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Although the prevalence of lead poisoning in southern Africa's Gyps vultures is now well-established, its finer physiological effects on these endangered species remain poorly characterised. We evaluated the sub-lethal impact of acute lead exposure on Cape and White-backed Vulture chicks from two breeding colonies in South Africa, by analysing its possible effects on key blood biochemistry parameters, immune function, packed cell volume and δ-aminolevulinic acid dehydratase (δ-ALAD) activity. All 37 White-backed Vulture nestlings sampled displayed elevated lead levels (>10 μg/dL), and seven had blood [Pb] >100 μg/dL. Eight of 28 Cape Vulture nestlings sampled had blood [Pb] exceeding background exposure, with one showing blood [Pb] >100 μg/dL. Delta-aminolevulinic acid dehydratase (δ-ALAD) activity was significantly and negatively related to blood [Pb] in nestlings from both species, with 50% inhibition of the enzyme predicted to occur at blood [Pb] = 52.8 μg/dL (White-backed Vulture) and 18.8 μg/dL (Cape Vulture). Although no significant relationship was found between % packed cell volume (PCV) and blood [Pb], the relatively lower mean PCV of 32.9% in White-backed Vulture chicks, combined with normal serum protein values, is likely indicative of depression or haemolytic anaemia. The leukogram was consistent in both species, although the presence of immature heterophils suggested an inflammatory response in White-backed Vulture chicks with blood [Pb] >100 μg/dL. Values for cholesterol, triglycerides, total serum protein, albumin, globulin, albumin/globulin ratio, alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT) were consistent with values previously reported. Calcium and phosphorus concentrations suggested no adverse effects on bone metabolism. A significant decrease in urea: uric acid (U:UA) ratio at blood [Pb] >100 μg/dL in White-backed Vulture chicks, brought about by a decrease in urea production, raises the possibility of hepatic abnormality. These results suggest that δ-ALAD activity may serve as a sensitive biomarker of lead toxicity in both species, while highlighting the need to better understand the significant variability in sensitivity that is observed, even between closely related members of the same genus., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Sub-Saharan Africa is under-represented in global biodiversity datasets, particularly regarding the impact of land use on species' population abundances. Drawing on recent advances in expert elicitation to ensure data consistency, 200 experts were convened using a modified-Delphi process to estimate 'intactness scores': the remaining proportion of an 'intact' reference population of a species group in a particular land use, on a scale from 0 (no remaining individuals) to 1 (same abundance as the reference) and, in rare cases, to 2 (populations that thrive in human-modified landscapes). The resulting bii4africa dataset contains intactness scores representing terrestrial vertebrates (tetrapods: ±5,400 amphibians, reptiles, birds, mammals) and vascular plants (±45,000 forbs, graminoids, trees, shrubs) in sub-Saharan Africa across the region's major land uses (urban, cropland, rangeland, plantation, protected, etc.) and intensities (e.g., large-scale vs smallholder cropland). This dataset was co-produced as part of the Biodiversity Intactness Index for Africa Project. Additional uses include assessing ecosystem condition; rectifying geographic/taxonomic biases in global biodiversity indicators and maps; and informing the Red List of Ecosystems., (© 2024. The Author(s).)

Elevated lead levels in scavenging raptors can originate from a variety of environmental and anthropogenic sources, including soil, water, mining activities and legacy lead from leaded fuel, but has mostly been attributed to fragments of lead-based ammunition embedded in the tissues of carcasses. To identify the origins of lead in the tissues of white-backed vulture (Gyps africanus) chicks at Dronfield Nature Reserve, South Africa, we used MC-ICP-MS to compare the isotopic composition of lead in blood samples to those of soil in the chicks' immediate environment, different mining activities in South Africa and lead ammunition commonly used in hunting and game management practices. The isotopic ratios in vulture blood samples ranged widely ( 207 Pb/ 206 Pb: 0.827-0.911), but fell within those measured for ammunition (0.761-0.938). Dronfield water can be excluded as a significant source, as the lead concentration for water was below detection limits. Uranium, coal, atmospheric Pb, legacy Pb from fuel and Pb mining can also be excluded as significant sources, based on the limited overlap with Pb isotopic ratios measured in vulture blood. Whereas 55% of chicks we sampled displayed isotopic ratios consistent with Dronfield soil, the low local Pb concentration and the low extractable Pb levels in South African soil in general, imply that soil Pb is unlikely the major source of Pb in WBV chicks, especially in birds with elevated blood Pb levels, i.e. > 20 µg/dL. Our results, when considered in the context of vulture feeding ecology and low Pb levels in non-scavenging birds in South Africa, imply the major source of elevated Pb levels in WBV chicks to be fragments of lead-based ammunition embedded in the carrion fed to them by their parents., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Pure fruit juice is comparable to sugar-sweetened beverages (SSBs) with respect to its sugar and fructose content. However, it also contains favorable components like polyphenols. From this perspective, pure fruit juice is more comparable with whole fruit. SSBs have been associated with higher asthma risk, while whole fruit consumption has been associated with lower prevalence of asthma (symptoms). Associations with pure fruit juice have been rarely studied. Therefore, we studied the associations of consumption of pure fruit juice, SSBs and whole fruit with asthma prevalence in 3046 children of the Dutch Prevention and Incidence of Asthma and Mite Allergy (PIAMA) birth cohort growing up from 11 to 20 years. Consumption of pure fruit juice, SSBs and fruit was self-reported at the ages of 11, 14, 17 and 20 years. Presence of asthma was defined based on parental reports of asthma diagnosis ever, and wheezing and asthma medication in the last 12 months. Odds ratios (OR) were estimated using generalized linear mixed models accounting for correlation between repeated measurements within subjects. No associations were found between pure fruit juice, SSBs and fruit consumption and the overall prevalence of asthma from 11 to 20 years. An earlier reported association of low pure fruit juice consumption with higher asthma prevalence at the age of 11 years in the PIAMA population was confirmed, but no associations were found at the ages of 14, 17 and 20 years., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors. Published by Elsevier Inc.)

Objective: Dietary guidelines on pure fruit juice differ between countries regarding the question whether pure fruit juice (without added sugars) is an acceptable substitute for fruit or should be avoided because of its comparable sugar content with that of sugar-sweetened beverages (SSB). We modelled whether substituting pure fruit juice for fruit or SSB was associated with cardiometabolic risk., Design: Prospective cohort study., Setting: Based on a validated FFQ at baseline, we calculated the relative contribution of pure fruit juice to total consumption of fruit and pure fruit juice (${{{\rm{pure}}\;{\rm{fruit}}\;{\rm{juice}}\;\;\left( {{\rm{g}}/{\rm{day}}} \right)} \over {{\rm{fruit}}\; + \;{\rm{pure}}\;{\rm{fruit}}\;{\rm{juice}}\;\left( {{\rm{g}}/{\rm{day}}} \right)}}$) and to total consumption of SSB and pure fruit juice (${{{\rm{pure}}\;{\rm{fruit}}\;{\rm{juice}}\;\;\left( {{\rm{g}}/{\rm{day}}} \right)} \over {{\rm{SSBs}}\; + \;{\rm{pure}}\;{\rm{fruit}}\;{\rm{juice}}\;\left( {{\rm{g}}/{\rm{day}}} \right)}}$). In multivariate analyses (Cox regression), we assessed associations with incidence of type 2 diabetes, CVD, CHD and stroke after an average follow-up of 14·6 years., Participants: About 35 000 participants from the EPIC-NL study, aged 20-70 years at enrolment., Results: Substitution of pure fruit juice for SSB was associated with lower risk of all endpoints. For type 2 diabetes and CHD, for example, drinking 75-100 % (as compared with 0-<25 %) of total SSB + pure fruit juice as pure fruit juice showed hazard ratio (95 % CI) of 0·74 (95 % CI 0·64, 0·85) and 0·85 (95 % CI 0·76, 0·96), respectively. Substitution of pure fruit juice for fruit was not associated with the risk of type 2 diabetes, CVD, CHD and stroke., Conclusions: Substituting pure fruit juice for SSB was associated with lower cardiometabolic risk, whereas substituting pure fruit juice for fruit was not associated with cardiometabolic risk.

The white-winged flufftail is listed as critically endangered, and limited knowledge about the species' ecology has been identified as a limiting factor to effectively conserving the bird. Little is known about the vegetation inhabited by the white-winged flufftail, which hampers the identification and management of its habitat. This study presents a fine-scale classification and description of the vegetation of wetland sites where the bird is known to be present. A plant phytosociological study was conducted to describe the plant communities and vegetation structure of the habitat. Three sites were selected at Verloren Valei Nature Reserve and two at Middelpunt Wetland, Mpumalanga, South Africa, shortly after the white-winged flufftail breeding season. A total of 60 sample plots were placed within the study sites, where all plant species present were recorded and identified. Other aspects such as plant height, water depth and anthropogenic influences were also documented. A modified TWINSPAN analysis resulted in the identification of three sub-communities that can be grouped into one major community. The Cyperaceae, Asteraceae and Poaceae families dominate the vegetation, with the sedges Carex austro-africana and Cyperus denudatus being dominant, and the grasses Leersia hexandra and Arundinella nepalensis co-dominant. The broad habitat structure consisted of medium to tall herbaceous plants (0.5-0.7 m) with shallow slow-flowing water., (© 2021 The Authors.)

Background: The incidence of childhood overweight and obesity is rising. It is hypothesized that infections in early childhood are associated with being overweight. This study investigated the association between the number of symptomatic infections or antibiotic prescriptions in the first 3 years of life and body mass index (BMI) in adolescence., Subjects: The current study is part of the Prevention and Incidence of Asthma and Mite Allergy population-based birth cohort study. Weight and height were measured by trained research staff at ages 12 and 16 years. The 3015 active participants at age 18 years were asked for informed consent for general practitioner (GP) data collection and 1519 gave written informed consent. Studied exposures include (1) GP-diagnosed infections, (2) antibiotic prescriptions, and (3) parent-reported infections in the first 3 years of life. Generalized estimating equation analysis was used to determine the association between each of these exposures and BMI z-score., Results: Exposure data and BMI measurement in adolescence were available for 622 participants. The frequencies of GP-diagnosed infections and antibiotic prescriptions were not associated with BMI z-score in adolescence with estimates being 0.14 (95% CI -0.09-0.37) and 0.10 (95% CI -0.14-0.34) for the highest exposure categories, respectively. Having ≥6 parent-reported infections up to age 3 years was associated with a 0.23 (95% CI 0.01-0.44) higher BMI z-score compared to <2 parent-reported infections., Conclusions: For all infectious disease measures an increase in BMI z-score for the highest childhood exposure to infectious disease was observed, although only statistically significant for parent-reported infections. These results do not show an evident link with infection severity, but suggest a possible cumulative effect of repeated symptomatic infections on overweight development.

Introduction: The adolescent years represent a key period for the development of musculoskeletal complaints (MSC) and the differences between boys and girls. We evaluated the prevalence and course of MSC and factors associated with MSC while growing up from age 11 to age 20., Methods: Questionnaire-based data at age 11 (n = 2,638), age 14 (n = 2,517), age 17 (n = 2,094) and at age 20 (n = 2,206) from the ongoing Prevention and Incidence of Asthma and Mite Allergy (PIAMA) birth cohort were analyzed. MSC refers to pain of lower back, upper- and/or lower extremities. A multivariable logistic regression analysis was used to evaluate a number of factors in relation to persistent pain (pain reported at three out of four measurements)., Results: Prevalence of MSC increased from 14.2% at age 11 to 22.1% at age 20 for boys, and from 17.4% at age 11 to 37.9% at age 20 for girls. Persistent pain was found among 5.1% of the boys and 16.5% of the girls. Being bullied, sleeping problems and tiredness during the day were significantly associated with persistent pain, in both boys and girls, while the latter two were more prevalent among girls. Self-reported (sports-) accidents, and among girls also early onset of puberty, were also significantly associated with persistent pain, but lifestyle factors, such as physical activity and smoking, were not., Conclusion: The prevalence of MSC increases during adolescence, with a widening gap between boys and girls. The factors associated with MSC are similar in boys and girls, though the prevalence of some of these differ by sex., Significance: Measuring a group of youngsters 4 times between age 11 and 20 shows an increase in the percentage reporting musculoskeletal complaints (MSC) with a widening gap between girls and boys, with more pain among girls. Boys and girls do hardly differ with respect to factors associated with MSC, being mainly psychosocial factors and (sports) accidents., (© 2021 The Authors. European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation - EFIC®.)

Purpose: It is controversial whether a higher intake of n-3 long-chain polyunsaturated fatty acids (n-3 LC PUFA) through breastfeeding is associated or not to a lower blood pressure (BP) during childhood. We aimed to clarify this point by undertaking a meta-analysis involving the data from seven European birth cohorts., Methods: We searched https://www.birthcohort.net for studies that had collected breast milk samples, and had at least one BP measurement in childhood. Principal investigators were contacted, and all agreed to share data. One additional study was identified by contacts with the principal investigators. For each cohort, we analyzed the association of breast milk n-3 LC PUFAs with systolic and diastolic BP with linear mixed effects models or linear regression, and pooled the estimates with a random effects model. We also investigated age-specific and sex-specific associations., Results: A total of 2188 participants from 7 cohorts were included. Overall, no associations between breast milk n-3 LC PUFAs and BP were observed. In the pooled analysis, each 0.1 wt% increment in breast milk docosahexaenoic acid (DHA) was associated with a 1.19 (95% CI - 3.31, 0.94) mmHg lower systolic BP. Associations were similar for boys and girls and at different ages., Conclusion: In this individual participant meta-analysis, we found no evidence for an association between breast milk n-3 LC PUFAs and BP.

Background: House dust endotoxin may have beneficial effects on allergic sensitization and asthma in children. Evidence is scarce for adolescents and most studies so far have been cross-sectional and limited to a single exposure measurement., Objective: We assessed associations of house dust endotoxin with asthma and allergic sensitization from birth to age 17 years longitudinally taking into account exposure early in life and at primary school age., Methods: We used data of 854 participants of the prospective Dutch PIAMA birth cohort study with house dust endotoxin measurements at 3 months and/or 5-6 years and data on asthma and/or allergic sensitization from at least one of 11 follow-ups until age 17. We assessed overall and age-specific associations of the prevalence of asthma and sensitization with mattress and living room floor dust concentrations (per gram of dust) and loads (per m 2 of sampling surface)., Results: Higher living room floor dust endotoxin concentrations at 3 months were associated with lower odds of asthma until age 4 [odds ratio (95% confidence interval) ranging from 0.70 (0.51-0.97) at age 1 to 0.76 (0.57-1.00) at age 3 per interquartile range increase], but not thereafter in children of allergic mothers. Higher living room floor dust endotoxin at 5-6 years was associated with higher odds of sensitization at 8-16 years [eg odds ratio (95% confidence interval) 1.70 (1.17-2.47) per interquartile range increase in endotoxin load]., Conclusions and Clinical Relevance: House dust endotoxin may have beneficial effects on asthma in preschool children of allergic mothers, which do not persist into adolescence. Beneficial associations with allergic sensitization could not be confirmed., (© 2020 The Authors. Clinical & Experimental Allergy published by John Wiley & Sons Ltd.)

Background: Air pollution is associated with asthma development in children and adults, but the impact on asthma development during the transition from adolescence to adulthood is unclear. Adult studies lack historical exposures and consequently cannot assess the relevance of exposure during different periods of life. We assessed the relevance of early-life and more recent air pollution exposure for asthma development from birth until early adulthood., Methods: We used data of 3687 participants of the prospective Dutch PIAMA (Prevention and Incidence of Asthma and Mite Allergy) birth cohort and linked asthma incidence until age 20 years to estimated concentrations of nitrogen dioxide (NO 2 ), particulate matter with a diameter <2.5 μm (PM 2.5 ), <10 μm (PM 10 ), and 2.5-10 μm, and PM 2.5 absorbance ("soot") at the residential address. We assessed overall and age-specific associations with air pollution exposure with discrete time-hazard models, adjusting for potential confounders., Results: Overall, we found higher incidence of asthma until the age of 20 years with higher exposure to all pollutants at the birth address (adjusted odds ratio (95% CI) ranging from 1.09 (1.01-1.18) for PM 10 to 1.20 (1.10-1.32) for NO 2 ) per interquartile range increase) that were rather persistent with age. Similar associations were observed with more recent exposure defined as exposure at the current home address. In two-pollutant models with particulate matter, associations with NO 2 persisted., Conclusions: Exposure to air pollution, especially from motorised traffic, early in life may have long-term consequences for asthma development, as it is associated with an increased risk of developing asthma through childhood and adolescence into early adulthood., Competing Interests: Conflict of interest: U. Gehring has nothing to disclose. Conflict of interest: A.H. Wijga has nothing to disclose. Conflict of interest: G.H. Koppelman reports grants from Lung Foundation of the Netherlands, during the conduct of the study; grants from Tetri Foundation, Ubbo Emmius Foundation, TEVA the Netherlands, Vertex and GSK, institutional fees from GSK, outside the submitted work. Conflict of interest: J.M. Vonk has nothing to disclose. Conflict of interest: H.A. Smit has nothing to disclose. Conflict of interest: B. Brunekreef has nothing to disclose., (Copyright ©ERS 2020.)

Background: Dietary guidelines on pure fruit juice consumption vary from country to country regarding the inclusion of pure fruit juice in the recommendations as an acceptable alternative for fruit. Current epidemiological evidence on the association between pure fruit juice consumption and diabetes risk is scarce., Objective: We studied the association of both pure fruit juice and fruit consumption with diabetes risk and investigated the differences between low and high fruit consumers in the association of pure fruit juice consumption with diabetes risk., Methods: This prospective cohort study included 36,147 participants in the European Prospective Investigation into Cancer and Nutrition-Netherlands (EPIC-NL) Study aged 20-69 y at baseline. Fruit juice and fruit consumption were assessed using a validated food-frequency questionnaire; amounts of consumption were divided into 5 categories and quintiles, respectively. Incident type 2 diabetes cases were mainly self-reported and verified against medical records. Cox regression was used to estimate adjusted HRs and 95% CIs., Results: After an average follow-up of 14.6 y, 1477 verified incident cases of type 2 diabetes were documented. Compared with no consumption, pure fruit juice consumption was not significantly associated with type 2 diabetes, with adjusted HRs ranging from 0.92 (95% CI: 0.79, 1.09) to 1.03 (95% CI: 0.83, 1.26). The associations did not differ between participants with low and high fruit consumption. None of the categories of fruit consumption were associated with type 2 diabetes (lowest quintile as reference). Adjusted HRs ranged between 0.93 (95% CI: 0.78, 1.10) and 1.00 (95% CI: 0.84, 1.19). Adjustment for the Dutch Healthy Diet Index, as an overall measure of dietary quality, strongly attenuated the observed associations of type 2 diabetes with both fruit juice and fruit consumption., Conclusions: We found no evidence for associations between pure fruit juice and fruit consumption and diabetes risk after adjustment for overall dietary quality for participants in the EPIC-NL study. This trial was registered at https://www.trialregister.nl/trial/6939 as NL6939., (Copyright © The Author(s) 2020.)

Background: Epigenetic signatures in the nasal epithelium, which is a primary interface with the environment and an accessible proxy for the bronchial epithelium, might provide insights into mechanisms of allergic disease., Objective: We aimed to identify and interpret methylation signatures in nasal epithelial brushes associated with rhinitis and asthma., Methods: Nasal epithelial brushes were obtained from 455 children at the 16-year follow-up of the Dutch Prevention and Incidence of Asthma and Mite Allergy birth cohort study. Epigenome-wide association studies were performed on children with asthma, rhinitis, and asthma and/or rhinitis (AsRh) by using logistic regression, and the top results were replicated in 2 independent cohorts of African American and Puerto Rican children. Significant CpG sites were related to environmental exposures (pets, active and passive smoking, and molds) during secondary school and were correlated with gene expression by RNA-sequencing (n = 244)., Results: The epigenome-wide association studies identified CpG sites significantly associated with rhinitis (n = 81) and AsRh (n = 75), but not with asthma. We significantly replicated 62 of 81 CpG sites with rhinitis and 60 of 75 with AsRh, as well as 1 CpG site with asthma. Methylation of cg03565274 was negatively associated with AsRh and positively associated with exposure to pets during secondary school. DNA methylation signals associated with AsRh were mainly driven by specific IgE-positive subjects. DNA methylation related to gene transcripts that were enriched for immune pathways and expressed in immune and epithelial cells. Nasal CpG sites performed well in predicting AsRh., Conclusions: We identified replicable DNA methylation profiles of asthma and rhinitis in nasal brushes. Exposure to pets may affect nasal epithelial methylation in relation to asthma and rhinitis., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: It is well known that maternal smoking during pregnancy and maternal pre-pregnancy overweight have opposite effects on the infants' birth weight. We report on the association of the combination between both risk factors and the infants' birth weight., Methods: We studied 3241 infants born at term in the PIAMA birth cohort. Maternal smoking during pregnancy and pre-pregnancy height and weight were self-reported. Multivariable regression analysis was performed to assess the associations between infants of mothers who only smoked during pregnancy, who only had pre-pregnancy overweight and who had both risk factors simultaneously, on term birth weight and the risk of being SGA or LGA., Results: Of 3241 infants, 421 infants (13%) were born to smoking, non-overweight mothers, 514 (15.8%) to non-smoking, overweight mothers, 129 (4%) to smoking and overweight mothers and 2177 (67%) to non-smoking, non-overweight mothers (reference group). Infants of mothers who smoked and also had pre-pregnancy overweight had similar term birth weight (- 26.6 g, 95%CI: - 113.0, 59.8), SGA risk (OR = 1.06, 95%CI: 0.56, 2.04), and LGA risk (OR = 1.09, 95%CI: 0.61, 1.96) as the reference group., Conclusions: Our findings suggested that the effects of maternal smoking during pregnancy and maternal pre-pregnancy overweight on infants' birth weight cancel each other out. Therefore, birth weight may not be a good indicator of an infant's health status in perinatal practice because it may mask potential health risks due to these maternal risk factors when both present together.

Background: The relevance of timing of exposure in the associations of secondhand tobacco smoke (SHS), pets, and dampness or mould exposure with lung function is unclear. We investigated the relevance of timing of these exposures for lung function in adolescence., Methods: We used data from participants of the Dutch Prevention and Incidence of Asthma and Mite Allergy (PIAMA) cohort with spirometric measurements at ages 12 and 16 years (n=552). Data on residential exposure to SHS, pets, and dampness or mould were obtained by repeated parental questionnaires. We characterised timing of exposure through longitudinal patterns using latent class growth modelling and assessed associations of these patterns with FEV 1 and FVC at ages 12 and 16 and FEV 1 and FVC growth between ages 12 and 16 using linear regression models., Results: Childhood SHS exposure was associated with reduced FEV 1 growth/year (95% CI) (-0.34% (-0.64% to -0.04%)). Late childhood and early life pet exposure was associated with increased FEV 1 growth (0.41% (0.14% to 0.67%)) and reduced FVC growth (-0.28% (-0.53% to -0.03%)), respectively, compared with very low exposure. Early life dampness or mould exposure was associated with reduced lung function growth. All time windows of SHS exposure tended to be associated with lower attained lung function and pet exposure tended to be associated with higher FEV 1 ., Conclusion: SHS exposure during childhood could lead to reduced lung function growth and lower attained lung function in adolescence. While pet exposure in late childhood may not adversely affect lung function, early childhood pet exposure may slow down FVC growth in adolescence., Competing Interests: Competing interests: GHK received grants from the Dutch Lung Foundation, grants from Ubbo Emmius Foundation, grants from Teva The Netherlands and grants from Stichting Astma Bestrijding, outside the submitted work. UG reports receiving grants from the Dutch Lung Foundation during the conduct of this study., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Hypertensive disorders of pregnancy (HDPs) are among the leading causes of maternal and perinatal morbidity and mortality worldwide and have been suggested to increase long-term cardiovascular disease risk in the offspring., Objective: The objective of this study was to investigate whether HDPs are associated with cardiometabolic markers in childhood., Search Strategy: PubMed, The Cochrane Library and reference lists of included studies up to January 2019., Selection Criteria: Studies comparing cardiometabolic markers in 2-18-year-old children of mothers with HDP in utero, to children of mothers without HDP., Data Collection and Analysis: Sixteen studies reported in 25 publications were included in this systematic review, of which three were considered as having high risk of bias. Thus 13 studies were included in the evidence synthesis: respectively two and eight reported pregnancy induced hypertension and preeclampsia, and three studies reported on both HDPs., Main Results: Most studies ( n  = 4/5) found a higher blood pressure in children exposed to pregnancy induced hypertension. Most studies ( n  = 7/10) found no statistically significantly higher blood pressure in children exposed to preeclampsia. No association was found between exposure to HDP and levels of cholesterol, triglycerides or glucose ( n  = 5/5). No studies investigated an association with (carotid) intima-media thickness, glycated haemoglobin or diabetes mellitus type 2., Conclusions: Most studies showed that exposure to pregnancy induced hypertension is associated with a higher offspring blood pressure. There is no convincing evidence for an association between exposure to preeclampsia and blood pressure in childhood. Based on current evidence, exposure to HDP is not associated with blood levels of cholesterol, triglycerides and glucose in childhood.

Background: Pet and dampness or mould exposure are considered risk factors for asthma and sensitization. It is unclear whether timing of exposure to these factors is differentially associated with asthma risk and sensitization in adolescence., Objective: We investigated the role of timing of pet and dampness or mould exposure in asthma and sensitization in adolescence. Understanding this role is essential to build targeted prevention strategies., Methods: We used data from 1871 participants of the Dutch Prevention and Incidence of Asthma and Mite Allergy (PIAMA) cohort. Residential exposure to pets, dampness or mould was assessed by repeated parental questionnaires. We used asthma data from the 17-year questionnaire and sensitization data from the 16-year medical examination. We characterized timing using longitudinal exposure patterns from pregnancy till age 17 using longitudinal latent class growth modelling. We used logistic regression models to analyse associations of exposure patterns with asthma at age 17 and sensitization at age 16., Results: For none of the time windows, exposure to pets and dampness or mould was associated with asthma at age 17, but a lower sensitization risk at age 16 was suggested, for example the odds ratio (95% confidence interval) for sensitization was 0.63 (0.35-1.11) and 0.69 (0.44-1.08) for early life and persistently high pet exposure, respectively, compared with very low exposure. An inverse association was also suggested for sensitization and moderate early childhood dampness or mould exposure (0.71 [0.42-1.19])., Conclusion and Clinical Relevance: Different timing of pet and dampness or mould exposure was not associated with asthma, but lower risk of sensitization in adolescence was suggested, which could be partly attributable to reversed causation. Current findings are not sufficient to recommend pet avoidance to prevent allergic disease. More prospective studies are needed to obtain insights that can be used in clinical practice., (© 2019 John Wiley & Sons Ltd.)

Background: There is growing evidence for a protective effect of breastfeeding against overweight and diabetes. It is less clear though, whether breastfed infants also have a more favorable cardiometabolic profile in childhood., Objective: We investigated whether children who were breastfed in infancy had more favorable cardiometabolic markers at 12 years of age than children who were never breastfed and received formula milk instead, and whether associations depended on the duration of breastfeeding., Methods: In 1509 participants of the population-based PIAMA birth cohort study, cardiometabolic markers were measured at 12 years of age. Duration of breastfeeding in weeks was assessed through parental questionnaires at 3 months and 1 year of age. Multivariable linear regression analysis was used to investigate associations of breastfeeding (any vs. never breastfeeding and duration of breastfeeding in categories <3 months, 3 to <6 months, and ≥6 months breastfeeding vs. never breastfeeding) with systolic and diastolic blood pressure (SBP and DBP, in Z-scores adjusted for age, sex, and height), total-to-high-density lipoprotein cholesterol (TC/HDLC), glycated hemoglobin (HbA1c, in mmol/mol), body mass index (BMI, in Z-scores adjusted for age and sex) and waist circumference (WC, in cm). Multivariable logistic regression was used to investigate the association of breastfeeding with odds of being overweight., Results: 1288 of 1509 children (85.3%) received any breastmilk in infancy. Breastfed children had a lower SBP Z-score (-0.21 SD (≈ -2.29 mmHg), 95% CI -0.37, -0.06), a lower DBP Z-score (-0.10 SD (≈ -1.19 mmHg), 95% CI -0.20, -0.00), a smaller WC (-1.12 cm, 95% CI -2.20; -0.04), and lower odds of being overweight (OR 0.61, 95% CI 0.38, 0.97) than never breastfed children. These associations were not different between children with shorter and longer duration of breastfeeding. No statistically significant differences in TC/HDLC, HbA1c, and BMI were observed between breastfed and never breastfed children., Conclusions: We observed that breastfeeding was associated with a lower blood pressure, a smaller waist circumference and a lower risk of overweight in 12-year old children. These associations were independent of the duration of breastfeeding. No associations were observed between breastfeeding and other cardiometabolic markers.

Adolescents with high educational attainment generally have better outcomes across the lifespan than adolescents with lower educational attainment. This study investigated how three measures of socioeconomic status (SES)-maternal education, paternal education, and neighbourhood SES-combined to predict adolescent educational attainment (track level at age 17). We proposed three mechanisms for this pathway: cognitive ability (at age 11), primary school teacher assessment (stating the secondary education level suitable for a child at age 11), and educational expectations (at age 14). Using the data of 2,814 Dutch adolescents from the Prevention and Incidence of Asthma and Mite Allergy (PIAMA) study, logistic regressions tested associations between SES and educational attainment. Structural equation modelling (SEM) tested mediational pathways between SES and educational attainment. In models with three SES measures, having a medium-educated mother was associated with higher educational attainment relative to having a low-educated mother (OR; 95% CI: 1.83; 1.41-2.38), and having a high-educated mother was associated with higher educational attainment relative to having a low-educated mother (OR; 95% CI: 3.44; 2.59-4.55). The odds ratios for paternal education showed a similar pattern. We found no association between neighbourhood SES and adolescent educational attainment, so neighbourhood SES was removed from further analyses. Mediational analyses revealed that cognitive ability (30.0%), teacher assessment (28.5%), and educational expectations (1.2%) explained 59.8% of the total association between parental SES and educational attainment. The results showed that mother education and father education were both important for understanding the strong association between parental SES and adolescent educational attainment. In the Netherlands, the association between parental SES and educational attainment can be largely explained by cognitive ability and teacher assessments., Competing Interests: The authors have declared that no competing interests exist.

Observational studies suggest that breast-feeding is associated with a more favourable BMI and cardio-metabolic markers, but potential underlying mechanisms are unclear. As serum adiponectin has an important function in adults for glucose and lipid metabolism, we assessed 251 participants of the Prevention and Incidence of Asthma and Mite Allergy birth cohort whether breast milk adiponectin is associated with childhood BMI and cardio-metabolic markers. We measured adiponectin levels in breast milk collected around 3 months after birth of the child and subsequently obtained weight and height repeatedly up to the age of 17 years. A medical examination (including blood pressure, glycated Hb and cholesterol) was performed at the age of 8, 12 and 16 years. We used multivariable mixed models to assess the association between breast milk adiponectin and BMI and cardio-metabolic markers at these ages. In models adjusted for exact age of breast milk collection, maternal age, presence of siblings, maternal BMI, pregnancy weight gain and child's birth weight, each unit increase in log breast milk adiponectin (in ng/ml) was associated with a 0·28 lower BMI z score (95 % CI -0·56, 0·00) at 3 months. After the age of 1 year, there was a tendency towards a higher BMI z score with increased breast milk adiponectin at some ages, but this pattern was not consistent throughout childhood. There were no associations between breast milk adiponectin and any of the cardio-metabolic markers in childhood. We conclude that in our study with follow-up until 17 years of age, breast milk adiponectin has no long-term effect on BMI and cardio-metabolic health during childhood.

Dietary guidelines for pure fruit juice consumption differ between countries, regarding the question whether pure fruit juice is an acceptable alternative for fruit. Currently, little is known about pure fruit juice consumption and the risk of CVD. In this prospective cohort study, we studied the association of pure fruit juice and fruit consumption with the incidence of fatal and non-fatal CVD, CHD and stroke and investigated the differences in association with pure fruit juice consumption between low and high fruit consumers. A validated FFQ was used to estimate dietary intake of 34 560 participants (26·0 % men and 74·0 % women) aged 20-69 years from the European Prospective Investigation into Cancer and Nutrition-Netherlands study. Adjusted hazard ratios (HR) were estimated using Cox regression after average follow-up of 14·6 years. Compared with no consumption, pure fruit juice consumption up to 7 glasses/week - but not consumption of ≥8 glasses - was significantly associated with reduced risk of CVD and CHD, with HR from 0·83 (95 % CI 0·73, 0·95) to 0·88 (95 % CI 0·80, 0·97). Consumption of 1-4 and 4-8 glasses/week was significantly associated with lower risk of stroke with HR of 0·80 (95 % CI 0·64, 0·99) and 0·76 (95 % CI 0·61, 0·94), respectively. Associations did not differ considerably between low and high fruit consumers. The highest three quintiles of fruit consumption (≥121 g/d) were significantly associated with lower incidence of CVD, with HR of 0·87 (95 % CI 0·78, 0·97) and 0·88 (95 % CI 0·80, 0·98). In conclusion, although we observed favourable associations of moderate pure fruit juice consumption with CVD, for now consumption of whole fruit should be preferred because the evidence of the health benefits of fruit is more conclusive.

Background: Air pollution, traffic noise and absence of green space may contribute to the development of overweight in children., Objectives: To investigate the combined associations of air pollution, traffic noise and green space with overweight throughout childhood., Methods: We used data for 3680 participants of the Dutch PIAMA birth cohort. We estimated exposure to air pollution, traffic noise and green space (i.e. the average Normalized Difference Vegetation Index (NDVI) and percentages of green space in circular buffers of 300 m and 3000 m) at the children's home addresses at the time of parental reported weight and height measurements. Associations of these exposures with overweight from age 3 to 17 years were analyzed by generalized linear mixed models, adjusting for potential confounders. Odds ratios (OR's) are presented for an interquartile range increase in exposure., Results: odds of being overweight increased with increasing exposure to NO 2 (adjusted OR 1.40 [95% confidence interval (CI) 1.12-1.74] per 8.90 µg/m 3 ) and tended to decrease with increasing exposure to green space in a 3000 m buffer (adjusted OR 0.86 [95% CI 0.71-1.04] per 0.13 increase in the NDVI; adjusted OR 0.86 [95% CI 0.71-1.03] per 29.5% increase in the total percentage of green space). After adjustment for NO 2 , the associations with green space in a 3000 m buffer weakened. No associations of traffic noise with overweight throughout childhood were found. In children living in an urban area, living further away from a park was associated with a lower odds of being overweight (adjusted OR 0.67 [95% CI 0.52-0.85] per 359.6 m)., Conclusions: Exposure to traffic-related air pollution, but not traffic noise or green space, may contribute to childhood overweight. Future studies examining the associations of green space with childhood overweight should account for air pollution exposure., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Annual influenza immunization in medical risk groups is recommended in many countries. Recent evidence suggests that repeated inactivated influenza vaccine (IIV) immunization throughout childhood may impair long-term immunity against influenza. We assessed whether prior immunization altered the effect of IIV in children with preexisting medical conditions on primary care-diagnosed respiratory illness (RI) episodes during the influenza season., Methods: Electronic records of IIV-immunized children who met the criteria for annual IIV immunization according to Dutch guidelines were extracted from a primary care database from 2004 to 2015. For each year, we collected information on IIV immunization status, primary care-attended RI episodes (including influenza-like illness, acute RI, and asthma exacerbation), and potential confounders. Generalized estimating equations were used to model the association between prior IIV and occurrence of at least one RI episode during the influenza season, with "current year immunized but without IIV history" as reference group., Results: A total of 4,183 children (follow-up duration: 11,493 child-years) were IIV immunized at least once. Adjusted estimates showed lower odds for RI in current year-immunized children with prior IIV compared with those without (odds ratio [OR] = 0.61; 95% CI, 0.47-0.78 for "current year immunized and one IIV in previous 2 years"; OR = 0.85; 95% CI, 0.68-1.07 for "current year immunized and ≥2 IIVs in previous 3 years, including prior year")., Conclusion: Repeated IIV immunization in children with preexisting medical conditions has no negative impact on, and may even increase, long-term protection against RI episodes diagnosed during the influenza season in primary care., (© 2019 Annals of Family Medicine, Inc.)

Atherosclerotic changes can be measured as changes in common carotid intima media thickness (CIMT). It is hypothesised that repeated infection-associated inflammatory responses in childhood contribute to the atherosclerotic process. We set out to determine whether the frequency of infectious diseases in childhood is associated with CIMT in adolescence. The study is part of the Prevention and Incidence of Asthma and Mite Allergy (PIAMA) population-based birth cohort. At age 16 years, common CIMT was measured. We collected general practitioner (GP) diagnosed infections and prescribed antibiotics. Parent-reported infections were retrieved from annual questionnaires. Linear regression analysis assessed the association between number of infections during the first 4 years of life and common CIMT. Common CIMT measurement, GP and questionnaire data were available for 221 participants. No association was observed between the infection measures and CIMT. In a subgroup analysis, significant positive associations with CIMT were observed in participants with low parental education for 2-3 or ⩾7 GP diagnosed infections (+26.4 µm, 95% CI 0.4-52.4 and +26.8 µm, 95% CI 3.6-49.9, respectively) and ⩾3 antibiotic prescriptions (+35.5 µm, 95%CI 15.8-55.3). Overall, early childhood infections were not associated with common CIMT in adolescence. However, a higher number of childhood infections might contribute to the inflammatory process of atherosclerosis in subgroups with low education, this needs to be confirmed in future studies.

Background: Gestational weight gain differs according to pre-pregnancy body mass index and is related to the risks of adverse maternal and child health outcomes. Gestational weight gain charts for women in different pre-pregnancy body mass index groups enable identification of women and offspring at risk for adverse health outcomes. We aimed to construct gestational weight gain reference charts for underweight, normal weight, overweight, and grades 1, 2 and 3 obese women and to compare these charts with those obtained in women with uncomplicated term pregnancies., Methods: We used individual participant data from 218,216 pregnant women participating in 33 cohorts from Europe, North America, and Oceania. Of these women, 9065 (4.2%), 148,697 (68.1%), 42,678 (19.6%), 13,084 (6.0%), 3597 (1.6%), and 1095 (0.5%) were underweight, normal weight, overweight, and grades 1, 2, and 3 obese women, respectively. A total of 138, 517 women from 26 cohorts had pregnancies with no hypertensive or diabetic disorders and with term deliveries of appropriate for gestational age at birth infants. Gestational weight gain charts for underweight, normal weight, overweight, and grade 1, 2, and 3 obese women were derived by the Box-Cox t method using the generalized additive model for location, scale, and shape., Results: We observed that gestational weight gain strongly differed per maternal pre-pregnancy body mass index group. The median (interquartile range) gestational weight gain at 40 weeks was 14.2 kg (11.4-17.4) for underweight women, 14.5 kg (11.5-17.7) for normal weight women, 13.9 kg (10.1-17.9) for overweight women, and 11.2 kg (7.0-15.7), 8.7 kg (4.3-13.4) and 6.3 kg (1.9-11.1) for grades 1, 2, and 3 obese women, respectively. The rate of weight gain was lower in the first half than in the second half of pregnancy. No differences in the patterns of weight gain were observed between cohorts or countries. Similar weight gain patterns were observed in mothers without pregnancy complications., Conclusions: Gestational weight gain patterns are strongly related to pre-pregnancy body mass index. The derived charts can be used to assess gestational weight gain in etiological research and as a monitoring tool for weight gain during pregnancy in clinical practice.

The parallel epidemics of childhood asthma and obesity over the past few decades have spurred research into obesity as a risk factor for asthma. However, little is known regarding the role of asthma in obesity incidence. We examined whether early-onset asthma and related phenotypes are associated with the risk of developing obesity in childhood.This study includes 21 130 children born from 1990 to 2008 in Denmark, France, Germany, Greece, Italy, The Netherlands, Spain, Sweden and the UK. We followed non-obese children at 3-4 years of age for incident obesity up to 8 years of age. Physician-diagnosed asthma, wheezing and allergic rhinitis were assessed up to 3-4 years of age.Children with physician-diagnosed asthma had a higher risk for incident obesity than those without asthma (adjusted hazard ratio (aHR) 1.66, 95% CI 1.18-2.33). Children with active asthma (wheeze in the last 12 months and physician-diagnosed asthma) exhibited a higher risk for obesity (aHR 1.98, 95% CI 1.31-3.00) than those without wheeze and asthma. Persistent wheezing was associated with increased risk for incident obesity compared to never wheezers (aHR 1.51, 95% CI 1.08-2.09).Early-onset asthma and wheezing may contribute to an increased risk of developing obesity in later childhood., Competing Interests: Conflict of interest: L. Duijts reports grants from European Union's Horizon 2020 co-funded programme ERA-Net on Biomarkers for Nutrition and Health (ERA HDHL) (the ALPHABET project (number 696295; 2017) and ZonMW The Netherlands (number 529051014; 2017)) and grants from the European Union's Horizon 2020 programme (the LIFECYCLE project, grant agreement number 733206; 2016), during the conduct of the study. Conflict of interest: B. Gerhard reports grants from the EU FP7, during the conduct of the study. Conflict of interest: H. Inskip reports grants (salary) from the UK Medical Research Council, grants from the British Heart Foundation, the UK Food Standards Agency, the British Lung Foundation, Arthritis Research UK, the NIHR Southampton Biomedical Research Centre and the European Union's Seventh Framework Programme (FP7/2007-2013, project EarlyNutrition under grant agreement number 289346), during the conduct of the study; and members of H. Inskip's team have received funding from Nestec, Abbott Nutrition and Danone Nutricia for various projects to which she is linked, but she has received no direct funding herself. Conflict of interest: S. Lau reports grants and personal fees (honoraria) from Symbiopharm and Allergopharma, personal fees (honoraria) and non-financial support (advisory board work) from DBV, personal fees from ALK, and non-financial support (advisory board work) from Boehringer and Merck, outside the submitted work. Conflict of interest: D. Maier reports grants from the European Commission (FP7 MeDALL, 261357), during the conduct of the study., (Copyright ©ERS 2018.)

Evidence for the effects of air pollution exposure on lung function growth into adolescence is scarce. We investigated associations of air pollution exposure with lung function and lung function growth until age 16.We conducted both longitudinal (n=915) and cross-sectional (n=721) analyses of associations of air pollution exposure with forced expiratory volume in 1 s (FEV 1 ) and forced vital capacity (FVC) growth from ages eight to 16 and FEV 1 and FVC at age 16. We estimated residential concentrations of nitrogen dioxide (NO 2 ), "soot" and particulate matter (PM x , where x is the 50% cut-off aerodynamic diameter in µm) with diameters of <2.5 µm (PM 2.5 ), <10 µm (PM 10 ) and 2.5-10 µm (PM coarse ) during the preschool, primary school and secondary school time windows by land use regression models. Associations with (growth in) FEV 1 and FVC were analysed by linear (mixed effects) regression.Higher air pollution exposure was associated with reduced FEV 1 growth ( e.g. adjusted difference -0.26% (95% CI -0.49 to -0.03%) per interquartile range increase in secondary school PM 2.5 ) and lower FEV 1 (adjusted difference -2.36% (95% CI -3.76 to -0.94%)), but was not adversely associated with FVC. Associations with FEV 1 were stronger in boys than girls and were not modified by asthma status.Higher air pollution exposure may lead to increased airway obstruction, but not reduced lung volume in adolescence., Competing Interests: Conflict of interest: G.H. Koppelman reports grants from the Lung Foundation of the Netherlands, during the conduct of the study; grants from the Lung Foundation of the Netherlands, the Ubbo Emmius Foundation, the TETRI Foundation and TEVA Netherlands, outside the submitted work. All funds were paid to G.H. Koppelman's institution., (Copyright ©ERS 2018.)

Purpose: To investigate whether early introduction of complementary foods (CF) is associated with an increased risk of overweight during childhood, and whether this association differs between formula-fed and breastfed infants., Methods: We included 2611 participants that were born at term from a Dutch population-based birth cohort (n = 3963) designed to investigate the development of asthma and allergies. Parents kept records of their infant's age when CF were first introduced. Weight and height were parent reported yearly from age 1 to 8 years, and at ages 11, 14 and 17 years. We used multivariate generalized estimating equations analysis to investigate the association between timing of CF introduction (before 4 months vs at or after 4 months of age) and overweight at ages 1-17 years., Results: Children with CF introduction before 4 months had higher odds of being overweight during childhood than children with CF introduction at or after 4 months (OR 1.32, 95% CI 1.19, 1.47). This association was observed in formula-fed infants (OR 1.51, 95% CI 1.17, 1.94) and breastfed infants (OR 1.32, 95% CI 1.19, 1.47). The duration of breastfeeding modified the association between CF introduction and overweight: children breastfed for shorter than 4 months, but not children breastfed for 4 months or longer with CF introduction before 4 months had higher odds of being overweight (OR 1.37, 95% CI 1.19, 1.57 and 1.07, 95% CI 0.87, 1.32, respectively), compared to those with CF introduction at or after 4 months., Conclusions: In children born at term, formula-fed infants and infants who were breastfed for shorter than 4 months, but not infants who were breastfed for 4 months or longer, had a higher risk of being overweight during childhood when being introduced to CF before 4 months of age.

Background: Air pollution has been found to adversely affect children's lung function. Forced expiratory volume in 1 s and forced vital capacity from spirometry have been studied most frequently, but measurements of airway resistance may provide additional information. We assessed associations of long-term air pollution exposure with airway resistance., Methods: We measured airway resistance at age 8 with the interrupter resistance technique (R int ) in participants of the Dutch PIAMA birth cohort study. We linked R int with estimated annual average air pollution concentrations [nitrogen oxides (NO 2 , NO x ), PM 2.5 absorbance ("soot"), and particulate matter < 2.5 μm (PM 2.5 ), < 10 μm (PM 10 ) and 2.5-10 μm (PM coarse )] at the birth address and current home address (n = 983). Associations between air pollution exposure and interrupter resistance (R int ) were assessed using multiple linear regression adjusting for potential confounders., Results: We found that higher levels of NO 2 at the current address were associated with higher R int [adj. mean difference (95% confidence interval) per interquartile range increase in NO 2 : 0.018 (0.001, 0.035) kPa·s·L - 1 ]. Similar trends were observed for the other pollutants, except, PM 10 . No association was found between R int and exposure at the birth address., Conclusions: Our results support the hypothesis that air pollution exposure is associated with a lower lung function in schoolchildren.

The objective of this study was to explore trajectories of lung function decline with age in the general population, and to study the effect of sociodemographic and life style related risk factors, in particular smoking and BMI. For this purpose, we used data from the Doetinchem Cohort Study (DCS) of men and women, selected randomly from the general population and aged 20-59 years at inclusion in 1987-1991, and followed until the present. Participants in the DCS are assessed every five years. Spirometry has been performed as part of this assessment from 1994 onwards. Participants were included in this study if spirometric measurement of FEV1, which in this study was the main parameter of interest, was acceptable and reproducible on at least one measurement round, leading to the inclusion of 5727 individuals (3008 females). Statistical analysis revealed three typical trajectories. The majority of participants followed a trajectory that closely adhered to the Global Lung Initiative Reference values (94.9% of men and 96.4% of women). Two other trajectories showed a more pronounced decline. Smoking and the presence of respiratory complaints were the best predictors of a trajectory with stronger decline. A greater BMI over the follow-up period was associated with a more unfavorable FEV1 course both in men (β = -0.027 (SD = 0.002); P < 0.001) and in women (β = -0.008 (SD = 0.001); P < 0.001). Smokers at baseline who quit the habit during follow-up, showed smaller decline in FEV1 in comparison to persistent smokers, independent of BMI change (In men β = -0.074 (SD = 0.020); P < 0.001. In women β = -0.277 (SD = 0.068); P < 0.001). In conclusion, three typical trajectories of age-related FEV1 decline could be distinguished. Change in the lifestyle related risk factors, BMI and smoking, significantly impact aging-related decline of lung function. Identifying deviant trajectories may help in early recognition of those at risk of a diagnosis of lung disease later in life.

Background: DNA methylation profiles associated with childhood asthma might provide novel insights into disease pathogenesis. We did an epigenome-wide association study to assess methylation profiles associated with childhood asthma., Methods: We did a large-scale epigenome-wide association study (EWAS) within the Mechanisms of the Development of ALLergy (MeDALL) project. We examined epigenome-wide methylation using Illumina Infinium Human Methylation450 BeadChips (450K) in whole blood in 207 children with asthma and 610 controls at age 4-5 years, and 185 children with asthma and 546 controls at age 8 years using a cross-sectional case-control design. After identification of differentially methylated CpG sites in the discovery analysis, we did a validation study in children (4-16 years; 247 cases and 2949 controls) from six additional European cohorts and meta-analysed the results. We next investigated whether replicated CpG sites in cord blood predict later asthma in 1316 children. We subsequently investigated cell-type-specific methylation of the identified CpG sites in eosinophils and respiratory epithelial cells and their related gene-expression signatures. We studied cell-type specificity of the asthma association of the replicated CpG sites in 455 respiratory epithelial cell samples, collected by nasal brushing of 16-year-old children as well as in DNA isolated from blood eosinophils (16 with asthma, eight controls [age 2-56 years]) and compared this with whole-blood DNA samples of 74 individuals with asthma and 93 controls (age 1-79 years). Whole-blood transcriptional profiles associated with replicated CpG sites were annotated using RNA-seq data of subsets of peripheral blood mononuclear cells sorted by fluorescence-activated cell sorting., Findings: 27 methylated CpG sites were identified in the discovery analysis. 14 of these CpG sites were replicated and passed genome-wide significance (p<1·14 × 10 -7 ) after meta-analysis. Consistently lower methylation levels were observed at all associated loci across childhood from age 4 to 16 years in participants with asthma, but not in cord blood at birth. All 14 CpG sites were significantly associated with asthma in the second replication study using whole-blood DNA, and were strongly associated with asthma in purified eosinophils. Whole-blood transcriptional signatures associated with these CpG sites indicated increased activation of eosinophils, effector and memory CD8 T cells and natural killer cells, and reduced number of naive T cells. Five of the 14 CpG sites were associated with asthma in respiratory epithelial cells, indicating cross-tissue epigenetic effects., Interpretation: Reduced whole-blood DNA methylation at 14 CpG sites acquired after birth was strongly associated with childhood asthma. These CpG sites and their associated transcriptional profiles indicate activation of eosinophils and cytotoxic T cells in childhood asthma. Our findings merit further investigations of the role of epigenetics in a clinical context., Funding: EU and the Seventh Framework Programme (the MeDALL project)., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Green space may influence health through several pathways, for example, increased physical activity, enhanced social cohesion, reduced stress, and improved air quality. For green space to increase physical activity and social cohesion, spending time in green spaces is likely to be important., Objectives: We examined whether adolescents visit green spaces and for what purposes. Furthermore, we assessed the predictors of green space visits., Methods: In this cross-sectional study, data for 1911 participants of the Dutch PIAMA (Prevention and Incidence of Asthma and Mite Allergy) birth cohort were analyzed. At age 17, adolescents reported how often they visited green spaces for physical activities, social activities, relaxation, and to experience nature and quietness. We assessed the predictors of green space visits altogether and for different purposes by log-binomial regression., Results: Fifty-three percent of the adolescents visited green spaces at least once a week in summer, mostly for physical and social activities. Adolescents reporting that a green environment was (very) important to them visited green spaces most frequently {adjusted prevalence ratio (PR) [95% confidence interval (CI)] very vs. not important: 6.84 (5.10, 9.17) for physical activities and 4.76 (3.72, 6.09) for social activities}. Boys and adolescents with highly educated fathers visited green spaces more often for physical and social activities. Adolescents who own a dog visited green spaces more often to experience nature and quietness. Green space visits were not associated with the objectively measured quantity of residential green space, i.e., the average normalized difference vegetation index (NDVI) and percentages of urban, agricultural, and natural green space in circular buffers around the adolescents' homes., Conclusions: Subjective variables are stronger predictors of green space visits in adolescents than the objectively measured quantity of residential green space. https://doi.org/10.1289/EHP2429.

Background: The role of tobacco smoke exposure in the development and persistence of asthma and rhinoconjunctivitis through childhood into adolescence is unclear., Objectives: We assessed the associations of parental smoking from fetal life through adolescence with asthma and rhinoconjunctivitis during childhood and adolescence., Methods: We analyzed data for 10,860 participants of five European birth cohort studies from the Mechanisms of the Development of Allergy (MeDALL) consortium. Parental smoking habits and health outcomes (early transient, persistent, and adolescent-onset asthma and rhinoconjunctivitis) were based on questionnaires covering the period from pregnancy to 14-16 y of age. Data were combined and analyzed using a one-stage and two-stage individual participant data meta-analysis., Results: Overall, any maternal smoking during pregnancy tended to be associated with an increased odds of prevalent asthma [adjusted odds ratio (aOR)=1.19 (95% CI: 0.98, 1.43)], but not prevalent rhinoconjunctivitis [aOR=1.05 (95% CI: 0.90, 1.22)], during childhood and adolescence. In analyses with phenotypes related to age of onset and persistence of disease, any maternal smoking during pregnancy was associated with early transient asthma [aOR=1.79 (95% CI: 1.14, 2.83)]. Maternal smoking of ≥10 cigarettes/day during pregnancy was associated with persistent asthma [aOR=1.66 (95% CI: 1.29, 2.15)] and persistent rhinoconjunctivitis [aOR=1.55 (95% CI, 1.09, 2.20)]. Tobacco smoke exposure during fetal life, infancy, childhood, and adolescence was not associated with adolescent-onset asthma or rhinoconjunctivitis., Conclusions: Findings from this combined analysis of five European birth cohorts strengthen evidence linking early exposure to tobacco smoke with asthma during childhood and adolescence. Children with high early-life exposure were more likely than unexposed children to have early transient and persistent asthma and persistent rhinoconjunctivitis. https://doi.org/10.1289/EHP2738.

To investigate whether children who consumed infant formula supplemented with long-chain polyunsaturated fatty acids (LCPUFAs) had a more favourable cardiovascular profile than children who consumed formula without these fatty acids, we used the Wheezing Illnesses Study Leidsche Rijn, a birth cohort that included 2,468 newborns between 2001 and 2014. Data on infant feeding were obtained by questionnaires. At age 5, blood pressure, carotid intima-media thickness (CIMT), and carotid distension were measured. We used multivariable linear regression analysis to compare levels of cardiovascular markers in formula-fed children born before and after the LCPUFA supplementation. To account for secular trends, we compared levels of cardiovascular markers in a control group of breastfed children from the same cohort born before and after the supplementation. Formula-fed children born after the LCPUFA supplementation (n = 48) had no different systolic blood pressure (-2.58 mmHg, 95% confidence interval, CI [-5.5, 0.30]), diastolic blood pressure (-0.13 mmHg, 95% CI [-2.3, 2.1]), or carotid distension (24.8 MPa -1 , 95% CI [-47.1, 96.6]) and had a higher CIMT (18.6 μm, 95% CI [3.7, 33.5]) than formula-fed children born before the supplementation (n = 163). In the control group, children born after the LCPUFA supplementation (n = 98) had no different systolic- or diastolic-blood pressure, or CIMT, and a higher carotid distension than children born before the supplementation (n = 142). In conclusion, children who consumed infant formula supplemented with LCPUFAs did not have a more favourable cardiovascular profile in early childhood than children who consumed formula without LCPUFAs., (© 2017 John Wiley & Sons Ltd.)

Introduction: Cardiovascular diseases (CVDs) are the most common cause of non-communicable disease mortality in sub-Saharan African (SSA) countries. Gaps in knowledge of CVD conditions and their risk factors are important barriers in effective prevention and treatment. Yet, evidence on the awareness and knowledge level of CVD and associated risk factors among populations of SSA is scarce. This review aimed to synthesize available evidence of the level of knowledge of and perceptions towards CVDs and risk factors in the SSA region., Methods: Five databases were searched for publications up to December 2016. Narrative synthesis was conducted for knowledge level of CVDs, knowledge of risk factors and clinical signs, factors influencing knowledge of CVDs and source of health information on CVDs. The review was registered with Prospero (CRD42016049165)., Results: Of 2212 titles and abstracts screened, 45 full-text papers were retrieved and reviewed and 20 were included: eighteen quantitative and two qualitative studies. Levels of knowledge and awareness for CVD and risk factors were generally low, coupled with poor perception. Most studies reported less than half of their study participants having good knowledge of CVDs and/or risk factors. Proportion of participants who were unable to identify a single risk factor and clinical symptom for CVDs ranged from 1.8% in a study among hospital staff in Nigeria to a high of 73% in a population-based survey in Uganda and 7% among University staff in Nigeria to 75.1% in a general population in Uganda respectively. High educational attainment and place of residence had a significant influence on the levels of knowledge for CVDs among SSA populations., Conclusion: Low knowledge of CVDs, risk factors and clinical symptoms is strongly associated with the low levels of educational attainment and rural residency in the region. These findings provide useful information for implementers of interventions targeted at the prevention and control of CVDs, and encourages them to incorporate health promotion and awareness campaigns in order to enhance knowledge and awareness of CVDs in the region.

Background: Population cohort studies are useful to study infectious diseases episodes not attended by health care services, but conventional paper diaries and questionnaires to capture cases are prone to noncompliance and recall bias. Use of smart technology in this setting may improve case finding., Objective: The objective of our study was to validate an interactive mobile app for monitoring occurrence of acute infectious diseases episodes in individuals, independent of health care seeking, using acute otitis media (AOM) symptom episodes in infants as a case study. We were interested in determining participant compliance and app performance in detecting and ascertaining (parent-reported) AOM symptom episodes with this novel tool compared with traditional methods used for monitoring study participants., Methods: We tested the InfectieApp research app to detect AOM symptom episodes. In 2013, we followed 155 children aged 0 to 3 years for 4 months. Parents recorded the presence of AOM symptoms in a paper diary for 4 consecutive months and completed additional disease questionnaires when AOM symptoms were present. In 2015 in a similar cohort of 69 children, parents used an AOM diary and questionnaire app instead., Results: During conventional and app-based recording, 93.13% (17,244/18,516) and 94.56% (7438/7866) of symptom diaries were returned, respectively, and at least one symptom was recorded for 32.50% (n=5606) and 43.99% (n=3272) of diary days (P<.01). The incidence of AOM symptom episodes was 605 and 835 per 1000 child-years, respectively. Disease questionnaires were completed for 59% (17/29) of episodes when participants were using conventional recording, compared with 100% (18/18) for app-based recording., Conclusions: The use of the study's smart diary app improved AOM case finding and disease questionnaire completeness. For common infectious diseases that often remain undetected by health care services, use of this technology can substantially improve the accurateness of disease burden estimates., (©Annemarijn C Prins-van Ginkel, Marieke LA de Hoog, C Uiterwaal, Henriette A Smit, Patricia CJ Bruijning-Verhagen. Originally published in JMIR Mhealth and Uhealth (http://mhealth.jmir.org), 28.11.2017.)

Pre-pregnancy maternal obesity is associated with adverse offspring outcomes at birth and later in life. Individual studies have shown that epigenetic modifications such as DNA methylation could contribute. Within the Pregnancy and Childhood Epigenetics (PACE) Consortium, we meta-analysed the association between pre-pregnancy maternal BMI and methylation at over 450,000 sites in newborn blood DNA, across 19 cohorts (9,340 mother-newborn pairs). We attempted to infer causality by comparing the effects of maternal versus paternal BMI and incorporating genetic variation. In four additional cohorts (1,817 mother-child pairs), we meta-analysed the association between maternal BMI at the start of pregnancy and blood methylation in adolescents. In newborns, maternal BMI was associated with small (<0.2% per BMI unit (1 kg/m2), P < 1.06 × 10-7) methylation variation at 9,044 sites throughout the genome. Adjustment for estimated cell proportions greatly attenuated the number of significant CpGs to 104, including 86 sites common to the unadjusted model. At 72/86 sites, the direction of the association was the same in newborns and adolescents, suggesting persistence of signals. However, we found evidence for acausal intrauterine effect of maternal BMI on newborn methylation at just 8/86 sites. In conclusion, this well-powered analysis identified robust associations between maternal adiposity and variations in newborn blood DNA methylation, but these small effects may be better explained by genetic or lifestyle factors than a causal intrauterine mechanism. This highlights the need for large-scale collaborative approaches and the application of causal inference techniques in epigenetic epidemiology., (© The Author 2017. Published by Oxford University Press.)

Objective: To examine the association between pubertal timing and cardiometabolic markers among adolescents., Study Design: We used data from Dutch adolescents participating in a birth cohort study. The study population for the current study consisted of 799 adolescents of whom data were available for at least 1 of the exposure variables (pubertal timing and/or age at menarche) and any of the cardiometabolic markers (waist circumference, cholesterol, blood pressure [BP], glycated hemoglobin) measured at age 16 years. Adolescents self-reported pubertal development at ages 11, 14, and 16 years. We categorized participants with early (84 girls, 88 boys), intermediate (240 girls, 211 boys), or late pubertal timing (89 girls, 85 boys). We estimated differences in cardiometabolic markers using linear regression analysis., Results: Girls with early pubertal timing had 1.54 cm larger waist circumference (95% CI .05; 3.03) and 3.98 mm Hg higher systolic BP (95% CI 1.69; 6.27) at age 16 years than girls with intermediate pubertal timing. The association with systolic BP remained after adjusting for childhood body mass index (BMI) (age 8 years) but attenuated after adjusting for BMI in adolescence (age 16 years). Boys with early pubertal timing had 0.79 mmol/mol lower glycated hemoglobin (95%CI -1.38; -0.20) than boys with intermediate pubertal timing., Conclusions: Girls with early pubertal timing had unfavorable BP levels at age 16 years, independent of BMI in childhood. Girls and boys with late pubertal timing had a tendency for lower waist circumference, but no differences in other cardiometabolic markers. Late pubertal timing does not appear to be a risk factor for unfavorable cardiometabolic markers in adolescence., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Being born large for gestational age (LGA) is a marker of increased growth velocity in fetal life and a risk factor for childhood overweight. Both being born LGA and childhood overweight may influence the development of asthma, although the role of overweight in the association between LGA and childhood asthma is unclear. Importantly, recent studies have suggested that the association between overweight and asthma may be related to non-allergic pathways. If this also applies to the association between LGA and asthma, the association between being born LGA and asthma may be different for atopic and non-atopic children., Objective: We investigated the association of being LGA with the prevalence of asthma at age 8 in atopic and non-atopic children and the role of overweight in this association., Methods: Complete data on asthma, anthropometry and atopy at age of 8 years, and potential confounders were available for 1608 participants of the PIAMA birth cohort. Odds ratios for the association between LGA and asthma in atopic and non-atopic children were estimated by logistic regression analysis adjusting for potential confounders. Overweight was assessed as a potential modifier of the association between LGA and asthma., Results: Being born LGA was not significantly associated with asthma at age of 8 in atopic and non-atopic children. However, overweight at age of 8 years modified the association between asthma at age of 8 and LGA. In non-atopic children, children who were born LGA and were overweight at age of 8 years had a significantly increased odds of asthma compared to non-LGA, non-overweight children (adj OR 7.04; 95% CI 2.2-24)., Conclusions: We observed that non-atopic children born LGA, who were overweight by 8 years have an increased risk of asthma. If confirmed, these findings suggest that non-atopic children born LGA may be identified early in life as a high-risk group for asthma., (© 2017 John Wiley & Sons Ltd.)

While there is evidence for variations in prevalence rates of childhood wheeze and asthma between countries, longitudinal, individual-level data are needed to understand these differences. The aim of this study was to examine variations in prevalence rates of childhood asthma, wheeze and wheeze with asthma in Europe. We analysed datasets from 10 MeDALL (Mechanisms of the Development of ALLergy) cohorts in eight countries, representing 26 663 children, to calculate prevalence rates of wheeze and asthma by child age and wheeze with asthma at age 4 years. Harmonised variables included outcomes parent-reported wheeze and parent-reported doctor-diagnosed asthma, and covariates maternal education, parental smoking, pets, parental asthma, doctor-diagnosed allergic rhinitis, doctor-diagnosed eczema and wheeze severity. At age 4 years, asthma prevalence varied from 1.72% in Germany to 13.48% in England and the prevalence of wheeze varied from 9.82% in Greece to 55.37% in Spain. Adjusted estimates of the proportion of 4-year-old children with wheeze diagnosed with asthma remained highest in England (38.14%, 95% CI 31.38-44.90%) and lowest in Spain (15.94%, 95% CI 6.16-25.71%). The large differences in prevalence rates of asthma, wheeze and wheeze with asthma at age 4 years between European cohorts may indicate that childhood asthma is more readily diagnosed in some countries while going unrecognised elsewhere., Competing Interests: Conflict of interest: Disclosures can be found alongside this article at openres.ersjournals.com

Background: Risk factors often develop at young age and are maintained over time, but it is not fully understood how risk factors develop over time preceding type 2 diabetes. We examined how levels and trajectories of metabolic risk factors and biochemical markers prior to diagnosis differ between persons with and without type 2 diabetes over 15-20 years., Methods: A total of 355 incident type 2 diabetes cases (285 self-reported, 70 with random glucose ⩾11.1 mmol l -1 ) and 2130 controls were identified in a prospective cohort between 1987-2012. Risk factors were measured at 5-year intervals. Trajectories preceding case ascertainment were analysed using generalised estimating equations., Results: Among participants with a 21-year follow-up period, those with type 2 diabetes had higher levels of metabolic risk factors and biochemical markers 15-20 years before case ascertainment. Subsequent trajectories were more unfavourable in participants with type 2 diabetes for body mass index (BMI), HDL cholesterol and glucose (P<0.01), and to a lesser extent for waist circumference, diastolic and systolic blood pressure, triglycerides, alanine aminotransferase, gamma glutamyltransferase, C-reactive protein, uric acid and estimated glomerular filtration rate compared with participants without type 2 diabetes. Among persons with type 2 diabetes, BMI increased by 5-8% over 15 years, whereas the increase among persons without type 2 diabetes was 0-2% (P<0.01). The observed differences in trajectories of metabolic risk factors and biochemical markers were largely attenuated after inclusion of BMI in the models. Results were similar for men and women., Conclusions: Participants with diabetes had more unfavourable levels of metabolic risk factors and biochemical markers already 15-20 years before diagnosis and worse subsequent trajectories than others. Our results highlight the need, in particular, for maintenance of a healthy weight from young adulthood onwards for diabetes prevention.

The mitochondrial genome of Sarothrura ayresi was sequenced using next generation sequencing technology. The size of the genome is reported as 16,767 bp and comprises 13 protein-coding genes, 2 rRNAs and 22 tRNAs. The organization of the genome is comparable to that of other bird species. A phylogenetic comparison mapped the relative relationship of Sarothrura ayresi with respect to other species in the order Gruiformes., Competing Interests: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper., (© 2017 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Background: Age at exposure to acute otitis media (AOM) risk factors such as day care attendance, lack of breastfeeding and tobacco smoke is little studied but important for targeting AOM prevention strategies. Moreover, studies are typically restricted to clinically diagnosed AOM, while a significant subset can occur outside the health care system, depending on the country setting. This study aims to determine risk factor exposure and effect of its timing within the first year of life on parent-reported AOM symptom episodes., Methods: In the WHeezing and Illnesses STudy LEidsche Rijn birth-cohort study, 1056 children were prospectively followed during their first year of life. Group day care attendance, breastfeeding and tobacco smoke exposure were recorded monthly and parent-reported AOM symptoms daily. Generalized estimating equations were used to estimate the association between the time-varying risk factors and AOM symptom episodes, while correcting for confounding by indication., Results: The first-year incidence rate of parent-reported AOM was 569/1000 child-years [95% confidence interval (CI): 523-618]. Children who attended day care had higher odds of developing AOM symptom episodes compared with those not attending (odds ratio: 5.0; 95% CI: 2.6-9.6). Tobacco smoke exposure and (a history of) breastfeeding were not associated with AOM. Test for interaction revealed that the effect of day care increased with each month younger in age., Conclusions: First-year day care attendance is a major risk factor for AOM symptom episodes among infants in the community. This adjusted effect estimate is higher than previously reported and is age-dependent. AOM prevention strategies in day care facilities should therefore focus in particular on the youngest age groups.

Background: Secondhand smoke (SHS) exposure is a modifiable risk factor associated with childhood asthma. Associations with adolescent asthma and the relevance of the timing and patterns of exposure are unclear. Knowledge of critical windows of exposure is important for targeted interventions., Methods: We used data until age 17 from 1454 children of the Dutch population-based PIAMA birth cohort. Residential SHS exposure was assessed through parental questionnaires completed at ages 3 months, 1-8 (yearly), 11, 14, and 17 years. Lifetime exposure was determined as; a) time window-specific exposure (prenatal, infancy, preschool, primary school, and secondary school); b) lifetime cumulative exposure; c) longitudinal exposure patterns using latent class growth modeling (LCGM). Generalized estimation equations and logistic regression were used to analyze associations between exposure and asthma at ages 4 to 17 years, adjusting for potential confounders., Results: With all three methods, we consistently found no association between SHS exposure and asthma at ages 4 to 17 years e.g. adjusted overall odds ratio (95% confidence interval) 0.67 (0.41-1.12), 1.00 (0.66-1.51) and 0.67 (0.41-1.11) for prenatal maternal active smoking, infancy, and preschool school time window exposures, respectively., Conclusion: We assessed lifetime SHS exposure using different methods. Different timing and patterns of SHS exposure were not associated with an increased risk of asthma in childhood and adolescence in our study. More longitudinal studies could investigate effects of lifetime SHS exposure on asthma in adolescence and later life.