity) between four and eight years were defined with reference to WHO growth charts. Single mediation analysis was performed using the imputation approach and multiple mediation analysis using the extended-imputation approach. Results: Single mediation suggested that the effect of maternal education, pregnancy weight gain, parity, and gestational age on rapid postnatal growth but not on childhood overweight was partly mediated by seven metabolites, including cholestenone, decenoylcarnitine(C10:1), phosphatidylcholine(C34:3), progesterone and three unidentified metabolites; and the effect of gestational age on childhood overweight was mainly mediated by rapid postnatal growth. Multiple mediation suggested that the effect of gestational age on childhood overweight was mainly mediated by rapid postnatal growth and that the mediating role of the metabolites was marginal. Conclusion: Our findings provide evidence of the involvement of in utero metabolism in the propensity to rapid postnatal growth and of rapid postnatal growth in the propensity to childhood overweight. We did not find evidence supporting a mediating role of the studied metabolites alone between the studied prenatal exposures and the propensity to childhood overweight. This work is supported by the Bijzonder Onderzoeksfonds Hasselt University through a PhD fellowship [to RA], by the UKRI Future Leaders Fellowship [MR/S03532X/1, to OR] and by the European Commission Horizon 2020 Grant to the ‘STOP Project’ [Grant ref 774548]. The ENVIRONAGE birth cohort is supported by the European Research Council [ERC-2012-StG.310898], and by funds of the Flemish Scientific Research council [FWO, G.0.733.15.N]. The Piccolipiù cohort was initially supported by the Italian National Center for Disease Prevention and Control (CCM grants years 2010 and 2014) and by the Italian Ministry of Health (art 12 and 12 bis D.lgs 502/92). The Rhea study has been funded by various European grants since 2006 and by the Greek Ministry of Health. INMA data collections were supported by grants from the Instituto de Salud Carlos III, CIBERESP, and the Generalitat de Catalunya-CIRIT. ISGlobal acknowledges support from the Spanish Ministry of Science, Innovation and Universities, “Centro de Excelencia Severo Ochoa 2013-2017”, SEV-2012-0208, and “Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement de la Generalitat de Catalunya” (2017SGR595).

Childhood obesity has become a global epidemic and carries significant long-term consequences to physical and mental health. Metabolomics, the global profiling of small molecules or metabolites, may reveal the mechanisms of development of childhood obesity and clarify links between obesity and metabolic disease. A systematic review of metabolomic studies of childhood obesity was conducted, following Preferred Reporting Items for Systematic Reviews (PRISMA) guidelines, searching across Scopus, Ovid, Web of Science and PubMed databases for articles published from January 1, 2005 to July 8, 2020, retrieving 1271 different records and retaining 41 articles for qualitative synthesis. Study quality was assessed using a modified Newcastle-Ottawa Scale. Thirty-three studies were conducted on blood, six on urine, three on umbilical cord blood, and one on saliva. Thirty studies were primarily cross-sectional, five studies were primarily longitudinal, and seven studies examined effects of weight-loss following a life-style intervention. A consistent metabolic profile of childhood obesity was observed including amino acids (particularly branched chain and aromatic), carnitines, lipids, and steroids. Although the use of metabolomics in childhood obesity research is still developing, the identified metabolites have provided additional insight into the pathogenesis of many obesity-related diseases. Further longitudinal research is needed into the role of metabolic profiles and child obesity risk.

The tremendous increase in childhood obesity prevalence over the last few decades cannot merely be explained by genetics and evolutionary changes in the genome, implying that gene-environment interactions, such as epigenetic modifications, likely play a major role. This systematic review aims to summarize the evidence of the association between epigenetics and childhood obesity. A literature search was performed via PubMed and Scopus engines using a combination of terms related to epigenetics and pediatric obesity. Articles studying the association between epigenetic mechanisms (including DNA methylation and hydroxymethylation, non-coding RNAs, and chromatin and histones modification) and obesity and/or overweight (or any related anthropometric parameters) in children (0-18 years) were included. The risk of bias was assessed with a modified Newcastle-Ottawa scale for non-randomized studies. One hundred twenty-one studies explored epigenetic changes related to childhood obesity. DNA methylation was the most widely investigated mechanism (N = 101 studies), followed by non-coding RNAs (N = 19 studies) with evidence suggestive of an association with childhood obesity for DNA methylation of specific genes and microRNAs (miRNAs). One study, focusing on histones modification, was identified. Heterogeneity of findings may have hindered more insights into the epigenetic changes related to childhood obesity. Gaps and challenges that future research should face are herein described.

Introduction Metabolomics may identify biological pathways predisposing children to the risk of overweight and obesity. In this study, we have investigated the cord blood metabolic signatures of rapid growth in infancy and overweight in early childhood in four European birth cohorts. Methods Untargeted liquid chromatography-mass spectrometry metabolomic profiles were measured in cord blood from 399 newborns from four European cohorts (ENVIRONAGE, Rhea, INMA and Piccolipiu). Rapid growth in the first year of life and overweight in childhood was defined with reference to WHO growth charts. Metabolome-wide association scans for rapid growth and overweight on over 4500 metabolic features were performed using multiple adjusted logistic mixed-effect models and controlling the false discovery rate (FDR) at 5%. In addition, we performed a look-up analysis of 43 pre-annotated metabolites, previously associated with birthweight or rapid growth. Results In the Metabolome-Wide Association Study analysis, we identified three and eight metabolites associated with rapid growth and overweight, respectively, after FDR correction. Higher levels of cholestenone, a cholesterol derivative produced by microbial catabolism, were predictive of rapid growth (p = 1.6 x 10(-3)). Lower levels of the branched-chain amino acid (BCAA) valine (p = 8.6 x 10(-6)) were predictive of overweight in childhood. The area under the receiver operator curve for multivariate prediction models including these metabolites and traditional risk factors was 0.77 for rapid growth and 0.82 for overweight, compared with 0.69 and 0.69, respectively, for models using traditional risk factors alone. Among the 43 pre-annotated metabolites, seven and five metabolites were nominally associated (P < 0.05) with rapid growth and overweight, respectively. The BCAA leucine, remained associated (1.6 x 10(-3)) with overweight after FDR correction. Conclusion The metabolites identified here may assist in the identification of children at risk of developing obesity and improve understanding of mechanisms involved in postnatal growth. Cholestenone and BCAAs are suggestive of a role of the gut microbiome and nutrient signalling respectively in child growth trajectories. This research was supported by European Commission Horizon 2020 Grant to the ‘STOP Project’ (Grant ref. 774548). This study was funded by the European Union Social Fund and the Hellenic Ministry of Health (“Programme of prevention and early diagnosis of obesity and neurodevelopment disorders in preschool-age children in the prefecture of Heraklion, Crete, Greece’ MIS number 349580, NSRF 2007-2013). Additional funding from the National Institute of Environmental Health Sciences (NIEHS) supported Dr. Chatzi (R01ES030691, R01ES029944, R01ES030364, R21ES029681, R21ES028903 and P30ES007048). The ENVIRONAGE birth-cohort is supported by the EU Program ‘Ideas’ (ERC-2012-StG-310898) and the FWO (G082317N), a PhD fellowship of the Bijzonder Onderzoeksfonds (BOF) at Hasselt University supported MD Alfano. We acknowledge support from the Spanish Ministry of Science, Innovation and Universities, ‘Centro de Excelencia Severo Ochoa 2013-2017”, SEV-2012-0208 and ‘Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement de la Generalitat de Catalunya’ (2017SGR595). O.R. was supported by a UKRI Future Leaders Fellowship (MR/S03532X/1).

to evaluate the implementation of an integrated care model for thyroid disease on thyroid surgery at the University Hospital "Federico II" of Naples (Campania Region, Southern Italy).quasi-experimental design employing an interrupted time series analysis.all subjects who were admitted to the University Hospital "Federico II" for thyroid surgery between January 2008 and December 2018. The integrated care model for thyroid disease was implemented starting from January 2016.rate of partial thyroidectomies over all thyroidectomies; rate of diagnosed thyroid cancers over all diagnosed thyroid tumours; length of stay (LOS). Differences pre- and post-interventions were assessed employing Poisson (for count outcomes) and linear (for continuous outcomes) regression models. Models were adjusted for age, gender, tumour diagnosis (none, benign, malignant), Charlson index, and discharge month.data on 4,233 thyroidectomies were included. There was no difference between pre- and post-intervention trends for the rate of partial thyroidectomies over all thyroidectomies (pre-intervention: IRR 1.00; 95%CI 0.99;1.00 - post-intervention: IRR 1.00; 95%CI 0.98;1.02) and for the rate of diagnosed thyroid cancers over all thyroid tumours (pre-intervention IRR 0.99; 95%CI 0.99;1.00 - post-intervention IRR 1.00; 95%CI 0.99;1.01). On the contrary, the LOS reduced from 4.5 (±4.3) days in 2008 to 3.2 (±3.2) days in 2018. The multivariate analysis confirmed this reduction, estimated to be 1.1 days on average in the pre-intervention eight-year period (pre-intervention coefficient -0.01; 95%CI -0.02;-0.01), followed by an even greater reduction in the post-intervention three-year period which was estimated to be 1.1 day (post-intervention: coefficient -0.03; 95%CI -0.05;-0.01).the implementation of an integrated care model for thyroid disease contributed to reduce the LOS for thyroidectomies, improving the efficiency in the management of thyroid disease. However, this intervention had no impact in reducing the rate of total thyroidectomies.

BackgroundAccumulating evidence links paternal adiposity in the peri-conceptional period to offspring health outcomes. DNA methylation has been proposed as a mediating mechanism, but very few studies have explored this possibility in humans.Methods and findingsIn the Pregnancy And Childhood Epigenetics (PACE) consortium, we conducted a meta-analysis of co-ordinated epigenome-wide association studies (EWAS) of paternal prenatal Body Mass Index (BMI) (with and without adjustment for maternal BMI) in relation to DNA methylation in offspring blood at birth (13 datasets; total n= 4,894) and in childhood (six datasets; total n = 1,982). We found little evidence of association at either time point: for all CpGs, the False Discovery Rate-adjusted P-values were >0.05. In sex-stratified analyses, we found just four CpGs where there was robust evidence of association in female offspring. To compare our findings to those of other studies, we conducted a systematic review, which identified seven studies, including five candidate gene studies showing associations between paternal BMI/obesity and offspring or sperm DNA methylation at imprinted regions. However, in our own study, we found very little evidence of enrichment for imprinted genes.ConclusionOur findings do not support the hypothesis that paternal BMI around the time of pregnancy is associated with offspring blood DNA methylation, even at imprinted regions.Author SummaryPrevious small, mostly candidate gene studies have shown associations between paternal pre-pregnancy BMI and offspring blood DNA methylation. However, in our large meta-analysis of co-ordinated EWAS results from a total of 19 datasets across two timepoints, we found little evidence to support these findings, even at imprinted regions. This does not rule out the possibility of a paternal epigenetic effect in different tissues, at regions not covered by the 450k array, via different mechanisms, or in populations with greater extremes of paternal BMI. More research is warranted to help understand the size and nature of contributions of paternal adiposity to offspring epigenetics and health outcomes.

According to the “Developmental Origins of Health and Disease” (DOHaD) concept, the early-life environment is a critical period for fetal programming. Given the epidemiological evidence that air pollution exposure during pregnancy adversely affects newborn outcomes such as birth weight and preterm birth, there is a need to pay attention to underlying modes of action to better understand not only these air pollution-induced early health effects but also its later-life consequences. In this review, we give an overview of air pollution-induced placental molecular alterations observed in the ENVIRONAGE birth cohort and evaluate the existing evidence. In general, we showed that prenatal exposure to air pollution is associated with nitrosative stress and epigenetic alterations in the placenta. Adversely affected CpG targets were involved in cellular processes including DNA repair, circadian rhythm, and energy metabolism. For miRNA expression, specific air pollution exposure windows were associated with altered miR-20a, miR-21, miR-146a, and miR-222 expression. Early-life aging markers including telomere length and mitochondrial DNA content are associated with air pollution exposure during pregnancy. Previously, we proposed the air pollution-induced telomere-mitochondrial aging hypothesis with a direct link between telomeres and mitochondria. Here, we extend this view with a potential co-interaction of different biological mechanisms on the level of placental oxidative stress, epigenetics, aging, and energy metabolism. Investigating the placenta is an opportunity for future research as it may help to understand the fundamental biology underpinning the DOHaD concept through the interactions between the underlying modes of action, prenatal environment, and disease risk in later life. To prevent lasting consequences from early-life exposures of air pollution, policy makers should get a basic understanding of biomolecular consequences and transgenerational risks. This review is supported by grants from the European Research Council (ERC-2012-StG 310898/POC INCALO) and FWO (G082317 N).

Background: Birthweight reflects in utero exposures and later health evolution. Despite existing studies employing high-dimensional molecular measurements, the understanding of underlying mechanisms of birthweight remains limited. Methods: To investigate the systems biology of birthweight, we integrated methylome, transcriptome, metabolome and a set of inflammatory proteins measured in cord blood samples from four birth-cohorts (n=489). We focused on two sets of 68 metabolites and 903 CpGs previously related to birthweight and investigated the correlation structures existing between these two sets and all the other variables from different groups of omic data via bipartite Pearson correlations. Findings: Results substantiated previously identified biomarkers related to birthweight in cord blood, mostly involved in the regulation of the immune system, and identified new multiple omic features. Three metabolic features [PC(34:2), plasmalogen PC(36:4)/PC(O-36:5), and a compound with m/z of 781.0545], two CpGs (on the DHCR24 and SC4MOL gene), and two proteins (periostin and CCL22), were identified as key signals related to birthweight. Due to importance of the epigenetic signals in cholesterol biosynthesis, we further studied the association of cholesterol levels in cord blood with birthweight in the ENVIRONAGE cohort (n=1,096), finding that the increase of birthweight an was associated with increment of high-density lipoprotein cholesterol. Interpretation: Our data suggested that cholesterol metabolism in cord blood is involved in the birthweight mechanism and that integration of different omic layers is a useful approach to generate new hypotheses about biological mechanisms. Funding Statement: This work is supported by the Bijzonder Onderzoeksfonds (BOF) Hasselt University through a PhD fellowship [to RA], the “EXPOsOMICS” grant [grant number 308610-FP7 European Commission to PV], and the “STOP” grant [grant number 774548-European Commission H2020 to PV]. The ENVIRONAGE birth-cohort is supported by the EU Program “Ideas” (ERC-2012-StG 310898) and the FWO (G082317N). Piccolipiu cohort has been approved and initially funded by the CCM grant 2010 and by the Italian Ministry of Health. Declaration of Interests: The authors declare that they have no conflict of interests. Ethics Approval Statement: Piccolipiu cohort has been approved and initially funded by the CCM grant 2010 and by the Italian Ministry of Health.

In Italy, to show the willingness to donate one's organs, there is the principle of the explicit consensus (or disagreement) (Law n. 91 of the 01.04.1999, Art. 23; Decree of the Italian Health Ministry of the 08.04.2000). According to data of the Italian Association for the donation of organs, tissues and cells (AIDO), in 2017 in Campania Region (Southern Italy) an average of 12.5 people x1,000,000 donated their organs vs. a national average of 23.7. This negative discrepancy between national and regional data highlights that it is imperative to promote awareness-raising measures to address to the population of Campania Region in order to improve the following of a practice which is still object of preconceptions and scarce knowledge. This paper describes a pilot project started in 2017 by the "Sportello amico trapianti" (friendly access to transplantation) to promote the donation of organs within the university-hospital "Federico II" (Naples, Campania Region). The first phase of this project was based on the nudge theory, that is the "little push" to direct decisional processes of groups and individuals. This phase took place during the "Atelier della salute" (a health workshop), organized by the Medicine and Surgery school of the university-hospital "Federico II": here, a questionnaire was administered to 60 people. The questionnaire consisted in 12 questions, answered by volunteers, which aim was to test the general knowledge about organ donation and transplantation. Analysing the answers, a panel of 7 experts (2 epidemiologists, 1 social worker, 2 experts in public and institutional communication, 1 biologist expert in donation of haematopoietic progenitor cell, 1 transplant surgeon), responsible for the coordination and monitoring of the activities, identified the critical elements to bring attention to in order to raise awareness in the population. The second phase consisted in a literary workshop which aim was to identify nudge cases. The text used was Never let me go by Kazuo Ishiguro, a novel focused on organ donation in a dystopic context where the protagonists are clones created to facilitate the donation of organs. Six students participated in this workshop: all six considered the dystopic scenario as a potential nudge to humanize the approach to organ donation and transplant. In conclusion, we believe that the nudge methodology may be used in order to improve awareness and adherence to donation of organs.

recently, healthcare network models have been proposed to improve general awareness of rare diseases for patients and specific knowledge about diagnosis, treatment, and management for healthcare services. Paroxysmal nocturnal hemoglobinuria (PNH) is a rare haematological disease that still has no framing in an official network.to describe the use of network models in diagnosis, treatment, and management of PNH patients both in Italy and abroad and its impact on patients and healthcare service. DISEGN: literature search was performed using the keywords "Hemoglobinuria", "Network", "PHN", and "Screening" in both MedLine and EMBASE. Search was restricted to the articles published in the last 5 years and written in English, French or Italian language.from the total 251 articles of the initial search, only 21 were finally included in our review. None of the included study explicitly described a network model. In general, we were able to identify two different kind of networks implicitly described in the studies: laboratory networks for diagnostic harmonization or screening of the population at risk of PNH (10/21 studies) and PNH registry as network of clinical information to be use for better understanding of the natural history of the disease and to assess therapeutic effectiveness (11/21 studies).few network approaches in PNH diagnosis, treatment, and management are described in literature. Despite the scarce application of the networks, our review highlights the positive impact that networks have in both patients and healthcare services.

PURPOSE OF REVIEW: This systematic review evaluated existing evidence linking air pollution exposure in humans to major epigenetic mechanisms: DNA methylation, microRNAs, long noncoding RNAs, and chromatin regulation. RECENT FINDINGS: Eighty-two manuscripts were eligible, most of which were observational (85%), conducted in adults (66%) and based on DNA methylation (79%). Most observational studies, except panel, demonstrated modest effects of air pollution on the methylome. Panel and experimental studies revealed a relatively large number of significant methylome alterations, though based on smaller sample sizes. Particulate matter levels were positively associated in several studies with global or LINE-1 hypomethylation, a hallmark of several diseases, and with decondensed chromatin structure. Several air pollution species altered the DNA methylation clock, inducing accelerated biological aging. The causal nature of identified associations is not clear, however, especially that most originate from countries with low air pollution levels. Existing evidence, gaps, and perspectives are highlighted herein. ispartof: Curr Environ Health Rep vol:5 issue:4 pages:544-578 ispartof: location:Switzerland status: published

Maternal exposure to airborne particulate matter (PM) has been associated with restricted fetal growth and reduced birthweight. Here, we performed methylome-wide analyses of cord and children's blood DNA in relation to residential exposure to PM smaller than 10 mu m (PM10). This study included participants of the Avon Longitudinal Study of Pregnancy and Childhood (ALSPAC, cord blood, n = 780; blood at age 7, n = 757 and age 15-17, n = 850) and the EXPosOMICS birth cohort consortium including cord blood from ENVIRON-AGE (n = 197), INMA (n = 84), Piccolipiu (n = 99) and Rhea (n = 75). We could not identify significant CpG sites, by meta-analyzing associations between maternal PM10 exposure during pregnancy and DNA methlation in cord blood, nor by studying DNA methylation and concordant annual exposure at 7 and 15-17 years. The CpG cg21785536 was inversly associated with PM10 exposure using a longitudinal model integrating the three studied age groups (-1.2% per 10 mu g/m(3); raw p-value = 3.82 X 10(-8)). Pathway analyses on the corresponding genes of the 100 strongest associated CpG sites of the longitudinal model revealed enriched pathways relating to the GABAergic synapse, p53 signaling and NOTCH1. We provided evidence that residential PM10 exposure in early life affects methylation of the CpG cg21785536 located on the EGF Domain Specific O-Linked N-Acetylglucosamine Transferase gene. This work was carried out within the scope of the European Commission seventh Framework program grant EXPOsOMICS (308610-FP7 to PV). M.P. received support for the was supported by the European Commission seventh Framework program Marie Curie Actions grant (628858). The Centre for Environment and Health is supported by the Medical Research Council and Public Health England (MR/L01341X/1). M.C.-H. acknowledges support from the "Mechanomics" Population Research Committee project (22184). The ENVIRONAGE birth cohort is supported by grants from the European Research Council (ERC-2012-StG310898) and the Flemish Scientific Fund (FWO, 1516112N/G.0873.11.N.10). ARIES was funded by the BBSRC (BBI025751/1 and BB/I025263/1). The ALSPAC study was core-supported by the Medical Research Council, the Wellcome Trust (Grant ref: 102215/2/13/1), and the University of Bristol. Financial support for the generation of DNA methylation data within the ARIES study was provided by MRC, National Institutes for Health. ARIES is maintained and hosted within the MRC Integrative Epidemiology Unit at the University of Bristol (MC_UU_12013/2 and MC_UU_12013/8). Piccolipiu cohort funded by the Italian National Centre for Disease Prevention and Control (CCM grant 2010) and by the Italian Ministry of Health (art 12 and 12bis Dl.gs.vo 502/92). A.G. acknowledges support from Plan Cancer-Eva-Inserm research grant. Piccolipiu cohort acknowledges Andrea Ranzi for his contribution to the assessment of exposure to air pollution.

The term “triangle of death” was used for the first time by Senior and Mazza in the journal The Lancet Oncology referring to the eastern area of the Campania Region (Southern Italy) which has one of the worst records of illegal waste dumping practices. In the past decades, many studies have focused on the potential of illegal waste disposal to cause adverse effects on human health in this area. The great heterogeneity in the findings, and the bias in media communication has generated great healthcare doubts, anxieties and alarm. This paper addresses a review of the up-to-date literature on the “triangle of death”, bringing together the available information on the occurrence and severity of health effects related to illegal waste disposal. The Scopus database was searched using the search terms “waste”, “Campania”, “Naples”, “triangle of death” and “human biomonitoring”. Despite the methodological and sampling heterogeneity between the studies, this review examines the evidence from published data concerning cancer incidence, childhood mortality and birth defects, so that the current situation, knowledge gaps and research priorities can be established. The review aims to provide a contribution to the scientific community, and to respond to the concerns of the general population.

Background Legionellosis’ treatment failures have been recently reported showing the possibility of resistance development to traditional therapy, especially in healthcare related disease cases. Environmental impact of antibiotic residues, especially in hospital waters, may act on the resistome of Legionella resulting in developing resistance mechanisms. Objectives In this study we investigate the antibiotic susceptibility of environmental Legionella pneumophila (Lpn) strains isolated from hospital water systems in Campania, a region located in Southwest Italy. Methods 5321 hospital water samples were investigated for the presence of Lpn. Among positive samples, antibiotic susceptibility was tested for a random subset of 125 Lpn strains (25 Lpn isolates from each of the following serogroups: 1, 3, 5, 6, 8). Susceptibility testing was performed, using the E-test on buffered charcoal yeast extract agar supplemented with α-ketoglutarate, for 10 antimicrobial drugs: azithromycin, cefotaxime, clarithromycin, doxycycline, erythromycin, rifampicin, tigecycline, ciprofloxacin, levofloxacin and moxifloxacin. Non parametric tests were used to determine and assess the significant differences in susceptibility to the different antimicrobics between the serogroups. Results Among the isolated strains, none showed resistance to the antibiotics tested. Rifampicin was the most active antibiotic against overall Legionella strains, followed by levofloxacin. Between the macrolides the clarithromycin was overall the most active drug, instead the azithromycin was the less active. Analyzing the different serogroups a significant difference was found between serogroup 1 and non-1 serogroup isolates for doxycycline and tigecycline. Conclusions Antibiotic susceptibility of environmental isolates of Legionella spp. might be useful for the early detection of resistance to antibiotics that directly impacts on mortality and length of hospital stay.

Background: The epidemiological decrease of Helicobacter pylori (Hp) infection has been recently associated to the increase of several extra-intestinal allergic disorders. Objective: We investigated the role of specific Hp IgG production in the development of IgE or not IgE mediated food allergy (FA) in children affected by atopic dermatitis (AD). Methods: From January 2010 to July 2013, 290 South Italian children, aged between 26 and 142 months, were consecutively referred to the Pediatric Clinic of the Pediatric Department at Second University of Naples and were diagnosed as affected by AD. The patients were classified in two groups on the basis of diagnosis of food allergy (88 FA affected and 202 not FA affected) and further divided on the basis of the diagnosis of atopy (63 IgE mediated and 23 not IgE mediated). Hp serum IgG was detected using an enzyme linked immunosorbent assay (ELISA) kit (Wampole Helicobactor pylori IgG ELISA II, Wampole Laboratories, Cranbury, NJ) and Hp stool antigens using enzyme immunoassay (Premier Platinum HpSa plus, Cincinnati OH). Results: We found a statistically significant higher prevalence of Hp serology positivity in not FA vs. FA AD-affected children (p ¼0.032) and a significant inverse association between FA and Hp immunization (1/OR 0.32 95% CI 0.11–0.95). Further, we identified an absolute prevalence Hp serology positivity in not-IgE-mediated rather than in IgE-mediated FA AD-affected patients (p ¼0.0006). Conclusion: We hypothesize that specific Hp IgG production could protect against the development of both FA and atopy in AD-affected children.

Exposure to chemicals released during urban waste disposal and treatment is increasingly regarded as a potential occupational health issue. Indeed, several toxic metals emitted by an incinerator, including As, Be, Cd, Cr, Pb, Mn, Hg, Ni and V, have potentially toxic properties and their exposure, therefore, may be of concern for the health of the workers involved. The levels of exposure should therefore be carefully measured. Environmental monitoring, however, may be unable, alone, to assess true exposure, due to its intrinsic limitations mainly concerning its inability to assess oral and dermal absorption. In these cases biological monitoring may represent a fundamental supplementary tool for the definition of the workers' true occupational exposure and for the prevention of the related health effects. There is, therefore, an increasing interest in developing and using, in these workers, sensitive and specific biomarkers for health risk assessment, particularly at low or even very low levels of exposure. Despite the large number of original and review articles present in the literature on the biomonitoring of workers exposed to metals, the data on subjects employed in waste treatment activities are scattered and results are sometimes inconsistent. This is the first systematic review, performed according to PRISMA methodology, of the major studies investigating the levels of different toxic metals measured in the main biological matrices (blood, urine, hair) of incinerator workers. The results show that the levels of metals measured in incinerators' workers are generally low, with some notable exceptions for Cd and Pb. These results, though, can be affected by several confounders related either to non-occupational exposure, including diet, area of residence and others, and/or by a number of methodological limitations, as we found in the reported studies. Future work should focus on an integrated approach, using ideally both biological and environmental monitoring. A particular emphasis should be given to the measurement of the different granulometric fractions of the dust containing metals, i.e. inhalable, thoracic, respirable and ultrafine fractions. Moreover, an accurate description of the work tasks and the characteristics and levels of non-occupational exposure should always be provided.

Introduction Birthweight is a known risk factor for diseases in adult life however; the biomolecular mechanisms leading to disease processes remain poorly understood. DNA modifications, transcripts, proteins and metabolites have the potential to imprint biological responses during early life and drive adult risk profiles to chronic conditions. The aim of this study is to enhance the understanding of the complex pathways related to birthweight through integration of multiple OMIC techniques. Methods This study combines methylation (n = 468,408 CpGs), transcriptomics (n = 29,164 transcripts), inflammatory proteins (n = 16) and metabolomics (n = 4712 metabolic features) profiles from cord blood of participants in the EXPOsOMICS birth cohort consortium including ENVIRONAGE (n = 200), INMA (n = 85), Rhea (n = 99) and Piccolipiu (n = 99). We computed Pearson correlation coefficients between pairs of OMICs. Specifically, using a metabolites and methylation driven approaches, we respectively correlated metabolic (n = 68) and epigenetic (n = 8696) signatures of birthweight identified in previous EXPOsOMICS birth cohort study with the other omics platforms. The OMIC platforms have been denoised using technical variables, pairs were considered significant after Bonferroni correction for multiple testing. Significant correlations were visualized in a globe plot with the Circos visualization toolkit version 0.69–6. Transcripts that were significantly correlated to metabolites and to CpGs sites were studied in an overrepresentation analysis (ORA) using DAVID software ( https://www.david.ncifcrf.gov ). Results In the metabolites driven approach, of 33,835,984 correlations between metabolomics and the other levels, 20,097 (0.06%) were significant, mainly inverse (94%) and with a mean absolute correlation coefficient of 0.30 (range = 0.19–0.57). Over the 68 metabolites under study, 13 were significantly correlated with inflammatory proteins, 9 with the transcriptome and 20 with the methylome for a total of 28 unique metabolites. A globe plot of significant correlations showed that all the 9 metabolites were positively correlated with the transcriptome and had an inverse correlation with methylome. Few overlaps (n = 5) were detected in metabolites correlated with both methylome and proteins; the correlations in both pairs went in the same direction (mainly positive). ORA of the 38 genes associated to the significant 41 transcripts resulted in 8 significant pathways, including immune response (such as NK mediated cell cytotoxicity), signaling (MAPK signaling pathway) and also diseases-related (diabetes mellitus and thyroid autoimmunity) pathways. In the methylation driven approach, 0.02% (n = 66,719) of a total 293,606,396 correlations were identified as significant with correlation coefficients having absolute mean of 0.42 (range 0.23–0.69), and mostly negative (67%). Over the 8,663 CpG sites under study, 57 were significantly correlated with proteins, 1,467 with the transcriptome and 2174with the methylome. The globe plot of the significant correlations showed that 13 CpGs appeared in both transcripts and proteins correlation sets, 27 CpGs were common to metabolites and proteins correlation sets, and 791 CpGs were common to metabolites and transcripts correlation sets. Significant correlations in the metabolites and methylation driven approaches shared 34 transcripts, 14 metabolites, 529 CpG sites and 3 proteins. ORA among the 333 genes associated to the 391 unique transcripts significantly correlated to the methylome identified 61 pathways including 4 over the 9 pathways detected in the metabolites driven analysis (including NK mediated cell cytotoxicity and antigen processing and presentation), and also hormone (progesterone-mediated oocyte maturation) and nitrogen metabolism pathways. Conclusion This study provides initial insights into the molecular mechanisms related to birthweight and the biological pathways potentially leading to adverse health effects.

We thank Bifulco [1] for his interest in reading our article and his time in writing his comments on our work [2]. Our response to his concerns are as follows: The diseases studies in the papers that we cited in our Review on the Triangle of Death, and also others we did not include because they did not meet the inclusion criteria (Scopus, etc.), have a long period of latency. Environmental exposure related diseases require a long time before a diagnosis occurs. Diagnosis is made when the diseases ascertained, but latency refers to the length of time it takes from being exposed until when the disease becomes apparent in a clinical examination. Latency can be as short as 10 years or as long as 50, but the average length of latency for the diseases we studied is about 20 years between exposure and diagnosis (average for malignant mesothelioma is 35 to 40 years between exposure and diagnosis). The application of genetics to disease susceptibility moves away from the clinic towards the population, that integrated with the observational methods of epidemiology can potentially support more effective public health measures. The majority of genetic variants or single nucleotide polymorphisms in the human genome are of low penetrance, also for genes involved in metabolism of environmental chemicals, immunity, lipid metabolism, and hemostasis among others. The high prevalence of these single nucleotide polymorphisms means that, despite the low penetrance, they could provide a significant contribution to population disease burden. Exposure-disease associations and the interplay with genetic susceptibility requires further fundamental knowledge and studies on genetic variation, environment, lifestyle, and chronic disease, that are pivotal to provide insights into disease etiology at the population level. In alignment with this vision, Prof. Bifulco reports: “In my opinion, despite preliminary scientific studies suggest a link between hazardous exposure from toxic wastes and cancer occurrence [4], to definitively clarify this point further extensive and analytical studies are required”. Indeed, Barba et al. [3] conclude that currently available evidence suffers from limitations mainly due to study design, lack of consideration of confounders and quality of the exposure data. Despite all the sufferings and the concerns that the many issues and implications linked to the Land of Fires raise, it still provides an invaluable opportunity for research. The characterization of pollution types and sources would support effective and targeted measures to eliminate and reduce associated health risks, contributing to improved health outcomes for the population.

Background Socioeconomic experiences are recognized determinants of health, and recent work has shown that social disadvantages in early life may induce sustained biological changes at molecular level that are detectable later in life. However, the dynamics and persistence of biological embedding of socioeconomic position (SEP) remains vastly unexplored. Methods Using the data from the ALSPAC birth cohort, we performed epigenome-wide association studies of DNA methylation changes at three life stages (birth, n = 914; childhood at mean age 7.5 years, n = 973; and adolescence at mean age 15.5 years, n = 974), measured using the Illumina HumanMethylation450 Beadchip, in relation to pregnancy SEP indicators (maternal and paternal education and occupation). Results Across the four early life SEP metrics investigated, only maternal education was associated with methylation levels at birth, and four CpGs mapped to SULF1, GLB1L2 and RPUSD1 genes were identified [false discovery rate (FDR)-corrected P-value