Examining potential Long COVID effects through utilization of healthcare resources: a retrospective, population-based, matched cohort study comparing individuals with and without prior SARS-CoV-2 infection.

BACKGROUND: A significant proportion of individuals reports persistent clinical manifestations following SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) acute infection. Nevertheless, knowledge of the burden of this condition-often referred to as 'Long COVID'-on the health care system remains limited. This study aimed to evaluate healthcare utilization potentially related to Long COVID. METHODS: Population-based, retrospective, multi-center cohort study that analyzed hospital admissions and utilization of outpatient visits and diagnostic tests between adults aged 40 years and older recovered from SARS-CoV-2 infection occurred between February 2020 and December 2021 and matched unexposed individuals during a 6-month observation period. Healthcare utilization was analyzed by considering the setting of care for acute SARS-CoV-2 infection [non-hospitalized, hospitalized and intensive care unit (ICU)-admitted] as a proxy for the severity of acute infection and epidemic phases characterized by different SARS-CoV-2 variants. Data were retrieved from regional health administrative databases of three Italian Regions. RESULTS: The final cohort consisted of 307 994 previously SARS-CoV-2 infected matched with 307 994 uninfected individuals. Among exposed individuals, 92.2% were not hospitalized during the acute infection, 7.3% were hospitalized in a non-ICU ward and 0.5% were admitted to ICU. Individuals previously infected with SARS-CoV-2 (vs. unexposed), especially those hospitalized or admitted to ICU, reported higher utilization of outpatient visits (range of pooled Incidence Rate Ratios across phases; non-hospitalized: 1.11-1.33, hospitalized: 1.93-2.19, ICU-admitted: 3.01-3.40), diagnostic tests (non-hospitalized: 1.35-1.84, hospitalized: 2.86-3.43, ICU-admitted: 4.72-7.03) and hospitalizations (non-hospitalized: 1.00-1.52, hospitalized: 1.87-2.36, ICU-admitted: 4.69-5.38). CONCLUSIONS: This study found that SARS-CoV-2 infection was associated with increased use of health care in the 6 months following infection, and association was mainly driven by acute infection severity.

Clinical Outcomes of Thermal Ablation Re-Treatment of Benign Thyroid Nodules: A Multicenter Study from the Italian Minimally Invasive Treatments of the Thyroid Group.

Background: Thermal ablation (TA) is an established therapeutic option alternative to surgery in patients with solid benign thyroid nodules causing local symptoms. However, a variable part of thyroid nodules remain viable after these nonsurgical treatments, and as many as 15% of nodules treated with TA may require a second treatment over time. This study aimed to evaluate the outcomes of TA re-treatment on symptomatic benign thyroid nodules where the volume decreased by <50% after the first procedure ( = technique inefficacy). Methods: We performed a multicenter retrospective cohort study including patients who underwent re-treatment with TA for benign thyroid nodules, whose volume decreased by <50% after initial treatment. The primary aim was to evaluate volume and volume reduction ratio (VRR) over time and compare the 6- and 12-month VRR after first versus second treatment. The secondary aim was to identify protective or risk factors for technique inefficacy, regrowth, and further treatments, expressed as adjusted hazard ratios (HRs) and confidence interval [CI], after adjustment for sex, age, nodule volume, structure and function, nodule regrowth or symptom relapse, technique used and if the same technique was used for the first and second TA and time between them. Results: We included 135 patients. Re-treatment led to VRR of 50% and 52.2% after 6 and 12 months. VRR after re-treatment was greater than after first treatment in small and medium size nodules (<30 mL), while there were no differences for large nodules (>30 mL). After re-treatment technique inefficacy rate was 51.9%, regrowth rate was 12.6%, and further treatment rate was 15.6%. Radiofrequency ablation (RFA) was protective toward technique inefficacy (HR = 0.40 [CI 0.24-0.65]) and need of further treatments (HR = 0.30 [CI 0.12-0.76]). Large nodule volume (>30 mL) was associated with increased risk of re-treatment (HR = 4.52 [CI 1.38-14.82]). Conclusions: This is the first study evaluating the outcomes of re-treatment on symptomatic benign thyroid nodules with a VRR <50% after the initial TA treatment. Best results were seen in small and medium nodules (<30 mL) and after RFA. Prospective confirmatory studies are needed.

Determinants of exposure to acrylamide in European children and adults based on urinary biomarkers: results from the "European Human Biomonitoring Initiative" HBM4EU participating studies.

Little is known about exposure determinants of acrylamide (AA), a genotoxic food-processing contaminant, in Europe. We assessed determinants of AA exposure, measured by urinary mercapturic acids of AA (AAMA) and glycidamide (GAMA), its main metabolite, in 3157 children/adolescents and 1297 adults in the European Human Biomonitoring Initiative. Harmonized individual-level questionnaires data and quality assured measurements of AAMA and GAMA (urine collection: 2014-2021), the short-term validated biomarkers of AA exposure, were obtained from four studies (Italy, France, Germany, and Norway) in children/adolescents (age range: 3-18 years) and six studies (Portugal, Spain, France, Germany, Luxembourg, and Iceland) in adults (age range: 20-45 years). Multivariable-adjusted pooled quantile regressions were employed to assess median differences (ß coefficients) with 95% confidence intervals (95% CI) in AAMA and GAMA (µg/g creatinine) in relation to exposure determinants. Southern European studies had higher AAMA than Northern studies. In children/adolescents, we observed significant lower AA associated with high socioeconomic status (AAMA:ß = - 9.1 µg/g creatinine, 95% CI - 15.8, - 2.4; GAMA: ß = - 3.4 µg/g creatinine, 95% CI - 4.7, - 2.2), living in rural areas (AAMA:ß = - 4.7 µg/g creatinine, 95% CI - 8.6, - 0.8; GAMA:ß = - 1.1 µg/g creatinine, 95% CI - 1.9, - 0.4) and increasing age (AAMA:ß = - 1.9 µg/g creatinine, 95% CI - 2.4, - 1.4; GAMA:ß = - 0.7 µg/g creatinine, 95% CI - 0.8, - 0.6). In adults, higher AAMA was also associated with high consumption of fried potatoes whereas lower AAMA was associated with higher body-mass-index. Based on this large-scale study, several potential determinants of AA exposure were identified in children/adolescents and adults in European countries.

COVID-19 vaccination effectiveness in the population of Friuli Venezia Giulia, North-East Italy. Control of bias associated with divergent compliance to policies in a test-negative case-control study.

BACKGROUND: Vaccine effectiveness (VE) studies consolidate knowledge of real-world effectiveness in different contexts. However, methodological issues may undermine their conclusions: to assess the VE against COVID-19 within the Italian population, a specific threat to validity is related to the consequences of divergent compliance to the Green Pass policy. METHODS: To address this challenge we conducted a test negative case-control (TNCC) study and multiple sensitivity analysis among residents aged ≥ 12 in Friuli Venezia Giulia Region (FVG), North-east Italy, from February 1, 2021 to March 31, 2022. Information regarding 211,437 cases of COVID-19 infection and 845,748 matched controls was obtained from the regional computerized health database. The investigation considered: COVID-19 infection, hospitalization, and death. Multiple conditional logistic regressions adjusted for covariates were performed and VE was estimated as (1-OR COVID-19vaccinated vs. unvaccinated)x100. Mediation analyses were carried out to offset potential collider variables, particularly, the number of swabs performed after the introduction of pandemic restrictions. RESULTS: Full-cycle VE against infection decreased from 96% (95% CI: 96, 97) in the Alpha period to 43% (95% CI: 42, 45) in the Omicron period. Booster dose raised the protection in Omicron period to 67% (95% CI: 66, 67). Against the evasive Omicron variant, the protection of the booster dose was 87% (95% CI: 83, 90) for hospitalization and 90% (95% CI: 82, 95) for death. The number of swabs performed was included as a covariate in the adjustments, and the mediation analysis confirmed that it was a strong mediator between vaccination and COVID-19-related outcomes. CONCLUSIONS: The study suggests that, under similar TNCC settings, mediation analysis and adjustment for number of diagnostic tests should be included, as an effective approach to the challenge of differential testing behavior that may determine substantial selection bias. This correction allowed us to align with results from other studies that show how full-cycle VE against infection was initially high but decreased over time by variant circulation, counterbalanced by booster dose that raised protection across variants and outcome severity.

Cognitive Performance and Exposure to Organophosphate Flame Retardants in Children: Evidence from a Cross-Sectional Analysis of Two European Mother-Child Cohorts.

The knowledge of the effects of organophosphate flame retardants on children's neurodevelopment is limited. The purpose of the present research is to evaluate the association between exposure to organophosphate flame retardants and children's neurodevelopment in two European cohorts involved in the Human Biomonitoring Initiative Aligned Studies. The participants were school-aged children belonging to the Odense Child Cohort (Denmark) and the PCB cohort (Slovakia). In each cohort, the children's neurodevelopment was assessed through the Full-Scale Intelligence Quotient score of the Wechsler Intelligence Scale for Children, using two different editions. The children's urine samples, collected at one point in time, were analyzed for several metabolites of organophosphate flame retardants. The association between neurodevelopment and each organophosphate flame retardant metabolite was explored by applying separate multiple linear regressions based on the approach of MM-estimation in each cohort. In the Danish cohort, the mean ± standard deviation for the neurodevelopment score was 98 ± 12; the geometric mean (95% confidence interval (95% CI)) of bis(1,3-dichloro-2-propyl) phosphate (BDCIPP) standardized by creatinine (crt) was 0.52 µg/g crt (95% CI = 0.49; 0.60), while that of diphenyl phosphate (DPHP) standardized by crt was 1.44 µg/g crt (95% CI = 1.31; 1.58). The neurodevelopment score showed a small, negative, statistically imprecise trend with BDCIPP standardized by crt (ß = -1.30; 95%CI = -2.72; 0.11; p-value = 0.07) and no clear association with DPHP standardized by crt (ß = -0.98; 95%CI = -2.96; 0.99; p-value = 0.33). The neurodevelopment score showed a negative trend with BDCIPP (ß = -1.42; 95% CI = -2.70; -0.06; p-value = 0.04) and no clear association with DPHP (ß = -1.09; 95% CI = -2.87; 0.68; p-value = 0.23). In the Slovakian cohort, the mean ± standard deviation for the neurodevelopment score was 81 ± 15; the geometric mean of BDCIPP standardized by crt was 0.18 µg/g crt (95% CI = 0.16; 0.20), while that of DPHP standardized by crt was 2.24 µg/g crt (95% CI = 2.00; 3.52). The association of the neurodevelopment score with BDCIPP standardized by crt was -0.49 (95%CI = -1.85; 0.87; p-value = 0.48), and with DPHP standardized by crt it was -0.35 (95%CI = -1.90; 1.20; p-value = 0.66). No clear associations were observed between the neurodevelopment score and BDCIPP/DPHP concentrations that were not standardized by crt. No clear associations were observed with bis(1-chloro-2-propyl) phosphate (BCIPP) in either cohort, due to the low detection frequency of this compound. In conclusion, this study provides only limited evidence of an inverse association between neurodevelopment and exposure to BDCIPP and DPHP. The timing of exposure and effect modification of other organophosphate flame retardant metabolites and other substances should be the subject of further investigations that address this scientific hypothesis.

Current exposure to phthalates and DINCH in European children and adolescents - Results from the HBM4EU Aligned Studies 2014 to 2021.

Phthalates are mainly used as plasticizers for polyvinyl chloride (PVC). Exposure to several phthalates is associated with different adverse effects most prominently on the development of reproductive functions. The HBM4EU Aligned Studies (2014-2021) have investigated current European exposure to ten phthalates (DEP, BBzP, DiBP, DnBP, DCHP, DnPeP, DEHP, DiNP, DiDP, DnOP) and the substitute DINCH to answer the open policy relevant questions which were defined by HBM4EU partner countries and EU institutions as the starting point of the programme. The exposure dataset includes ∼5,600 children (6-11 years) and adolescents (12-18 years) from up to 12 countries per age group and covering the North, East, South and West European regions. Study data from participating studies were harmonised with respect to sample size and selection of participants, selection of biomarkers, and quality and comparability of analytical results to provide a comparable perspective of European exposure. Phthalate and DINCH exposure were deduced from urinary excretions of metabolites, where concentrations were expressed as their key descriptor geometric mean (GM) and 95th percentile (P95). This study aims at reporting current exposure levels and differences in these between European studies and regions, as well as comparisons to human biomonitoring guidance values (HBM-GVs). GMs for children were highest for ∑DEHP metabolites (33.6 µg/L), MiBP (26.6 µg/L), and MEP (24.4 µg/L) and lowest for∑DiDP metabolites (1.91 µg/L) and ∑DINCH metabolites (3.57 µg/L). In adolescents highest GMs were found for MEP (43.3 µg/L), ∑DEHP metabolites (28.8 µg/L), and MiBP (25.6 µg/L) and lowest for ∑DiDP metabolites (= 2.02 µg/L) and ∑DINCH metabolites (2.51 µg/L). In addition, GMs and P95 stratified by European region, sex, household education level, and degree of urbanization are presented. Differences in average biomarker concentrations between sampling sites (data collections) ranged from factor 2 to 9. Compared to the European average, children in the sampling sites OCC (Denmark), InAirQ (Hungary), and SPECIMEn (The Netherlands) had the lowest concentrations across all metabolites and ESTEBAN (France), NAC II (Italy), and CROME (Greece) the highest. For adolescents, comparably higher metabolite concentrations were found in NEB II (Norway), PCB cohort (Slovakia), and ESTEBAN (France), and lower concentrations in POLAES (Poland), FLEHS IV (Belgium), and GerES V-sub (Germany). Multivariate analyses (Survey Generalized Linear Models) indicate compound-specific differences in average metabolite concentrations between the four European regions. Comparison of individual levels with HBM-GVs revealed highest rates of exceedances for DnBP and DiBP, with up to 3 and 5%, respectively, in children and adolescents. No exceedances were observed for DEP and DINCH. With our results we provide current, detailed, and comparable data on exposure to phthalates in children and - for the first time - in adolescents, and - for the first time - on DINCH in children and adolescents of all four regions of Europe which are particularly suited to inform exposure and risk assessment and answer open policy relevant questions.

ALAD and APOE polymorphisms are associated with lead and mercury levels in Italian pregnant women and their newborns with adequate nutritional status of zinc and selenium.

The impacts of single-nucleotide polymorphisms (SNPs) in ALAD and VDR genes on Pb health effects and/or kinetics are inconclusive at low exposure levels, while studies including APOE SNPs are rare. In this study, we examined the associations of ALAD, VDR and APOE SNPs with exposure biomarkers of Pb and other trace elements (TEs) in Italian pregnant women (N = 873, aged 18-44 years) and their newborns (N = 619) with low-level mixed-element exposure through diet, the environment or endogenously. DNA from maternal peripheral venous blood (mB), sampled during the second and third trimesters, was genotyped for ALAD (rs1800435, rs1805313, rs1139488, rs818708), VDR (rs2228570, rs1544410, rs7975232, rs731236) and APOE (rs429358, rs7421) using TaqMan SNP assays. Personal and lifestyle data and TE levels (mB, maternal plasma, hair and mixed umbilical cord blood [CB]) from the PHIME project were used. Multiple linear regression models, controlling for confounding variables, were performed to test the associations between SNPs and TEs. The geometric means of mB-Pb, mB-Hg, mB-As and mB-Cd (11.0 ng/g, 2.16 ng/g, 1.38 ng/g and 0.31 ng/g, respectively) indicated low exposure levels, whereas maternal plasma Zn and Se (0.72 µg/mL and 78.6 ng/g, respectively) indicated adequate micronutritional status. Variant alleles of ALAD rs1800435 and rs1805313 were negatively associated with mB-Pb levels, whereas a positive association was observed for rs1139488. None of the VDR SNPs or their haplotypes had any association with Pb levels. Regarding APOE, the ϵ4 allele was associated with lower mB-Hg and CB-Hg, while a positive association was found with the ϵ2 allele and CB-Pb when the model included only newborn girls. The observed associations indicate possible modification effects of ALAD and APOE SNPs on Pb or Hg kinetics in women and their newborns with low exposure to non-essential TEs, as well as an adequate nutritional status of Zn and Se.

From science to policy: How European HBM indicators help to answer policy questions related to phthalates and DINCH exposure.

Within the European Human Biomonitoring (HBM) Initiative HBM4EU we derived HBM indicators that were designed to help answering key policy questions and support chemical policies. The result indicators convey information on chemicals exposure of different age groups, sexes, geographical regions and time points by comparing median exposure values. If differences are observed for one group or the other, policy measures or risk management options can be implemented. Impact indicators support health risk assessment by comparing exposure values with health-based guidance values, such as human biomonitoring guidance values (HBM-GVs). In general, the indicators should be designed to translate complex scientific information into short and clear messages and make it accessible to policy makers but also to a broader audience such as stakeholders (e.g. NGO's), other scientists and the general public. Based on harmonized data from the HBM4EU Aligned Studies (2014-2021), the usefulness of our indicators was demonstrated for the age group children (6-11 years), using two case examples: one phthalate (Diisobutyl phthalate: DiBP) and one non-phthalate substitute (Di-isononyl cyclohexane-1,2- dicarboxylate: DINCH). For the comparison of age groups, these were compared to data for teenagers (12-18 years), and time periods were compared using data from the DEMOCOPHES project (2011-2012). Our result indicators proved to be suitable for demonstrating the effectiveness of policy measures for DiBP and the need of continuous monitoring for DINCH. They showed similar exposure for boys and girls, indicating that there is no need for gender focused interventions and/or no indication of sex-specific exposure patterns. They created a basis for a targeted approach by highlighting relevant geographical differences in internal exposure. An adequate data basis is essential for revealing differences for all indicators. This was particularly evident in our studies on the indicators on age differences. The impact indicator revealed that health risks based on exposure to DiBP cannot be excluded. This is an indication or flag for risk managers and policy makers that exposure to DiBP still is a relevant health issue. HBM indicators derived within HBM4EU are a valuable and important complement to existing indicator lists in the context of environment and health. Their applicability, current shortcomings and solution strategies are outlined.

Are Dietary Patterns Related to Cognitive Performance in 7-Year-Old Children? Evidence from a Birth Cohort in Friuli Venezia Giulia, Italy.

Research from different sources supports a link between nutrition and neurodevelopment, but evidence is still sparse regarding the relationship between a posteriori dietary patterns (DPs) and cognitive performance in school-aged children. Within the Northern Adriatic Cohort II, Friuli Venezia Giulia, Italy, 379 7-year-old children were cross-sectionally evaluated. Dietary patterns were identified through a principal component factor analysis based on 37 nutrients from children's 3-day dietary records. The Wechsler Intelligence Scale of Children (WISC-IV) test provided measures of cognitive performance, including the full-scale intelligence quotient (FSIQ) and single index scores. Each DP was related to FSIQ or single index scores through multiple robust linear regression models. We identified five DPs named "Dairy Products", "Plant-based Foods", "Fats", "Meat and Potatoes", and "Seafood" (63% of variance explained). After adjustment, no significant relationship was observed with the FSIQ score; positive associations were found between the "Seafood" DP and Verbal Comprehension Index or Perceptual Reasoning Index. The "Meat and Potatoes" and "Dairy Products" DPs were inversely associated with the Verbal Comprehension Index and Processing Speed Index scores, respectively. In the absence of a relation with the overall FSIQ score, single DPs might influence specific cognitive functions, including verbal and reasoning abilities, as targeted by single indexes, in the expected direction.

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 (ß = 2.56; 95% CI 0.58-4.55; N = 270), 5OH-MEHP+5cx-MEPP (ß = 2.48; 95% CI 0.47-4.49; N = 270) and 5OH-MEHP (ß = 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.

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

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.

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

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.

Harmonization of Human Biomonitoring Studies in Europe: Characteristics of the HBM4EU-Aligned Studies Participants.

Human biomonitoring has become a pivotal tool for supporting chemicals' policies. It provides information on real-life human exposures and is increasingly used to prioritize chemicals of health concern and to evaluate the success of chemical policies. Europe has launched the ambitious REACH program in 2007 to improve the protection of human health and the environment. In October 2020 the EU commission published its new chemicals strategy for sustainability towards a toxic-free environment. The European Parliament called upon the commission to collect human biomonitoring data to support chemical's risk assessment and risk management. This manuscript describes the organization of the first HBM4EU-aligned studies that obtain comparable human biomonitoring (HBM) data of European citizens to monitor their internal exposure to environmental chemicals. The HBM4EU-aligned studies build on existing HBM capacity in Europe by aligning national or regional HBM studies. The HBM4EU-aligned studies focus on three age groups: children, teenagers, and adults. The participants are recruited between 2014 and 2021 in 11 to 12 primary sampling units that are geographically distributed across Europe. Urine samples are collected in all age groups, and blood samples are collected in children and teenagers. Auxiliary information on socio-demographics, lifestyle, health status, environment, and diet is collected using questionnaires. In total, biological samples from 3137 children aged 6-12 years are collected for the analysis of biomarkers for phthalates, HEXAMOLL® DINCH, and flame retardants. Samples from 2950 teenagers aged 12-18 years are collected for the analysis of biomarkers for phthalates, Hexamoll® DINCH, and per- and polyfluoroalkyl substances (PFASs), and samples from 3522 adults aged 20-39 years are collected for the analysis of cadmium, bisphenols, and metabolites of polyaromatic hydrocarbons (PAHs). The children's group consists of 50.4% boys and 49.5% girls, of which 44.1% live in cities, 29.0% live in towns/suburbs, and 26.8% live in rural areas. The teenagers' group includes 50.6% girls and 49.4% boys, with 37.7% of residents in cities, 31.2% in towns/suburbs, and 30.2% in rural areas. The adult group consists of 52.6% women and 47.4% men, 71.9% live in cities, 14.2% in towns/suburbs, and only 13.4% live in rural areas. The study population approaches the characteristics of the general European population based on age-matched EUROSTAT EU-28, 2017 data; however, individuals who obtained no to lower educational level (ISCED 0-2) are underrepresented. The data on internal human exposure to priority chemicals from this unique cohort will provide a baseline for Europe's strategy towards a non-toxic environment and challenges and recommendations to improve the sampling frame for future EU-wide HBM surveys are discussed.

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 < 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 < 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.

Spatial Patterns of Endometriosis Incidence. A Study in Friuli Venezia Giulia (Italy) in the Period 2004-2017.

BACKGROUND: Diagnosis of endometriosis and evaluation of incidence data are complex tasks because the disease is identified laparoscopically and confirmed histologically. Incidence estimates reported in literature are widely inconsistent, presumably reflecting geographical variability of risk and the difficulty of obtaining reliable data. METHODS: We retrieved incident cases of endometriosis in women aged 15-50 years using hospital discharge records and pathology databases of the Friuli Venezia Giulia region in the calendar period 2004-2017. We studied the spatial pattern of endometriosis incidence applying Bayesian approaches to Disease Mapping, and profiled municipalities at higher risk controlling for multiple comparisons using both q-values and a fully Bayesian approach. RESULTS: 4125 new cases of endometriosis were identified in the age range 15 to 50 years in the period 2004-2017. The incidence rate (x100 000) is 111 (95% CI 110-112), with a maximum of 160 in the age group 31-35 years. The geographical distribution of endometriosis incidence showed a very strong north-south spatial gradient. We consistently identified a group of five neighboring municipalities at higher risk (RR 1.31 95% CI 1.13; 1.52), even accounting for ascertainment bias. CONCLUSIONS: The cluster of 5 municipalities in the industrialized and polluted south-east part of the region is suggestive. However, due to the ecologic nature of the present study, information on the patients' characteristics and exposure histories are limited. Individual studies, including biomonitoring, and life-course studies are necessary to better evaluate our findings.

Nutrient Intake during Pregnancy and Adherence to Dietary Recommendations: The Mediterranean PHIME Cohort.

Few studies provide a detailed description of dietary habits during pregnancy, despite the central role of nutrition for the health of the mother and offspring. This paper describes the dietary habits, energy and nutrient intake in pregnant women from four countries belonging to the Mediterranean PHIME cohort (Croatia, Greece, Italy and Slovenia) and evaluates their adherence to the European Food Safety Authority (EFSA) recommendations. A total of 1436 women were included in the present analysis. Maternal diet was assessed using a food frequency questionnaire (FFQ). The mean macro and micronutrient intakes were estimated and compared with the dietary reference values (DRVs). The percentage distribution of the 16 food groups in the total intake of each macronutrient was estimated. All women shared a similar diet during pregnancy; almost all the women in the four countries exceeded the DRV for sugars, and the total fat intake was above the DRV in most women in all the countries, as was the contribution of saturated fatty acids (SFAs) to the total energy intake. In all four countries, we observed an increased risk of micronutrient deficiency for iron, folate and vitamin D. Shared guidelines, implemented at both the national and European level, are essential to improve the maternal nutritional status during pregnancy.

Impact of Methylmercury and Other Heavy Metals Exposure on Neurocognitive Function in Children Aged 7 Years: 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's neurodevelopment is controversial and may appear in the 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. The study enrolled 900 pregnant women, and 632 and 470 children underwent neurodevelopmental evaluation at 18 and 40 months of age, respectively. The NAC-II cohort is a part of the Mediterranean cohort in the "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 who 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. DISCUSSION: This 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 social economic status of children's families. Longitudinal analysis of neurodevelopment, assessed in different ages (18 months, 40 months, and 7 years), are performed.

The role of mercury, selenium and the Se-Hg antagonism on cognitive neurodevelopment: A 40-month follow-up of the Italian mother-child PHIME cohort.

Despite a 15-year long effort to define the "safety" of fish intake during pregnancy, there remains still uncertainty on this important public health issue. The evaluation of the toxic effects of contaminants, particularly mercury (Hg) in fish-eating populations is complicated by the fact that sea-food is also rich in beneficial nutrients, such as selenium (Se). There is toxicological plausibility of an antagonistic effects between Se and Hg, and some theoretical support for the inclusion of the Se-Hg interaction to better assess the risk linked with fish intake. To assess the effects of exposure to low-level Hg through fish consumption on the developing brain and the interaction between Hg and Se, we conducted an analysis at age 40 months in Italian children, enrolled in a prospective mother-child cohort, comparing additive and multiplicative models. Participant subjects were the 470 children born within the Northern Adriatic Cohort II (NAC-II) cohort who were tested by using the Bayley Scales of Infant and Toddler Development third edition (Bayley-III) (BSID-III) at age 40. Family demographic and socioeconomic information, pregnancy and delivery history, parental and child medical history and food consumption were assessed through questionnaires. Maternal blood samples were collected during pregnancy, cord blood at birth and maternal milk 1 month after delivery. As other exposures of interest, we considered the level of Se in maternal and cord blood and in breast milk and the potential Se-Hg antagonism. Se and inverse of THg (1:THg) concentrations were categorized according to the tertiles of their distributions, in low, medium and high levels of exposure. The lower end of the composite cognitive score distribution closest to 20% was defined as suboptimal development. Multiple logistic regression were applied to assess the association between the dichotomized composite cognitive score and the categorized exposure to Se and 1:THg, and the antagonism between Se and 1:THg. In the recruiting period, 900 pregnant women were enrolled in the cohort; 767 of these remained in the study at delivery and 470 children at 40 months. After excluding preterm births, 456 children were used in the final analyses. The larger difference in risk for suboptimal neurodevelopment was observed for the category with High THg and Low Se with OR = 2.55 (90% CI 1.02; 6.41) under the multiplicative and OR = 1.33 (90% CI 0.80; 1.87) under the additive model. The category High THg and High Se showed a very slightly better fit of the additive model (OR = 1.07, 90% CI 0.65; 1.50) versus the multiplicative (OR = 1.66, 90% CI 0.73; 1.77). A negative - antagonistic - interaction term for this category was estimated under the multiplicative model giving an OR = 1.17 (90% CI 0.42; 3.28). Although this evidence of the effects of the Se-Hg antagonism on the children neuro-development needs to be confirmed, if Se can counterbalance Hg toxicity, the evaluation of the effect on human health of fish consumption, should also consider the diverse ratios between Se and Hg concentration in different fish species.

Measuring the impact of a social programme on healthcare: a 10-year retrospective cohort study in Trieste, Italy.

OBJECTIVES: Poor social conditions are strong determinants of poor health but positive health and healthcare changes caused by social interventions are difficult to demonstrate. In 2006, in Trieste (Italy), a social intervention known as 'Habitat Microaree' (HM) project was implemented in eight deprived neighbourhoods. In 2016, an observational study was launched to assess the impact of the HM project on healthcare. DESIGN: Retrospective cohort study. SETTING: The eight geographically defined neighbourhoods of Trieste involved in the 2006 HM project, accounting for a total of 11 380 residents. PARTICIPANTS: Participants were all residents in the intervention areas. By means of a propensity score based on deprivation index, age, sex, Charlson index and drug utilisation, a non-participating, comparison group was defined. INTERVENTION: The community-based intervention consisted of facilitating access to social services and outpatient healthcare facilities, coordinating intersectoral public services and specifically planning hospital discharge. These services were not provided in other areas of the city. OUTCOME MEASURES: Hospital admissions and emergency department access. RESULTS: We followed 16 256 subjects between 2008 and 2015. Living in microareas was associated with an HR for first hospital admission, for all causes, of 0.95 (95% CI 0.91 to 0.99); while the HR for urgent admissions in females was 0.92 (95% CI 0.85 to 1.00). The HR for psychiatric disorders, in females, was 0.39 (95%CI 0.18 to 0.82); in particular, the HR for psychosis was 0.15 (95% CI 0.05 to 0.51). The HR for acute respiratory diseases in females was 0.44 (95% CI 0.21 to 0.95). In males, the HR for genitourinary diseases and heart diseases were 0.65 (95% CI 0.42 to 1.01) and 0.72 (95% CI 0.54 to 0.97), respectively. Concerning urgent multiple admissions, the OR for fractures in females was 0.75 (95% CI 0.58 to 0.97). CONCLUSION: In the study period, the effects on healthcare appear evident, especially in females.