Concurrent Assessment of Phthalates/HEXAMOLL® DINCH Exposure and Wechsler Intelligence Scale for Children Performance in Three European Cohorts of the HBM4EU Aligned Studies

Information about the effects of phthalates and non-phthalate substitute cyclohexane-1,2-dicarboxylic acid diisononyl ester (HEXAMOLL (R) DINCH) on children's neurodevelopment is limited. The aim of the present research is to evaluate the association between phthalate /HEXAMOLL (R) DINCH exposure and child neurodevelopment in three European cohorts involved in HBM4EU Aligned Studies. Participating subjects were school-aged children belonging to the Northern Adriatic cohort II (NAC-II), Italy, Odense Child Cohort (OCC), Denmark, and PCB cohort, Slovakia. In each cohort, children's neurodevelopment was assessed through the Full-Scale Intelligence Quotient score (FSIQ) of the Wechsler Intelligence Scale of Children test using three different editions. The children's urine samples, collected for one point in time concurrently with the neurodevelopmental evaluation, were analyzed for several phthalates/HEXAMOLL (R) DINCH biomarkers. The relation between phthalates/HEXAMOLL (R) DINCH and FSIQ was explored by applying separate multiple linear regressions in each cohort. The means and standard deviations of FSIQ were 109 +/- 11 (NAC-II), 98 +/- 12 (OCC), and 81 +/- 15 (PCB cohort). In NAC-II, direct associations between FSIQ and DEHP's biomarkers were found: 50H-MEHP+5oxo-MEHP ((3 = 2.56; 95% CI 0.58-4.55; N = 270), 50H-MEHP+5cx-MEPP (beta = 2.48; 95% CI 0.47-4.49; N = 270) and 5OH-MEHP (beta = 2.58; 95% CI 0.65-4.51; N = 270). On the contrary, in the OCC the relation between DEHP's biomarkers and FSIQ tended to be inverse but imprecise (p-value >= 0.10). No associations were found in the PCB cohort. FSIQ was not associated with HEXAMOLL (R) DINCH in any cohort. In conclusion, these results do not provide evidence of an association between concurrent phthalate/DINCHHEXAMOLLR DINCH exposure and IQ in children.European Commission 733032 European Union through its Sixth Framework Program for RTD FOOD-CT-2006-016253Institute for Maternal and Child Health IRCCS "Burlo Garofolo", Trieste, Italy (Ministry of Health-Italy) RC 12/12CROME LIFE Project "Cross-Mediterranean Environment and Health Network" LIFE12 ENV/GR/001040Odense University Hospital, DenmarkUniversity of Southern Denmark Mental Health Service of the Region of Southern Denmark Odense Patient data Exploratory Network (OPEN), Denmark Danish Center for Hormone Disrupting Chemicals MST-611-00012Det Frie Forskningsrad (DFF) 4004-00352B_FSSNovo Nordisk Foundation NNF19OC0058266 NNF17OC0029404Sygeforsikring Danmark 2021-0173Odense University HospitalHelsefonden BeckettfondenDanish Mental Health FundHealth Insurance DenmarkVelux FondenSlovak Research and Development Agency APVV-0571-12Ministry of Health of the Slovak Republic 2014/47-SZU-11Region of Southern Denmark, The Municipality of Odense, DenmarkRigshospitale

Heparanase activity in alveolar and embryonal rhabdomyosarcoma: implications for tumor invasion

<p>Abstract</p> <p>Background</p> <p>Rhabdomyosarcoma (RMS) is a malignant soft tissue sarcoma of childhood including two major histological subtypes, alveolar (ARMS) and embryonal (ERMS) RMS. Like other human malignancies RMS possesses high metastatic potential, more pronounced in ARMS than in ERMS. This feature is influenced by several biological molecules, including soluble factors secreted by tumor cells, such as heparanase (HPSE). HPSE is an endo-β-D-glucuronidase that cleaves heparan sulphate proteoglycans.</p> <p>Methods</p> <p>We determined HPSE expression by Western blot analysis in ARMS and ERMS cells lines and activity in supernatants by an ELISA assay. Stable <it>HPSE </it>silencing has been performed by shRNA technique in RH30 and RD cell lines and their invasiveness has been evaluated by Matrigel-invasion assay. HPSE activity and mRNA expression have also been quantified in plasma and biopsies from RMS patients.</p> <p>Results</p> <p>HPSE expression and activity have been detected in all RMS cell lines. Stable <it>HPSE </it>silencing by shRNA technique determined a significant knockdown of gene expression equal to 76% and 58% in RH30 and RD cell lines respectively and induced a less invasive behaviour compared to untreated cells. Finally, we observed that <it>HPSE </it>mRNA expression in biopsies was higher than in foetal skeletal muscle and that plasma from RMS patients displayed significantly more elevated HPSE levels than healthy subjects with a trend to higher levels in ARMS.</p> <p>Conclusion</p> <p>In conclusion, our data demonstrate for the first time HPSE expression and activity in RMS and highlight its involvement in tumor cell invasion as revealed by shRNA silencing. Moreover, HPSE expression in RMS patients is significantly higher with respect to healthy subjects. Further studies are warranted to assess possible relationships between HPSE and clinical behaviour in RMS.</p

ADHD symptoms and school impairment history in parents of ADHD children are a fundamental diagnostic and therapeutic clue

Background Attention Deficit and Hyperactivity Disorder (ADHD) is a multi-factorial condition, with inheritance playing a major role. Recognizing parents' ADHD represents a clue not only for an earlier diagnosis of the disease in their children, but also to optimize psycho-educational therapy outcomes, by addressing the impairment of parenting related to untreated ADHD. This study aimed to assess the frequency of features suggestive of ADHD during childhood among parents of affected children, and the presence of school and emotional impairment. Methods We administered the Wender Utah Rating Scale-25, a self-assessment tool for the retrospective identification of symptoms consistent with ADHD during childhood, to a cohort of 120 parents of 60 children with ADHD, and to a consistent number of "controls". Results The WURS-25 proved positive in 49.1% of fathers and 30.0% of mothers of ADHD patients, compared to 1.7% of fathers and 1.7% of mothers of non-ADHD patients (p &lt; 0.0001). The questions addressing learning and emotional impairment provided significantly higher scores in parents with an overall positive test compared to those with negative test (p &lt; 0.0001). Conclusions This study demonstrates a remarkably high rate of symptoms consistent with ADHD during childhood in parents of affected children. Physicians should be aware that this is a relevant anamnestic clue and, given the relevance of parents' role in the management of children with ADHD, an important issue to address in order to optimize patients' treatment

Impatto dell’epidemia da COVID-19 in Friuli Venezia Giulia: Valutazione dei fattori associati al rischio di decesso mediante l’analisi dei rischi competitivi /Impact of the COVID-19 epidemic in Friuli Venezia Giulia Region (Northern Italy): assessment of factors associated with the risk of death by competing risks analysis

OBJECTIVES: To investigate the role of gender, age, province of residence, and nursing home residency on the risk of death for residents in the Friuli Venezia Giulia (FVG) Region (Northern Italy) tested positive for COVID-19, considering recovery as a competing event. The secondary objective is to describe the impact of the COVID-19 epidemic in FVG and in the Regions of Northern and Central Italy in terms of incidence and mortality compared to the national data. DESIGN: Retrospective cohort study. SETTING AND PARTICIPANTS: Resident population in FVG in the period between 29 February and 25 June 2020. MAIN OUTCOME MEASURES: In order to describe the impact of the COVID-19 outbreak in FVG, in terms of incidence and mortality compared to the national data, the standardized incidence (SIR) and mortality (SMR) ratios and their respective 95 confidence intervals (95CI) were calculated compared to the Italian population for the northern and central Regions of Italy and the autonomous Provinces (PA) of Trento and Bolzano. A retrospective cohort study was conducted on subjects residing in FVG to whom at least one naso-oropharyngeal swab (hereafter, named swab) resulted positive for COVID-19. For each subject included in the cohort, the observation period started with the first positive swab and ended with the first of the following events: Death, recovery or censored, which means that at the end of the observation period the subject was still alive and positive. The cause of death was assigned to COVID-19 if a subject had not yet recovered at the time when the event occurred. Cohort members were considered recovered after two negative consecutive swabs. The sub-hazard ratio (SHR) was estimated by applying the regression model of competing risks by Fine and Gray, in which the event of interest was the death caused by COVID-19 and the competing event was recovery. The explanatory variables included in the multiple models are: Gender, age at the beginning of the observation period, the Province of residence, and nursing home residency

Impact of methylmercury and other heavy metals exposure on neurocognitive function in children of 7 years old: study protocol of the follow-up

BACKGROUND: The extent to which prenatal low-level mercury (Hg) exposure through maternal fish intake and heavy metals exposure affect children neurodevelopment is controversial and may appear in long term. In 2007 a prospective cohort, the Northern Adriatic Cohort II (NAC-II), was established to investigate the association between prenatal Hg exposure from maternal fish consumption and child neurodevelopment. 900 pregnant women were enrolled. 632 and 470 children underwent neurodevelopmental evaluation, respectively, at 18 and 40 months of age. The NAC-II cohort is a part of the Mediterranean cohort in "Public health impact of long-term, low-level, mixed element exposure in susceptible population strata" project.METHODS: This protocol describes the follow-up assessment of the effects of prenatal low level Hg and other heavy metals exposure on the developing nervous system of the children born within the NAC-II and reached the age of 7 years. Child diet components are estimated through a Diet Diary. Child hair and urine are collected for determination of Hg level. In addition, levels of other potentially neurotoxic metals, namely Manganese, Cadmium, Lead, Arsenic and Selenium are also measured in the same matrices.DiscussionThis protocol extends to the first years of schooling age the evaluation of the neurotoxicant effect of Mercury and of the other heavy metals on children's neurodevelopment, adjusting for the potential confounders such as the lifestyles and the social economic status of children's families. Longitudinal analysis of neurodevelopment, assessed in different ages (18, 40 months and 7 years), are performed

Trends of Exposure to Acrylamide as Measured by Urinary Biomarkers Levels within the HBM4EU Biomonitoring Aligned Studies (2000–2021)

This article belongs to the Special Issue Analysis of Human Biomonitoring Data and Risk Assessment of Human Exposure to Environmental Chemicals: What Do We Learn for Prevention?Acrylamide, a substance potentially carcinogenic in humans, represents a very prevalent contaminant in food and is also contained in tobacco smoke. Occupational exposure to higher concentrations of acrylamide was shown to induce neurotoxicity in humans. To minimize related risks for public health, it is vital to obtain data on the actual level of exposure in differently affected segments of the population. To achieve this aim, acrylamide has been added to the list of substances of concern to be investigated in the HBM4EU project, a European initiative to obtain biomonitoring data for a number of pollutants highly relevant for public health. This report summarizes the results obtained for acrylamide, with a focus on time-trends and recent exposure levels, obtained by HBM4EU as well as by associated studies in a total of seven European countries. Mean biomarker levels were compared by sampling year and time-trends were analyzed using linear regression models and an adequate statistical test. An increasing trend of acrylamide biomarker concentrations was found in children for the years 2014–2017, while in adults an overall increase in exposure was found to be not significant for the time period of observation (2000–2021). For smokers, represented by two studies and sampling for, over a total three years, no clear tendency was observed. In conclusion, samples from European countries indicate that average acrylamide exposure still exceeds suggested benchmark levels and may be of specific concern in children. More research is required to confirm trends of declining values observed in most recent years.This work received external funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No. 733032 and received co-funding from the author’s organizations. The Norwegian Institute of Public Health (NIPH) contributed to the funding of the Norwegian Environmental Biobank (NEB). The laboratory measurements were partly funded by the Research Council of Norway through research projects (275903 and 268465).info:eu-repo/semantics/publishedVersio

Concurrent Assessment of Phthalates/HEXAMOLL® DINCH Exposure and Wechsler Intelligence Scale for Children Performance in Three European Cohorts of the HBM4EU Aligned Studies

Information about the effects of phthalates and non-phthalate substitute cyclohexane-1,2-dicarboxylic acid diisononyl ester (HEXAMOLL® DINCH) on children's neurodevelopment is limited. The aim of the present research is to evaluate the association between phthalate/HEXAMOLL® DINCH exposure and child neurodevelopment in three European cohorts involved in HBM4EU Aligned Studies. Participating subjects were school-aged children belonging to the Northern Adriatic cohort II (NAC-II), Italy, Odense Child Cohort (OCC), Denmark, and PCB cohort, Slovakia. In each cohort, children's neurodevelopment was assessed through the Full-Scale Intelligence Quotient score (FSIQ) of the Wechsler Intelligence Scale of Children test using three different editions. The children's urine samples, collected for one point in time concurrently with the neurodevelopmental evaluation, were analyzed for several phthalates/HEXAMOLL® DINCH biomarkers. The relation between phthalates/HEXAMOLL® DINCH and FSIQ was explored by applying separate multiple linear regressions in each cohort. The means and standard deviations of FSIQ were 109 ± 11 (NAC-II), 98 ± 12 (OCC), and 81 ± 15 (PCB cohort). In NAC-II, direct associations between FSIQ and DEHP's biomarkers were found: 5OH-MEHP+5oxo-MEHP (β = 2.56; 95% CI 0.58-4.55; N = 270), 5OH-MEHP+5cx-MEPP (β = 2.48; 95% CI 0.47-4.49; N = 270) and 5OH-MEHP (β = 2.58; 95% CI 0.65-4.51; N = 270). On the contrary, in the OCC the relation between DEHP's biomarkers and FSIQ tended to be inverse but imprecise (p-value ≥ 0.10). No associations were found in the PCB cohort. FSIQ was not associated with HEXAMOLL® DINCH in any cohort. In conclusion, these results do not provide evidence of an association between concurrent phthalate/DINCHHEXAMOLLR DINCH exposure and IQ in children.This work received external funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No. 733032 [“European Human Biomonitoring Initiative” (HBM4EU)] and received co-funding from the author’s organizations. NAC-II: This research was funded by: the European Union through its Sixth Framework Program for RTD (contract “PHIME” No. FOOD-CT-2006-016253); the Institute for Maternal and Child Health IRCCS “Burlo Garofolo”, Trieste, Italy (RC 12/12 funded by Ministry of Health—Italy); CROME LIFE Project “Cross-Mediterranean Environment and Health Network” (LIFE12 ENV/GR/001040). OCC: The cohort was funded by the Odense University Hospital, Denmark; the Region of Southern Denmark, The Municipality of Odense, Denmark; The University of Southern Denmark; the Mental Health Service of the Region of Southern Denmark; Odense Patient data Exploratory Network (OPEN), Den mark; The Danish Center for Hormone Disrupting Chemicals (MST-611-00012); The Danish Research Council (4004-00352B_FSS); Novo Nordisk Foundation, Denmark (grant no. NNF19OC0058266 and NNF17OC0029404); Sygeforsikring Danmark (journalnr. 2021-0173); The Collaborative foundation between Odense University Hospital and Rigshospitalet, Helsefonden, Beckettfonden, the Danish Mental Health Fund, Health Insurance Denmark. The LS-MS/MS equipment was financially supported by the Velux Foundation. PCB: PCB cohort was funded by the Slovak Research and Development Agency, project no. APVV-0571-12 and the Ministry of Health of the Slovak Republic, project no. 2014/47-SZU-11. The APC was funded by the European Union’s Horizon 2020 research and innovation program under grant agreement No. 733032.S

Time Trends of Acrylamide Exposure in Europe: Combined Analysis of Published Reports and Current HBM4EU Studies

This article belongs to the Special Issue Analysis of Human Biomonitoring Data and Risk Assessment of Human Exposure to Environmental Chemicals: What Do We Learn for Prevention?More than 20 years ago, acrylamide was added to the list of potential carcinogens found in many common dietary products and tobacco smoke. Consequently, human biomonitoring studies investigating exposure to acrylamide in the form of adducts in blood and metabolites in urine have been performed to obtain data on the actual burden in different populations of the world and in Europe. Recognizing the related health risk, the European Commission responded with measures to curb the acrylamide content in food products. In 2017, a trans-European human biomonitoring project (HBM4EU) was started with the aim to investigate exposure to several chemicals, including acrylamide. Here we set out to provide a combined analysis of previous and current European acrylamide biomonitoring study results by harmonizing and integrating different data sources, including HBM4EU aligned studies, with the aim to resolve overall and current time trends of acrylamide exposure in Europe. Data from 10 European countries were included in the analysis, comprising more than 5500 individual samples (3214 children and teenagers, 2293 adults). We utilized linear models as well as a non-linear fit and breakpoint analysis to investigate trends in temporal acrylamide exposure as well as descriptive statistics and statistical tests to validate findings. Our results indicate an overall increase in acrylamide exposure between the years 2001 and 2017. Studies with samples collected after 2018 focusing on adults do not indicate increasing exposure but show declining values. Regional differences appear to affect absolute values, but not the overall time-trend of exposure. As benchmark levels for acrylamide content in food have been adopted in Europe in 2018, our results may imply the effects of these measures, but only indicated for adults, as corresponding data are still missing for children.This work has received external funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No. 733032 and received co-funding from the author’s organizations. The Norwegian Institute of Public Health (NIPH) has contributed to the funding of the Norwegian Environmental Biobank (NEB). The laboratory measurements have partly been funded by the Research Council of Norway through research projects (275903 and 268465).info:eu-repo/semantics/publishedVersio

EU-wide exposure data of 11 chemical substance groups from the HBM4EU Aligned Studies (2014–2021)

Funding Information: The authors would like to thank everybody who contributed to the HBM4EU Aligned Studies: the participating children, teenagers, adults and their families, the fieldworkers that collected the samples and database managers that made the information available to HBM4EU, the HBM4EU project partners, especially those from WP7 for developing all materials supporting the fieldwork, WP9 for organizing the QA/QC scheme under HBM4EU and all laboratories who performed the analytical measurements. We would like to acknowledge Sun Kyoung Jung from the National Institute of Environmental Research of South-Korea for providing the KoNEHS Cycle III results (crt adjusted). HBM4EU is co-financed under Horizon 2020 (grant agreement No 733032). The authors thank all principal investigators of the contributing studies for their participation and contribution to the HBM4EU Aligned Studies and the national program owners for their financial support. Further details on funding for all the participating studies can be found in the Supplemental Material, Table S12.As one of the core elements of the European Human Biomonitoring Initiative (HBM4EU) a human biomonitoring (HBM) survey was conducted in 23 countries to generate EU-wide comparable HBM data. This survey has built on existing HBM capacity in Europe by aligning national or regional HBM studies, referred to as the HBM4EU Aligned Studies. The HBM4EU Aligned Studies included a total of 10,795 participants of three age groups: (i) 3,576 children aged 6–12 years, (ii) 3,117 teenagers aged 12–18 years and (iii) 4,102 young adults aged 20–39 years. The participants were recruited between 2014 and 2021 in 11–12 countries per age group, geographically distributed across Europe. Depending on the age group, internal exposure to phthalates and the substitute DINCH, halogenated and organophosphorus flame retardants, per- and polyfluoroalkyl substances (PFASs), cadmium, bisphenols, polycyclic aromatic hydrocarbons (PAHs), arsenic species, acrylamide, mycotoxins (deoxynivalenol (total DON)), benzophenones and selected pesticides was assessed by measuring substance specific biomarkers subjected to stringent quality control programs for chemical analysis. For substance groups analyzed in different age groups higher average exposure levels were observed in the youngest age group, i.e., phthalates/DINCH in children versus teenagers, acrylamide and pesticides in children versus adults, benzophenones in teenagers versus adults. Many biomarkers in teenagers and adults varied significantly according to educational attainment, with higher exposure levels of bisphenols, phthalates, benzophenones, PAHs and acrylamide in participants (from households) with lower educational attainment, while teenagers from households with higher educational attainment have higher exposure levels for PFASs and arsenic. In children, a social gradient was only observed for the non-specific pyrethroid metabolite 3-PBA and di-isodecyl phthalate (DiDP), with higher levels in children from households with higher educational attainment. Geographical variations were seen for all exposure biomarkers. For 15 biomarkers, the available health-based HBM guidance values were exceeded with highest exceedance rates for toxicologically relevant arsenic in teenagers (40%), 3-PBA in children (36%), and between 11 and 14% for total DON, Σ (PFOA + PFNA + PFHxS + PFOS), bisphenol S and cadmium. The infrastructure and harmonized approach succeeded in obtaining comparable European wide internal exposure data for a prioritized set of 11 chemical groups. These data serve as a reference for comparison at the global level, provide a baseline to compare the efficacy of the European Commission's chemical strategy for sustainability and will give leverage to national policy makers for the implementation of targeted measures.publishersversionpublishe

Harmonized human biomonitoring in European children, teenagers and adults: EU-wide exposure data of 11 chemical substance groups from the HBM4EU Aligned Studies (2014–2021)

HBM4EU is co-financed under Horizon 2020 (grant agreement No 733032).As one of the core elements of the European Human Biomonitoring Initiative (HBM4EU) a human biomonitoring (HBM) survey was conducted in 23 countries to generate EU-wide comparable HBM data. This survey has built on existing HBM capacity in Europe by aligning national or regional HBM studies, referred to as the HBM4EU Aligned Studies. The HBM4EU Aligned Studies included a total of 10,795 participants from three age groups: (i) 3,576 children aged 6-12 years, (ii) 3,117 teenagers aged 12-18 years, and (iii) 4,102 young adults aged 20-39 years. The participants were recruited between 2014 and 2021 in 11-12 countries per age group, geographically distributed across Europe. Depending on the age group, internal exposure to phthalates and the substitute DINCH, halogenated and organophosphorus flame retardants, per- and polyfluoroalkyl substances (PFASs), cadmium, bisphenols, polycyclic aromatic hydrocarbons (PAHs), arsenic species, acrylamide, mycotoxins (deoxynivalenol (total DON)), benzophenones and selected pesticides was assessed by measuring substance specific biomarkers subjected to stringent quality control programs for chemical analysis. For substance groups analyzed in different age groups higher average exposure levels were observed in the youngest age group, i.e., phthalates/DINCH in children versus teenagers, acrylamide and pesticides in children versus adults, and benzophenones in teenagers versus adults. Many biomarkers in teenagers and adults varied significantly according to educational attainment, with higher exposure levels of bisphenols, phthalates, benzophenones, PAHs, and acrylamide in participants (from households) with lower educational attainment, while teenagers from households with higher educational attainment have higher exposure levels for PFASs and arsenic. In children, a social gradient was only observed for the non-specific pyrethroid metabolite 3-PBA and di-isodecyl phthalate (DiDP), with higher levels in children from households with higher educational attainment. Geographical variations were seen for all exposure biomarkers. For 15 biomarkers, the available health-based HBM guidance values were exceeded with the highest exceedance rates for toxicologically relevant arsenic in teenagers (40%), 3-PBA in children (36%), and between 11 and 14% for total DON, Σ (PFOA + PFNA + PFHxS + PFOS), bisphenol S and cadmium. The infrastructure and harmonized approach succeeded in obtaining comparable European-wide internal exposure data for a prioritized set of 11 chemical groups. These data serve as a reference for comparison at the global level, provide a baseline to compare the efficacy of the European Commission's chemical strategy for sustainability, and will give leverage to national policymakers for the implementation of targeted measures.info:eu-repo/semantics/publishedVersio