Prenatal exposure to mixtures of per- and polyfluoroalkyl substances and organochlorines affects cognition in adolescence independent of postnatal exposure.

BACKGROUND: Studies on cognitive and neurodevelopmental outcomes have shown inconsistent results regarding the association with prenatal exposure to perfluoroalkyl substance (PFAS) and organochlorines. Assessment of mixture effects of correlated chemical exposures that persist in later life may contribute to the unbiased evaluation and understanding of dose-response associations in real-life exposures. METHODS: For a subset of the 4th Flemish Environment and Health Study (FLEHS), concentrations of four PFAS and six organochlorines were measured in respectively 99 and 153-160 cord plasma samples and 15 years later in adolescents' peripheral serum by Ultra Performance Liquid Chromatography-Tandem Mass Spectrometry (UPLC-MS/MS). Sustained and selective attention were measured at 14-15 years with the Continuous Performance Test (CPT) and Stroop Test as indicators of potential neurodevelopmental deficits. Quantile g-computation was applied to assess the joint associations between prenatal exposure to separate and combined groups of PFAS and organochlorines and performance in the CPT and Stroop Test at adolescence. Subsequently, individual effects of each chemical compound were analyzed in mixed effects models with two sets of covariates. Analytical data at birth and at the time of cognitive assessment allowed for off-setting postnatal exposure. RESULTS: In mixtures analysis, a simultaneous one-quantile increase in the natural log-transformed values of PFAS and organochlorines combined was associated with a decrease in the mean reaction time (RT) and the reaction time variability (RTV) in the CPT (ß = -15.54, 95% CI:-29.64, -1.45, and ß = -7.82, 95% CI: -14.97, -0.67 respectively) and for the mixture of PFAS alone with RT (ß = -11.94, 95% CI: -23.29, -0.60). In the single pollutant models, these results were confirmed for the association between perfluorohexanesulfonate (PFHxS) with RT (ß = -17.95, 95% CI = -33.35, -2.69) and hexachlorobenzene with RTV in the CPT (ß = -5.78, 95% CI: -10.39, -0.76). Furthermore, the participants with prenatal exposure above the limit of quantification for perfluorononanoic acid (PFNA) had a significantly shorter RT and RTV in the CPT (ß = -23.38, 95% CI: -41.55, -5.94, and ß = -9.54, 95% CI: -19.75, -0.43, respectively). CONCLUSION: Higher prenatal exposure to a PFAS mixture and a mixture of PFAS and organochlorines combined was associated with better sustained and selective attention during adolescence. The associations seemed to be driven by PFHxS and were not linked to exposure levels at the time of assessment.

Surveillance of multiple congenital anomalies; searching for new associations.

Many human teratogens are associated with a spectrum of congenital anomalies rather than a single defect, and therefore the identification of congenital anomalies occurring together more frequently than expected may improve the detection of teratogens. Thirty-two EUROCAT congenital anomaly registries covering 6,599,765 births provided 123,566 cases with one or more major congenital anomalies (excluding chromosomal and genetic syndromes) for the birth years 2008-2016. The EUROCAT multiple congenital anomaly algorithm identified 8804 cases with two or more major congenital anomalies in different organ systems, that were not recognized as part of a syndrome or sequence. For each pair of anomalies, the odds of a case having both anomalies relative to having only one anomaly was calculated and the p value was estimated using a two-sided Fisher's exact test. The Benjamini-Hochberg procedure adjusted p values to control the false discovery rate and pairs of anomalies with adjusted p values < 0.05 were identified. A total of 1386 combinations of two anomalies were analyzed. Out of the 31 statistically significant positive associations identified, 20 were found to be known associations or sequences already described in the literature and 11 were considered "potential new associations" by the EUROCAT Coding and Classification Committee. After a review of the literature and a detailed examination of the individual cases with the anomaly pairs, six pairs remained classified as new associations. In summary, systematically searching for congenital anomalies occurring together more frequently than expected using the EUROCAT database is worthwhile and has identified six new associations that merit further investigation.

Ethics and legal requirements for data linkage in 14 European countries for children with congenital anomalies.

INTRODUCTION: Linking healthcare data sets can create valuable resources for research, particularly when investigating rare exposures or outcomes. However, across Europe, the permissions processes required to access data can be complex. This paper documents the processes required by the EUROlinkCAT study investigators to research the health and survival of children with congenital anomalies in Europe. METHODS: Eighteen congenital anomaly registries in 14 countries provided information on all the permissions required to perform surveillance of congenital anomalies and to link their data on live births with available vital statistics and healthcare databases for research. Small number restrictions imposed by data providers were also documented. RESULTS: The permissions requirements varied substantially, with certain registries able to conduct congenital anomaly surveillance as part of national or regional healthcare provision, while others were required to obtain ethics approvals or informed consent. Data linkage and analysis for research purposes added additional layers of complexity for registries, with some required to obtain several permissions, including ethics approvals to link the data. Restrictions relating to small numbers often resulted in a registry's data on specific congenital anomalies being unusable. CONCLUSION: The permissions required to obtain and link data on children with congenital anomalies varied greatly across Europe. The variation and complexity present a significant obstacle to the use of such data, especially in large data linkage projects. Furthermore, small number restrictions severely limited the research that could be performed for children with specific rare congenital anomalies.

Relationship Between Baseline Prostate-specific Antigen on Cancer Detection and Prostate Cancer Death: Long-term Follow-up from the European Randomized Study of Screening for Prostate Cancer.

BACKGROUND: The European Association of Urology guidelines recommend a risk-based strategy for prostate cancer screening based on the first prostate-specific antigen (PSA) level and age. OBJECTIVE: To analyze the impact of the first PSA level on prostate cancer (PCa) detection and PCa-specific mortality (PCSM) in a population-based screening trial (repeat screening every 2-4 yr). DESIGN, SETTING, AND PARTICIPANTS: We evaluated 25589 men aged 55-59 yr, 16898 men aged 60-64 yr, and 12936 men aged 65-69 yr who attended at least one screening visit in the European Randomized Study of Screening for Prostate Cancer (ERSPC) trial (screening arm: repeat PSA testing every 2-4 yr and biopsy in cases with elevated PSA; control arm: no active screening offered) during 16-yr follow-up (FU). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We assessed the actuarial probability for any PCa and for clinically significant (cs)PCa (Gleason ≥7). Cox proportional-hazards regression was performed to assess whether the association between baseline PSA and PCSM was comparable for all age groups. A Lorenz curve was computed to assess the association between baseline PSA and PCSM for men aged 60-61 yr. RESULTS AND LIMITATIONS: The overall actuarial probability at 16 yr ranged from 12% to 16% for any PCa and from 3.7% to 5.7% for csPCa across the age groups. The actuarial probability of csPCa at 16 yr ranged from 1.2-1.5% for men with PSA <1.0 ng/ml to 13.3-13.8% for men with PSA ≥3.0 ng/ml. The association between baseline PSA and PCSM differed marginally among the three age groups. A Lorenz curve for men aged 60-61 yr showed that 92% of lethal PCa cases occurred among those with PSA above the median (1.21 ng/ml). In addition, for men initially screened at age 60-61 yr with baseline PSA <2 ng/ml, further continuation of screening is unlikely to be beneficial after the age of 68-70 yr if PSA is still <2 ng/ml. No case of PCSM emerged in the subsequent 8 yr (up to age 76-78 yr). A limitation is that these results may not be generalizable to an opportunistic screening setting or to contemporary clinical practice. CONCLUSIONS: In all age groups, baseline PSA can guide decisions on the repeat screening interval. Baseline PSA of <1.0 ng/ml for men aged 55-69 yr is a strong indicator to delay or stop further screening. PATIENT SUMMARY: In prostate cancer screening, the patient's baseline PSA (prostate-specific antigen) level can be used to guide decisions on when to repeat screening. The PSA test when used according to current knowledge is valuable in helping to reduce the burden of prostate cancer.

Maternal age and the prevalence of congenital heart defects in Europe, 1995-2015: A register-based study.

BACKGROUND: Evidence on the direction and strength of association between maternal age and the prevalence of congenital heart defects (CHD) in different age group categories is conflicting. Some studies have illustrated different trends with an increase in prevalence in younger and older age groups while other studies have reported a linear relationship. Given the increase in maternal age over recent years, it is important to study the CHD prevalence by maternal age. OBJECTIVES: To examine the association between maternal age and the prevalence of CHD in Europe between 1995 and 2015 using population-based data from 24 registries belonging to the European Surveillance of Congenital Anomalies (EUROCAT) network. METHODS: Associations over time of all nonsyndromic CHD according to maternal age category and for three CHD severity groupings (severity group I: very severe; severity group II: severe; severity group III: less severe) were examined using Bayesian multilevel Poisson regression modeling. Further subgroup analyses were undertaken within four maternal age-bands: ≤24, 25-29, 30-34 and 35-44 years. Descriptive summaries are also presented. RESULTS: There were 51,608 nonsyndromic CHD cases in Europe over the 20-year study period. Total prevalence for all CHD combined was increased for younger mothers (≤24 years) and for mothers 35-44 years of age when compared with mothers aged 25-29 years (reference group) (IRR: 1.05, 95% CI: 1.02, 1.07). The total prevalence was increased for severity group I (very severe) only for younger mothers compared to those aged 25-29 years (IRR: 1.14, 95% CI: 1.04, 1.23). We found an increased prevalence of the following CHD subtypes: double outlet right ventricle (IRR:1.33, 95% CI: 1.09, 1.60), hypoplastic left heart syndrome (IRR: 1.18, 95% CI: 1.05, 1.32), hypoplastic right heart syndrome (IRR: 1.41, 95% CI: 1.05, 1.84), atrioventricular septal defect (IRR: 1.15, 95% CI: 1.01, 1.32), coarctation of aorta (IRR: 1.15, 95% CI: 1.03, 1.28) and atrial septal defect (IRR: 1.08, 95% CI: 1.02, 1.13). For older mothers (35-44 years) compared to the reference category, we observed an increased risk in the prevalence for severity group II (IRR: 1.09, 95% CI: 1.03, 1.14), severity group III (IRR: 1.05, 95% CI: 1.01, 1.08) and an increased prevalence of the CHD subtypes: Pulmonary valve stenosis (IRR: 1.22, 95% CI: 1.09, 1.34), ASD (IRR: 1.07, 95% CI: 1.02, 1.13), CoA (IRR: 1.18, 95% CI: 1.06, 1.32) and Tetralogy of Fallot (IRR: 1.14, 95% CI: 1.01, 1.28). Finally, for all age categories compared to the reference category, different associations of ASD and an increased prevalence of CoA was also observed. CONCLUSIONS: Based on data for cases of CHD from 24 European population-based registries, evidence of a positive association between maternal age and the total prevalence of CHD for younger (≤24 years old) and older (35-44 years old) mothers was observed. The results suggest that young maternal age (≤24 years old) is a factor associated with severe CHD phenotypes while a positive association between advanced maternal age (35-44 years old) and mild CHD phenotypes was observed.

Epidemiology of aplasia cutis congenita: A population-based study in Europe.

BACKGROUND: Aplasia cutis congenita (ACC) is a rare congenital anomaly characterized by localized or widespread absence of skin at birth, mainly affecting the scalp. Most information about ACC exists as individual case reports and medium-sized studies. OBJECTIVES: This study aimed to investigate the epidemiology of ACC, using data from a large European network of population-based registries for congenital anomalies (EUROCAT). METHODS: Twenty-eight EUROCAT population-based registries in 16 European countries were involved. Poisson regression models were exploited to estimate the overall and live birth prevalence, to test time trends in prevalence between four 5-year periods and to evaluate the impact of the change of coding for ACC from the unspecific ICD9-BPA code to the specific ICD10 code. Proportions of ACC cases associated with other anomalies were reported. RESULTS: Five hundred cases were identified in the period 1998-2017 (prevalence: 5.10 per 100,000 births). Prevalence across 5-year periods did not differ significantly and no significant differences were evident due to the change from ICD9 to ICD10 in ACC coding. Heterogeneity in prevalence was observed across registries. The scalp was the most common site for ACC (96.4%) and associated congenital anomalies were present in 33.8% of cases. Patau and Adams-Oliver syndromes were the most frequent among the associated chromosomal anomalies (88.3%) and the associated genetic syndromes (57.7%), respectively. 16% of cases were associated with limb anomalies and 15.4% with congenital heart defects. A family history of ACC was found in 2% of cases. CONCLUSION: To our knowledge, this is the only population-based study on ACC. The EUROCAT methodologies provide reliable prevalence estimates and proportions of associated anomalies.

Amniotic band syndrome and limb body wall complex in Europe 1980-2019.

Amniotic band syndrome (ABS) and limb body wall complex (LBWC) have an overlapping phenotype of multiple congenital anomalies and their etiology is unknown. We aimed to determine the prevalence of ABS and LBWC in Europe from 1980 to 2019 and to describe the spectrum of congenital anomalies. In addition, we investigated maternal age and multiple birth as possible risk factors for the occurrence of ABS and LBWC. We used data from the European surveillance of congenital anomalies (EUROCAT) network including data from 30 registries over 1980-2019. We included all pregnancy outcomes, including live births, stillbirths, and terminations of pregnancy for fetal anomalies. ABS and LBWC cases were extracted from the central EUROCAT database using coding information responses from the registries. In total, 866 ABS cases and 451 LBWC cases were included in this study. The mean prevalence was 0.53/10,000 births for ABS and 0.34/10,000 births for LBWC during the 40 years. Prevalence of both ABS and LBWC was lower in the 1980s and higher in the United Kingdom. Limb anomalies and neural tube defects were commonly seen in ABS, whereas in LBWC abdominal and thoracic wall defects and limb anomalies were most prevalent. Twinning was confirmed as a risk factor for both ABS and LBWC. This study includes the largest cohort of ABS and LBWC cases ever reported over a large time period using standardized EUROCAT data. Prevalence, clinical characteristics, and the phenotypic spectrum are described, and twinning is confirmed as a risk factor.

Prevalence of congenital heart defects in Europe, 2008-2015: A registry-based study.

BACKGROUND: The total prevalence of congenital heart defects (CHDs) varies by populations and over time. Studies that examine trends in the prevalence of CHD in different regions may shed light on our understanding of the occurrence of CHD and the impact of different risk factors. OBJECTIVES: To examine trends in total and live birth prevalence of nonsyndromic CHD in Europe between the years 2008 and 2015 and to investigate if the decreasing trend reported by previous studies is continuing. METHODS: Cases of CHD delivered between January 1, 2008 and December 31, 2015 notified to 25 population-based EUROCAT (European Surveillance of Congenital Anomalies) registries in 14 countries, formed the population-based case-series. Prevalence (total/live) rates and 95% confidence intervals were calculated as the number of cases per 10,000 births (live and stillbirths). Time trends in prevalence of all nonsyndromic CHDs and for three CHD severity groups (very severe, severe, and less severe) were plotted using a Poisson regression multilevel approach. RESULTS: The total prevalence of nonsyndromic CHD was 57.1 per 10,000 births (live births and stillbirths) for the 8-year period and remained stable across the three CHD severity groups while the live birth prevalence was 60.2 per 10,000 births. There was considerable variation in the reported total CHD prevalence and the direction of trends by registry. A decreasing prevalence of CHD was observed for the Norway and England/Wales registries, whereas the CHD prevalence increased for registries in Italy and Croatia. CONCLUSIONS: The total prevalence of CHD in Europe between the years 2008 and 2015 remained stable for all CHD and across the three CHD severity groups. The decreasing trend reported by previous studies has not continued. However, we found significant differences in the total and live birth prevalence by registry.

Prevalence of vascular disruption anomalies and association with young maternal age: A EUROCAT study to compare the United Kingdom with other European countries.

BACKGROUND: Younger mothers are at a greater risk of having a pregnancy with gastroschisis and the risk is higher in the United Kingdom than other European countries. Gastroschisis is thought to be a vascular disruption anomaly and the aim of this study was to analyze the prevalence of other possible vascular disruption anomalies to determine whether both the younger maternal age and the UK associations also occur with these anomalies. METHODS: All pregnancies with anomalies considered potentially due to vascular disruption from January 1, 2005 to December 31, 2017 from 26 European population-based congenital anomaly registries who were members of EUROCAT were analyzed. Multilevel models were used to allow for differences between registries when analyzing associations with maternal age, year of birth and whether the registry was in the United Kingdom. RESULTS: There were 5,220 cases with potential vascular disruption anomalies, excluding chromosomal and genetic conditions, with a prevalence of 8.85 per 10,000 births in the United Kingdom and 5.44 in the other European countries. The prevalence per 10,000 births of gastroschisis (4.45 vs. 1.56) and congenital constriction bands (0.83 vs. 0.42) was significantly higher in the United Kingdom, even after adjusting for maternal age. However, transverse limb reduction defects had a similar prevalence (2.16 vs. 2.14 per 10,000). The expected increased prevalence in younger mothers was observed for vascular disruption anomalies overall and for the individual anomalies: gastroschisis and congenital constriction bands. CONCLUSION: Vascular disruption anomalies that had an increased risk for younger mothers (such as gastroschisis) had a higher maternal age standardized prevalence in the United Kingdom, while vascular disruption anomalies with weaker associations with younger mothers (such as transverse limb reduction defects) did not have an increased prevalence in the United Kingdom, which may indicate a different etiology for these anomalies.

Higher proportion of agricultural land use around the residence is associated with higher urinary concentrations of AMPA, a glyphosate metabolite.

INTRODUCTION: Pesticides, including herbicides, are widely used for agricultural and sanitary reasons and concerns have been raised about their various health effects. Little research has been done into the extent to which agricultural land use in the residential surroundings contributes to (internal) exposure of pesticides. OBJECTIVES: We investigated the associations between the proportion of agricultural land use around the residence and the exposure to pesticides in adolescents in Flanders (Belgium). MATERIAL AND METHODS: We included 424 adolescents participating in the fourth Flemish Environment and Health Study (FLEHS IV) between 2016 and 2020. The residential address of all participants was geocoded and the proportion of agricultural land use around the residence was estimated in several buffers (300 m, 500 m, 1000 m and 2000 m). The concentrations of the following biomarkers of pesticides were measured in urine and adjusted for the specific gravity: glyphosate and its metabolite, aminomethyl-phosphonic acid (AMPA); 3-phenoxybenzoic acid (3-PBA); 3,5,6-trichloro-2-pyridinol (TCPy) and 2,4-dichlophenoxy-acetic acid (2,4-D). We categorized the pesticide biomarkers in three categories according to the exposure levels and used ordinal logistic regression models adjusted for sex, season and household education to estimate the odds ratio for an increase in an interquartile range (IQR) of proportion of agricultural land use. We also used binary logistic regression models in which the category of highest exposure was compared to the category of lowest exposure. In addition, we explored potential effect modification by sex and season. RESULTS: We found a significant association between the proportion of agricultural land use in a buffer of 2000 m around the residence and the levels of urinary AMPA divided into three categories (OR = 1.35 for an IQR increase in the proportion of agricultural land use around residence; 95% CI: 1.00-1.83). This association was less pronounced and not statistically significant for the other studied pesticides (OR ranging between 0.95 and 1.16). Stratified analysis showed the strongest association of the proportion of agricultural land use within 2000 m buffers for AMPA among boys (OR = 1.89; 95% CI: 1.19-3.04). Results using smaller buffers were comparable, but did not reach statistical significance. CONCLUSION: Our findings suggest that a higher proportion of agricultural land use around the residence might increase exposure to AMPA.

Temporal and geographical variations in survival of children born with congenital anomalies in Europe: A multi-registry cohort study.

BACKGROUND: Congenital anomalies are a major cause of perinatal, neonatal and infant mortality. OBJECTIVES: The aim was to investigate temporal changes and geographical variation in survival of children with major congenital anomalies (CA) in different European areas. METHODS: In this population-based linkage cohort study, 17 CA registries members of EUROCAT, the European network for the surveillance of CAs, successfully linked data on 115,219 live births with CAs to mortality records. Registries estimated Kaplan-Meier survival at 28 days and 5 years of age and fitted Cox's proportional hazards models comparing mortality at 1 year and 1-9 years of age for children born during 2005-2014 with those born during 1995-2004. The hazard ratios (HR) from each registry were combined centrally using a random-effects model. The 5-year survival conditional on having survived to 28 days of age was calculated. RESULTS: The overall risk of death by 1 year of age for children born with any major CA in 2005-2014 decreased compared to 1995-2004 (HR 0.68, 95% confidence interval [CI] 0.53, 0.89). Survival at 5 years of age ranged between registries from 97.6% to 87.0%. The lowest survival was observed for the registry of OMNI-Net (Ukraine) (87.0%, 95% CI 86.1, 87.9). CONCLUSIONS: Survival of children with CAs improved for births in 2005-2014 compared with 1995-2004. The use of CA registry data linked to mortality data enables investigation of survival of children with CAs. Factors such as defining major CAs, proportion of terminations of pregnancy for foetal anomaly, source of mortality data and linkage methods are important to consider in the design of future studies and in the interpretation of the results on survival of children with CAs.

Glyphosate and AMPA exposure in relation to markers of biological aging in an adult population-based study.

BACKGROUND/AIM: Glyphosate, a broad-spectrum herbicide, and its main metabolite aminomethylphosphonic acid (AMPA) are persistent in the environment. Studies showed associations between glyphosate or AMPA exposure and several adverse cellular processes, including metabolic alterations and oxidative stress. OBJECTIVE: To determine the association between glyphosate and AMPA exposure and biomarkers of biological aging. METHODS: We examined glyphosate and AMPA exposure, mtDNA content and leukocyte telomere length in 181 adults, included in the third cycle of the Flemish Environment and Health Study (FLEHSIII). DNA was isolated from leukocytes and the relative mtDNA content and telomere length were determined using qPCR. Urinary glyphosate and AMPA concentrations were measured by Gas Chromatography-Tandem Mass Spectrometry (GC-MS-MS). We used multiple linear regression models to associate mtDNA content and leukocyte telomere length with glyphosate or AMPA exposure while adjusting for confounding variables. RESULTS: A doubling in urinary AMPA concentration was associated with 5.19% (95% CI: 0.49 to 10.11; p = 0.03) longer leukocyte telomere length, while no association was observed with urinary glyphosate concentration. No association between mtDNA content and urinary glyphosate nor AMPA levels was observed. CONCLUSIONS: This study showed that AMPA exposure may be associated with telomere biology in adults.

Higher surrounding green space is associated with better attention in Flemish adolescents.

INTRODUCTION: Previous studies suggested that green space is beneficial for the cognitive development in children. However, evidence in adolescents is limited. Therefore, we aim to investigate green space exposure in association with attention and behaviour in adolescents. METHODS: This study includes 596 Flemish adolescents between 13 and 17 years old. Attention was assessed with Stroop Test (selective attention) and Continuous Performance Test (sustained and selective attention). Behaviour was determined based on the Strengths and Difficulties Questionnaire. Green space was estimated in several radius distances around their current residence and school based on high-resolution land cover data. Multilevel regression analyses were used adjusting for participant's age, sex, education level of the mother, and area deprivation index. RESULTS: Surrounding green space in a 2000 m radius is associated with a faster reaction time in adolescents. An IQR (13%) increment in total green space within 2000 m of the residence and school combined, is associated with a 32.7 ms (95% CI: -58.9 to -6.5; p = 0.02) and a 7.28 ms (95% CI: -11.7 to -2.8; p = 0.001) shorter mean reaction time between the presentation of a stimulus and the response based on the Stroop Test and the Continuous Performance Test. Subdividing green space based on vegetation height, shows that green space higher than 3 m is associated with a faster reaction time of the Continuous Performance Test (-6.50 ms; 95% CI: -10.9 to -2.2; p = 0.004), while low green is not. We did not find an association between green space and behavioural development in adolescents. CONCLUSIONS: Our study shows that green space, especially trees, surrounding the residence and school combined is associated with better sustained and selected attention in adolescents. These findings indicate that the availability of green is important for adolescents that are growing up in a rapidly urbanizing world.

Determinants of Chronic Biological Stress, Measured as Hair Cortisol Concentration, in a General Population of Adolescents: From Individual and Household Characteristics to Neighborhood Urbanicity.

Chronic biological stress may adversely affect adolescents' physical and mental health, but insight in the personal and environmental factors that determine chronic stress is limited. We measured 3-month cumulative hair cortisol concentration (HCC) in 419 adolescents, participating in the Flemish Environment and Health Study. Adolescents' health and lifestyle characteristics, household and neighborhood socio-economic status as well as neighborhood urbanicity were assessed as potential determinants of HCC, using multiple linear regression models. We additionally explored heterogeneity of our results by sex. HCC were significantly higher in boys from densely populated neighborhoods, the association was not significant in girls. Accordingly, boys living outside cities had significantly lower HCC than boys, living in cities. HCC was significantly lower in adolescents with an optimal vitality, a measure of a positive mental health status. In adolescent girls, menarcheal status (pre-/postmenarche) was a significant determinant of HCC. Our findings are the first to suggest that residential urbanicity may have an impact on chronic biological stress in a general population of adolescent boys.

Intervention-related Deaths in the European Randomized Study of Screening for Prostate Cancer.

BACKGROUND: Identification of intervention-related deaths is important for an accurate assessment of the ratio of benefit to harm in screening trials. OBJECTIVE: To investigate intervention-related deaths by study arm in the European Randomized Study of Prostate Cancer Screening (ERSPC). DESIGN SETTING AND PARTICIPANTS: ERSPC is a multicenter trial initiated in the 1990s to investigate whether screening on the basis of prostate-specific antigen (PSA) can decrease prostate cancer mortality. The present study included men in the core age group (55-69 yr: screening group n = 112 553, control group n = 128 681) with 16-yr follow-up. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Causes of death among men with prostate cancer in ERSPC were predominantly evaluated by independent national committees via review of medical records according to a predefined algorithm. Intervention-related deaths were defined as deaths caused by complications during the screening procedure, treatment, or follow-up. Descriptive statistics were used for the results. RESULTS AND LIMITATIONS: In total, 34 deaths were determined to be intervention-related, of which 21 were in the screening arm and 13 in the control arm. The overall risk of intervention-related death was 1.41 (95% confidence interval 0.99-1.99) per 10 000 randomized men for both arms combined and varied among centers from 0 to 7.0 per 10 000 randomized men. A limitation of this study is that differences in procedures among centers decreased the comparability of the results. CONCLUSIONS: Intervention-related deaths were rare in ERSPC. Monitoring of intervention-related deaths in screening trials is important for assessment of harms. PATIENT SUMMARY: We investigated deaths due to screening or treatment to assess harm in a trial of prostate cancer screening. Few such deaths were identified.

Urinary Polycyclic Aromatic Hydrocarbon Metabolites Are Associated with Biomarkers of Chronic Endocrine Stress, Oxidative Stress, and Inflammation in Adolescents: FLEHS-4 (2016-2020).

Polycyclic aromatic hydrocarbons (PAHs) are environmental pollutants of public health concern. Multiple biological mechanisms have been hypothesized to contribute to PAHs-associated adverse health effects. Little is known about the impact of PAHs on endocrine stress and inflammation in adolescence. We examined 393 Flemish adolescents (14-15 years) cross-sectionally, measured urinary concentrations of hydroxylated naphthalene, fluorene, phenanthrene and pyrene metabolites, and calculated the sum of all measured metabolites. We determined hair cortisol concentration (HCC) as endocrine stress biomarker, leucocyte counts and neutrophil-lymphocyte ratio (NLR) in peripheral blood as inflammatory biomarkers, and urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) concentration as oxidative stress biomarker. Exposure-response associations were analyzed by multiple regression, adjusted for a priori selected covariates. A doubling of 1-hydroxypyrene concentration was associated with a factor of 1.13 (95% CI: 1.03, 1.24) increase in HCC and a factor of 1.07 (95% CI: 1.02, 1.13) increase in 8-oxodG. Doublings of 2- and 3-hydroxyphenanthrene concentrations were associated with a factor of 1.08 (95% CI: 1.02, 1.14) and 1.06 (95% CI: 1.00, 1.12) increase in 8-oxodG, respectively. Doubling of 2-hydroxyphenanthrene and of the sum of 2- and 3-hydroxyfluorene was associated with, respectively, a factor of 1.08 (95% CI: 1.02, 1.14) and 1.06 (95% CI: 1.01, 1.13) increase in NLR. Our results indicate the glucocorticoid pathway as a potential target for PAH exposure in adolescents and suggest oxidative stress, endocrine stress, and inflammation in adolescence as underlying mechanisms and early markers for PAH-related adverse health effects.

Long-term residential exposure to air pollution is associated with hair cortisol concentration and differential leucocyte count in Flemish adolescent boys.

BACKGROUND: Exposure to air pollution and traffic noise are associated with adverse health outcomes in adolescents. Chronic endocrine stress and systemic inflammation have been hypothesized to underlie the adverse health effects. Simultaneous assessment of inflammation and chronic endocrine stress in epidemiological studies is lacking. The aim of the study was to investigate biomarkers of chronic endocrine stress and inflammation in relation to long-term residential exposure to air pollution and traffic noise in adolescents. METHODS: In Flemish adolescents (14-15 years), we determined hair cortisol concentration (HCC) as a chronic stress biomarker in 3-cm scalp-near hair sections (n = 395), and leucocyte and leucocyte subtype counts (neutrophils, monocytes, lymphocytes) as inflammatory biomarkers in peripheral blood (n = 385). Daily particulate matter (PM2.5, PM10), nitrogen dioxide (NO2) and black carbon (BC) concentrations were modelled at the residential address and averaged over 3-month and 1-year periods prior to sampling. Residential traffic noise level was estimated and classified in 5 dB intervals. Sex-specific associations between residential exposures and effect biomarkers were studied using linear regression models, adjusted for a priori selected covariates. RESULTS: In boys, HCC increased with a factor 1.30 (95% CI: 1.10, 1.54) for an increase in 1-year mean NO2 from the 25th to 75th percentile (p75/p25), after adjustment for age, BMI, personal and neighborhood socioeconomic status. The corresponding estimate for PM10 was 1.24 (95% CI: 1.02, 1.51). Total leucocyte count in boys, adjusted for the aforementioned covariates and recent health complaints, was positively associated with PM2.5, PM10, NO2 and BC. In particular, the neutrophil count increased with a factor 1.11 (95% CI: 1.03, 1.19) for a (p75/p25)-factor increase in 1-year mean BC, corresponding estimates for PM2.5, PM10 and NO2 were 1.10 (95% CI: 1.01, 1.19), 1.10 (95% CI: 1.01, 1.20) and 1.08 (95% CI: 1.00, 1.16). Lymphocyte count increased with a factor 1.05 (95% CI: 1.01, 1.10) for a (p75/p25)-factor increase in 1-year mean NO2. Similar results were observed for 3-month mean exposures. Results were robust to adjustment for recent air pollution exposure. In girls, air pollutants were not associated with HCC or differential leucocyte count. Residential traffic noise level was not associated with HCC or leucocyte counts in boys nor girls. CONCLUSIONS: Long-term residential exposure to air pollutants was positively associated with chronic endocrine stress and inflammation in adolescent boys, not in girls. This study may contribute to a better understanding of the early pathophysiological changes that may underlie adverse health effects of air pollution exposure in adolescents.

Human Biomonitoring Data Enables Evidence-Informed Policy to Reduce Internal Exposure to Persistent Organic Compounds: A Case Study.

Human biomonitoring (HBM) monitors levels of environmental pollutants in human samples, which often is a topic of concern for residents near industrially contaminated sites (ICSs). Around an ICS area in Menen (Belgium), including a (former) municipal waste incinerator and a metal recovery plant, increasing environmental concentrations of dioxins and polychlorinated biphenyls (PCBs) were observed, causing growing concern among residents and authorities. The local community succeeded in convincing the responsible authorities to investigate the problem and offer research funding. Persistent organic pollutants (POPs) were measured in two consecutive HBM studies (2002-2006 and 2010-2011), in the context of the Flemish Environment and Health Study (FLEHS), as well as in soil and locally produced food. Meanwhile, local authorities discouraged consumption of locally produced food in a delineated area of higher exposure risk. Ultimately, HBM and environmental data enabled tailored dietary recommendations. This article demonstrates the usefulness of HBM in documenting the body burdens of residents near the ICS, identifying exposure routes, evaluating remediating actions and providing information for tailored policy strategies aiding to further exposure reduction. It also highlights the role of the local stakeholders as an example of community-based participatory research and how such an approach can create societal support for research and policy.

Epidemiology of Pierre-Robin sequence in Europe: A population-based EUROCAT study.

BACKGROUND: Pierre Robin sequence (PRS) is a rare congenital anomaly. Respiratory disorders and feeding difficulties represent the main burden. OBJECTIVE: The aim of this study was to investigate the epidemiology of PRS using a cohort of cases from EUROCAT, the European network of population-based registries of congenital anomalies. METHODS: We analysed cases of PRS born in the period 1998-2017 collected by 29 population-based congenital anomaly registries in 17 different countries. We calculated prevalence estimates, prenatal detection rate, survival up to 1 week, and proportions of associated anomalies. The effect of maternal age was tested using a Poisson regression model. RESULTS: Out of 11 669 155 surveyed births, a total of 1294 cases of PRS were identified. The estimate of the overall prevalence was 12.0 per 100 000 births (95% CI 9.9, 14.5). There was a total of 882 (68.2%) isolated cases, and the prevalence was 7.8 per 100 000 births (95% CI 6.7, 9.2). A total of 250 cases (19.3%) were associated with other structural congenital anomalies, 77 cases (6.0%) were associated with chromosomal anomalies and 77 (6.0%) with genetic syndromes. The prenatal detection rate in isolated cases was 12.0% (95% CI 9.8, 14.5) and increased to 16.0% (95% CI 12.7, 19.7) in the sub-period 2008-2017. The prevalence rate ratio of non-chromosomal cases with maternal age ≥35 was higher than in cases with maternal age <25 for total (PRR 1.26, 95% CI 1.05, 1.51) and isolated cases (PRR 1.33, 95% CI 1.00, 1.64). Survival of chromosomal cases (94.2%) and multiple anomaly cases (95.3%) were lower than survival of isolated cases (99.4%). CONCLUSIONS: This epidemiological study using a large series of cases of PRS provides insights into the epidemiological profile of PRS in Europe. We observed an association with higher maternal age, but further investigations are needed to test potential risk factors for PRS.

Signal Detection in EUROmediCAT: Identification and Evaluation of Medication-Congenital Anomaly Associations and Use of VigiBase as a Complementary Source of Reference.

INTRODUCTION: Knowledge on the safety of medication use during pregnancy is often sparse. Pregnant women are generally excluded from clinical trials, and there is a dependence on post-marketing surveillance to identify teratogenic medications. AIMS: This study aimed to identify signals of potentially teratogenic medications using EUROmediCAT registry data on medication exposure in pregnancies with a congenital anomaly, and to investigate the use of VigiBase reports of adverse events of medications in the evaluation of these signals. METHODS: Signals of medication-congenital anomaly associations were identified in EUROmediCAT (21,636 congenital anomaly cases with 32,619 medication exposures), then investigated in a subset of VigiBase (45,749 cases and 165,121 exposures), by reviewing statistical reporting patterns and VigiBase case reports. Evidence from the literature and quantitative and qualitative aspects of both datasets were considered before recommending signals as warranting further independent investigation. RESULTS: EUROmediCAT analysis identified 49 signals of medication-congenital anomaly associations. Incorporating investigation in VigiBase and the literature, these were categorised as follows: four non-specific medications; 11 likely due to maternal disease; 11 well-established teratogens; two reviewed in previous EUROmediCAT studies with limited additional evidence; and 13 with insufficient basis for recommending follow-up. Independent investigations are recommended for eight signals: pregnen (4) derivatives with limb reduction; nitrofuran derivatives with cleft palate and patent ductus arteriosus; salicylic acid and derivatives with atresia or stenosis of other parts of the small intestine and tetralogy of Fallot; carbamazepine with atrioventricular septal defect and severe congenital heart defect; and selective beta-2-adrenoreceptor agonists with posterior urethral valve and/or prune belly. CONCLUSION: EUROmediCAT data should continue to be used for signal detection, accompanied by information from VigiBase and review of the existing literature to prioritise signals for further independent evaluation.