Accelerometry-assessed sleep clusters and cardiometabolic risk factors in adolescents.

OBJECTIVE: This study aimed to identify sleep clusters based on objective multidimensional sleep characteristics and test their associations with adolescent cardiometabolic health. METHODS: The authors included 1090 participants aged 14.3 to 16.4 years (mean = 15.2 years) who wore 7-day accelerometers during the 15-year follow-up of the German Infant Study on the influence of Nutrition Intervention PLUS environmental and genetic influences on allergy development (GINIplus) and the Influence of Lifestyle factors on the development of the Immune System and Allergies in East and West Germany (LISA) birth cohorts. K-means cluster analysis was performed across 12 sleep characteristics reflecting sleep quantity, quality, schedule, variability, and regularity. Cardiometabolic risk factors included fat mass index (FMI), blood pressure, triglycerides, high-density lipoprotein cholesterol, high-sensitivity C-reactive protein, and insulin resistance (n = 505). Linear and logistic regression models were examined. RESULTS: Five sleep clusters were identified: good sleep (n = 337); delayed sleep phase (n = 244); sleep irregularity and variability (n = 108); fragmented sleep (n = 313); and prolonged sleep latency (n = 88). The "prolonged sleep latency" cluster was associated with increased sex-scaled FMI (ß = 0.39, 95% CI: 0.15-0.62) compared with the "good sleep" cluster. The "sleep irregularity and variability" cluster was associated with increased odds of high triglycerides only in male individuals (odds ratio: 9.50, 95% CI: 3.22-28.07), but this finding was not confirmed in linear models. CONCLUSIONS: The prolonged sleep latency cluster was associated with higher FMI in adolescents, whereas the sleep irregularity and variability cluster was specifically linked to elevated triglycerides (≥1.7 mmol/L) in male individuals.

The Influence of Short-Term Weather Parameters and Air Pollution on Adolescent Airway Inflammation.

Fraction of exhaled Nitric Oxide (FeNO) is a marker of airway inflammation. We examined the main effects and interactions of relative humidity (RH) and air pollution on adolescents' FeNO. Two thousand and forty-two participants from the 15-year follow-up of the German GINIplus and LISA birth cohorts were included. Daily meteorological (maximum [Tmax], minimum [Tmin] and mean [Tmean] temperatures and RH) and air pollution [Ozone (O3), nitrogen dioxide (NO2) and particulate matter < 2.5 µm (PM2.5)] were assessed. Linear models were fitted with Ln(FeNO) as the outcome. Increases in FeNO indicate an increase in lung inflammation. Increased FeNO was associated with an increase in temperature, PM2.5, O3 and NO2. A 5% increase in RH was associated with a decrease in FeNO. Interactions between RH and high (p = 0.007) and medium (p = 0.050) NO2 were associated with increases in FeNO; while interactions between RH and high (p = 0.042) and medium (p = 0.040) O3 were associated with decreases in FeNO. Adverse effects were present for male participants, participants with low SES, participants with chronic respiratory disease, and participants from Wesel. Short-term weather and air pollution have an effect on lung inflammation in German adolescents. Future research should focus on further assessing the short-term effect of multiple exposures on lung inflammation in adolescents.

Undiagnosed Pediatric Elevated Blood Pressure Is Characterized by Induction of Proinflammatory and Cytotoxic Mediators.

BACKGROUND: Inflammatory processes have been suggested as a culprit of vascular damage in pediatric hypertension. We aimed to investigate transcriptional changes of immune modulators and determine their association with office blood pressure in adolescents who were not diagnosed with hypertension at the time of the study visit. METHODS: Office blood pressure measurements and blood samples were taken from adolescents of 2 German birth cohorts, GINIplus (The German Infant Study on the Influence of Nutrition Intervention Plus Air Pollution and Genetics on Allergy Development; discovery cohort, n=1219) and LISA (Influences of Lifestyle-related factors on the Immune System and the Development of Allergies in Childhood; validation cohort, n=809), during the 15-year follow-up visit and categorized based on the European Society of Hypertension Guideline. Hs-CRP (high-sensitivity C-reactive protein) and expression of 51 genes encoding cytokines/receptors and transcription factors were analyzed. RESULTS: The prevalence of elevated systolic blood pressure (overweight/obese) was 14.0% (5.1%) and 16.4% (5.2%) in the discovery and validation cohorts, respectively. An enhanced cytotoxic (GZMB, PRF1, IL2RB) and proinflammatory (FOS, IL1B, hs-CRP) immune profile was observed in association with the hypertension class in both cohorts. Expression of hs-CRP and IL1B was driven by overweight with IL1B being identified as a mediator between body mass index and elevated systolic blood pressure (adj.ß/95% CI, 0.01/0.0002-0.02). The association of GZMB (adjusted odds ratio/95% CI, 1.67/1.26-2.21; P=0.0004) and PRF1 (adjusted odds ratio/95% CI, 1.70/1.26-2.29; P=0.0005) in the hypertension class remained significant in normal-weight individuals without parental predisposition. These effects were confirmed in LISA. CONCLUSIONS: Adolescent hypertension is not limited to known risk groups. As adolescents in the hypertension class show an inflammatory profile similar to that of established hypertension in adults, blood pressure monitoring at a young age is critical to ensure early intervention and prevention of adverse sequelae.

Full Breastfeeding and Allergic Diseases-Long-Term Protection or Rebound Effects?

A previous follow-up of the GINIplus study showed that breastfeeding could protect against early eczema. However, effects diminished in adolescence, possibly indicating a "rebound effect" in breastfed children after initial protection. We evaluated the role of early eczema until three years of age on allergies until young adulthood and assessed whether early eczema modifies the association between breastfeeding and allergies. Data from GINIplus until 20-years of age (N = 4058) were considered. Information on atopic eczema, asthma, and rhinitis was based on reported physician's diagnoses. Adjusted Odds Ratios (aOR) were modelled by using generalized estimating equations. Early eczema was associated with eczema (aORs = 3.2-14.4), asthma (aORs = 2.2-2.7), and rhinitis (aORs = 1.2-2.7) until young adulthood. For eczema, this association decreased with age (p-for-interaction = 0.002-0.006). Longitudinal models did not show associations between breastfeeding and the respective allergies from 5 to 20 years of age. Moreover, early eczema generally did not modify the association between milk feeding and allergies except for rhinitis in participants without family history of atopy. Early eczema strongly predicts allergies until young adulthood. While preventive effects of full breastfeeding on eczema in infants with family history of atopy does not persist until young adulthood, the hypothesis of a rebound effect after initial protection cannot be confirmed.

Gene-environment interaction in the association of residential greenness and 25(OH) vitamin D.

There is increasing awareness for beneficial health effects of green space surrounding the home, but the underlying mechanisms are not yet fully understood and challenging to study given the correlation with other exposures. Here, the association of residential greenness and vitamin D including a gene-environment interaction is investigated. 25-hydroxyvitamin D (25(OH)D) was measured by electrochemiluminescence at ages 10 and 15 years in participants of two German birth cohorts GINIplus and LISA. Greenness was measured using the Landsat-derived Normalized Difference Vegetation Index (NDVI) in a 500 m buffer surrounding the home. Linear and logistic regression models were applied at both time points adjusted for several covariates (N10Y = 2,504, N15Y = 2,613). In additional analyses vitamin D-related genes, physical activity, time spent outdoors, supplements, and measurement season were investigated as potential confounders or effect modifiers. A 1.5-SD increase in NDVI was significantly associated with increased 25(OH)D values at ages 10 and 15 years (ß10y = 2.41 nmol/l, p=<0.01; ß15y = 2.03 nmol/l, p = 0.02). In stratified analyses, the associations were not seen in participants spending more than 5 h/day outside in summer, having a high physical activity level, taking supplements, or being examined during the winter season. In a subset (n = 1,732) with genetic data, a significant gene-environment interaction of NDVI with CYP2R1, an upstream gene in 25(OH)D synthesis, was observed at age 10 years. When investigating 25(OH)D sufficiency, defined as values above 50 nmol/l, a 1.5-SD increase in NDVI was associated with significantly higher odds of having sufficient 25 (OH)D levels at age 10 years (OR = 1.48, 1.19-1.83). In conclusion, robust associations between residential greenness and 25 (OH)D levels were observed in children and adolescents independent of other confounders and additionally supported by the presence of a gene-environment interaction. Effects of NDVI were stronger in those having lower vitamin D levels at age 10 years due to their covariate profile or genetically lower 25(OH)D synthesis.

Global hypomethylation in childhood asthma identified by genome-wide DNA-methylation sequencing preferentially affects enhancer regions.

BACKGROUND: Childhood asthma is a result of a complex interaction of genetic and environmental components causing epigenetic and immune dysregulation, airway inflammation and impaired lung function. Although different microarray based EWAS studies have been conducted, the impact of epigenetic regulation in asthma development is still widely unknown. We have therefore applied unbiased whole genome bisulfite sequencing (WGBS) to characterize global DNA-methylation profiles of asthmatic children compared to healthy controls. METHODS: Peripheral blood samples of 40 asthmatic and 42 control children aged 5-15 years from three birth cohorts were sequenced together with paired cord blood samples. Identified differentially methylated regions (DMRs) were categorized in genotype-associated, cell-type-dependent, or prenatally primed. Network analysis and subsequent natural language processing of DMR-associated genes was complemented by targeted analysis of functional translation of epigenetic regulation on the transcriptional and protein level. RESULTS: In total, 158 DMRs were identified in asthmatic children compared to controls of which 37% were related to the eosinophil content. A global hypomethylation was identified affecting predominantly enhancer regions and regulating key immune genes such as IL4, IL5RA, and EPX. These DMRs were confirmed in n = 267 samples and could be linked to aberrant gene expression. Out of the 158 DMRs identified in the established phenotype, 56 were perturbed already at birth and linked, at least in part, to prenatal influences such as tobacco smoke exposure or phthalate exposure. CONCLUSION: This is the first epigenetic study based on whole genome sequencing to identify marked dysregulation of enhancer regions as a hallmark of childhood asthma.

Dietary digestible carbohydrates are associated with higher prevalence of asthma in humans and with aggravated lung allergic inflammation in mice.

BACKGROUND: Dietary carbohydrates and fats are intrinsically correlated within the habitual diet. We aimed to disentangle the associations of starch and sucrose from those of fat, in relation to allergic sensitization, asthma and rhinoconjuctivitis prevalence in humans, and to investigate underlying mechanisms using murine models. METHODS: Epidemiological data from participants of two German birth cohorts (age 15) were used in logistic regression analyses testing cross-sectional associations of starch and sucrose (and their main dietary sources) with aeroallergen sensitization, asthma and rhinoconjunctivitis, adjusting for correlated fats (saturated, monounsaturated, omega-6 and omega-3 polyunsaturated) and other covariates. For mechanistic insights, murine models of aeroallergen-induced allergic airway inflammation (AAI) fed with a low-fat-high-sucrose or -high-starch versus a high-fat diet were used to characterize and quantify disease development. Metabolic and physiologic parameters were used to track outcomes of dietary interventions and cellular and molecular responses to monitor the development of AAI. Oxidative stress biomarkers were measured in murine sera or lung homogenates. RESULTS: We demonstrate a direct association of dietary sucrose with asthma prevalence in males, while starch was associated with higher asthma prevalence in females. In mice, high-carbohydrate feeding, despite scant metabolic effects, aggravated AAI compared to high-fat in both sexes, as displayed by humoral response, mucus hypersecretion, lung inflammatory cell infiltration and TH 2-TH 17 profiles. Compared to high-fat, high-carbohydrate intake was associated with increased pulmonary oxidative stress, signals of metabolic switch to glycolysis and decreased systemic anti-oxidative capacity. CONCLUSION: High consumption of digestible carbohydrates is associated with an increased prevalence of asthma in humans and aggravated lung allergic inflammation in mice, involving oxidative stress-related mechanisms.

Allergic disease trajectories up to adolescence: Characteristics, early-life, and genetic determinants.

BACKGROUND: Allergic diseases often develop jointly during early childhood but differ in timing of onset, remission, and progression. Their disease course over time is often difficult to predict and determinants are not well understood. OBJECTIVES: We aimed to identify trajectories of allergic diseases up to adolescence and to investigate their association with early-life and genetic determinants and clinical characteristics. METHODS: Longitudinal k-means clustering was used to derive trajectories of allergic diseases (asthma, atopic dermatitis, and rhinitis) in two German birth cohorts (GINIplus/LISA). Associations with early-life determinants, polygenic risk scores, food and aeroallergen sensitization, and lung function were estimated by multinomial models. The results were replicated in the independent Swedish BAMSE cohort. RESULTS: Seven allergic disease trajectories were identified: "Intermittently allergic," "rhinitis," "early-resolving dermatitis," "mid-persisting dermatitis," "multimorbid," "persisting dermatitis plus rhinitis," and "early-transient asthma." Family history of allergies was more prevalent in all allergic disease trajectories compared the non-allergic controls with stronger effect sizes for clusters comprising more than one allergic disease (e.g., RRR = 5.0, 95% CI = [3.1-8.0] in the multimorbid versus 1.8 [1.4-2.4] in the mild intermittently allergic cluster). Specific polygenic risk scores for single allergic diseases were significantly associated with their relevant trajectories. The derived trajectories and their association with genetic effects and clinical characteristics showed similar results in BAMSE. CONCLUSION: Seven robust allergic clusters were identified and showed associations with early life and genetic factors as well as clinical characteristics.

Ambient ozone exposure and bone turnover markers in children: Results from the GINIplus and LISA birth cohorts.

BACKGROUND: Multiple environmental factors can regulate bone metabolism, and it is hypothesized that air pollution may be deleteriously involved in this regulation. However, only a few studies considered bone turnover markers (BTMs) - sensitive and specific markers of bone metabolism - as outcomes, and no study investigated the exposure to ambient ozone. Here, we intended to explore the associations between long-term exposure to ambient ozone and concentrations of two BTMs, osteocalcin and ß-isomer of C-terminal telopeptide of type I collagen (CTx), amongst 10-year-old children. METHODS: Based on the GINIplus and LISA birth cohorts, our cross-sectional analysis included 1848 children aged 10 years from Munich and Wesel. Serum osteocalcin and CTx concentrations were measured. We estimated ozone exposures by optimal interpolation, assessed nitrogen dioxide and particulate matter with an aerodynamic diameter <10 µm concentrations by land use regression models, and assigned the exposures to home addresses. Linear regression models were built and adjusted for covariates as well as co-pollutants. RESULTS: The mean concentrations were 93.09 ng/mL and 663.66 ng/L for osteocalcin and CTx, respectively. In general, higher levels of ozone were associated with decreased concentrations of both BTMs. This held true for the two areas and different exposure metrics. The number of days per year with a maximum 8-h average concentration exceeding 120 µg/m³ showed consistent results across different models. Specifically, models adjusted for co-pollutants illustrated that the beta estimates and 95% confidence intervals on osteocalcin and CTx were -2.51 (-3.78, -1.14) and -44.53 (-57.12, -31.93), respectively, for an increase of 10 days. CONCLUSIONS: We found that long-term exposure to ambient ozone was associated with decreased concentrations of BTMs in German children. This association might potentially affect bone metabolism. Nevertheless, unless other prospective studies confirm our results, the detrimental effects of ambient ozone on bone development in children should be interpreted cautiously.

Psychopathological symptoms as precursors of depressive symptoms in adolescence: a prospective analysis of the GINIplus and LISA birth cohort studies.

INTRODUCTION: Depressive symptoms are highly prevalent in adolescence, highlighting the need for early identification of precursors. Research into psychopathological symptoms predicting depressive psychopathology in adolescents is therefore of great relevance. Moreover, given that the prevalence of depressive symptomatology in adolescence shows marked differences between girls and boys, insight into potential sex-specific differences in precursors is important. METHODS: This study examined the relationships between emotional problems, conduct problems, hyperactivity/inattention, peer problems, and difficulties in prosocial behaviour at age 10 (Strengths and Difficulties Questionnaire), and the presence of depressive symptoms at age 15 (Depression Screener for Teenagers). Using data from 2824 participants of the GINIplus and LISA birth cohorts, the association of each SDQ subscale at age 10 years with the presence of depressive symptoms at age 15 years was analyzed using sex-specific logistic regression, adjusting for potential confounders. RESULTS: Emotional problems [odds ratio (OR) 1.99, p = 0.002 for boys and OR 1.77, p < 0.001 for girls] and peer problems (OR 2.62, p < 0.001 for boys, OR 1.91, p = 0.001 for girls) at age 10 showed an increased risk for the presence of depressive symptoms at age 15. Additionally, boys with conduct problems at age 10 were at greater risk of showing depressive symptoms in adolescence (OR 2.50, p < 0.001). DISCUSSION: Based on the identified prospective relationships in our study, it might be of particular importance to tailor prevention approaches during childhood to peer and emotional problems to reduce the risk of depressive psychopathology in adolescence. Moreover, particularly in boys, it seems important to also target conduct problems in childhood as a precursor of depressive symptoms in the adolescent period.

Obesogenic eating behaviour and dietary intake in German children and adolescents: results from the GINIplus and LISA birth cohort studies.

BACKGROUND/OBJECTIVES: The transition to adolescence is characterised by considerable behavioural changes, including diet. This study describes the level of obesogenic eating behaviours in 10- and 15-year-olds, and their association with dietary intake. SUBJECTS/METHODS: Participants of the 10- and 15-year follow-ups of the German GINIplus and LISA birth cohort studies were included (N10 = 2257; N15 = 1880). Eating behaviours and dietary intake were assessed via self-report questionnaires. Sex-stratified, cross-sectional associations of "external eating", "emotional eating" and "dietary restraint" (the latter at age 15 years only) with dietary intake (17 food groups-categorised into tertiles, macronutrients, and total energy) were assessed using multinomial logistic or multiple linear regression as required, adjusting for covariates and correcting for multiple testing. RESULTS: Reported levels of eating behaviours were low in both age-groups. External eating was higher in 10-year-old males than females, while all eating behaviours were most pronounced in 15-year-old females. At 10 years, emotional eating was associated with medium vegetable intake in females (Relative Risk Ratio (RRR) = 1.84, p = 0.0017). At 15 years, external eating was associated with total energy (kJ) in females (ß = 718, p = 0.0002) and high butter intake in males (RRR = 1.96, p = 0.0019). Dietary restraint in females was inversely associated with total energy (ß = -967, p < 0.0001) and omega-3 fatty acids (Means Ratio (MR) = 0.94, p = 0.0017), and positively associated with high fruit (RRR = 2.20, p = 0.0003) and whole grains (RRR = 1.94, p = 0.0013). CONCLUSION: Obesogenic eating behaviour scores are low among children and adolescents of a predominantly high socioeconomic status population and present only few associations with specific aspects of diet, mainly among adolescent females.

Early-life respiratory tract infections and the risk of school-age lower lung function and asthma: a meta-analysis of 150 000 European children.

BACKGROUND: Early-life respiratory tract infections might affect chronic obstructive respiratory diseases, but conclusive studies from general populations are lacking. Our objective was to examine if children with early-life respiratory tract infections had increased risks of lower lung function and asthma at school age. METHODS: We used individual participant data of 150 090 children primarily from the EU Child Cohort Network to examine the associations of upper and lower respiratory tract infections from age 6 months to 5 years with forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), FEV1/FVC, forced expiratory flow at 75% of FVC (FEF75%) and asthma at a median (range) age of 7 (4-15) years. RESULTS: Children with early-life lower, not upper, respiratory tract infections had a lower school-age FEV1, FEV1/FVC and FEF75% (z-score range: -0.09 (95% CI -0.14- -0.04) to -0.30 (95% CI -0.36- -0.24)). Children with early-life lower respiratory tract infections had a higher increased risk of school-age asthma than those with upper respiratory tract infections (OR range: 2.10 (95% CI 1.98-2.22) to 6.30 (95% CI 5.64-7.04) and 1.25 (95% CI 1.18-1.32) to 1.55 (95% CI 1.47-1.65), respectively). Adjustment for preceding respiratory tract infections slightly decreased the strength of the effects. Observed associations were similar for those with and without early-life wheezing as a proxy for early-life asthma. CONCLUSIONS: Our findings suggest that early-life respiratory tract infections affect development of chronic obstructive respiratory diseases in later life, with the strongest effects for lower respiratory tract infections.

Assessment of the Cow's Milk-related Symptom Score (CoMiSS) as a diagnostic tool for cow's milk protein allergy: a prospective, multicentre study in China (MOSAIC study).

OBJECTIVES: The MOSAIC study aimed to evaluate if the Cow's Milk-related Symptom Score (CoMiSS) can be used as a stand-alone diagnostic tool for cow's milk protein allergy (CMPA). DESIGN: Single-blinded, prospective, multicentre diagnostic accuracy study. SETTING: 10 paediatric centres in China. PARTICIPANTS: 300 non-breastfed infants (median age 16.1 weeks) with suspected CMPA. INTERVENTIONS: After performing the baseline CoMiSS, infants commenced a cow's milk protein elimination diet with amino acid-based formula for 14 days. CoMiSS was repeated at the end of the elimination trial. Infants then underwent an open oral food challenge (OFC) with cow's milk-based formula (CMF) in hospital. Infants who did not react during the OFC also completed a 14-day home challenge with CMF. A diagnosis of CMPA was made if acute or delayed reactions were reported. PRIMARY OUTCOME MEASURES: A logistic regression model for CoMiSS to predict CMPA was fitted and a receiver-operator characteristic (ROC) curve generated. An area under the curve (AUC) of ≥0.75 was deemed adequate to validate CoMiSS as a diagnostic tool (target sensitivity 80%-90% and specificity 60%-70%). RESULTS: Of 254 infants who commenced the OFC, 250 completed both challenges, and a diagnosis of CMPA made in 217 (85.4%). The median baseline CoMiSS in this group fell from 8 (IQR 5-10) to 5 (IQR 3-7) at visit 2 (p<0.000000001), with a median change of -3 (IQR -6 to -1). A baseline CoMiSS of ≥12 had a low sensitivity (20.3%), but high specificity (87.9%) and high positive predictive value (91.7%) for CMPA. The ROC analysis with an AUC of 0.67 fell short of the predefined primary endpoint. CONCLUSIONS: The present study did not support the use of CoMiSS as a stand-alone diagnostic tool for CMPA. Nevertheless, CoMiSS remains a clinically useful awareness tool to help identify infants with cow's milk-related symptoms. TRIAL REGISTRATION NUMBER: NCT03004729; Pre-results.

Residential green space and age at menarche in German and Australian adolescent girls: A longitudinal study.

BACKGROUND: A large multicentre European study reported later onset of menopause among women residing in greener areas. This influence on the timing of a reproductive event like menopause, raises the question whether similar associations can be observed with timing of menarche. We investigated whether exposure to residential green space was related to the age at menarche in German and Australian adolescent girls. METHODS: The analytic samples comprised of 1706 German and 1474 Australian adolescent girls. Percentage of green space was calculated in 1000 m buffers around a residential address or its surrogate at the previous follow-up. Mixed effects Cox proportional hazard models were used to explore the associations. The survival object was the occurrence of menarche at the time of follow-up (15-year follow-up of the German cohorts and the study wave at 14-15 years in the Australian cohort) and number of years since baseline (10-year follow-up in the German cohort and the study wave at 10-11 years in the Australian cohort). Participants who did not reach menarche were included as censored observations. RESULTS: A greener residence was not associated with the age at menarche. Null findings were consistent in the general population and in analyses stratified by socioeconomic status or urbanicity in both countries. Urban residents were more likely to have earlier menarche, and this association was consistent across Germany and Australia. CONCLUSION: The results of our analysis do not support the hypothesis that residing in places with more green space can influence timing of menarche. However, given the limitations of our study, researchers should not be discouraged to further explore environmental risk factors of early menarche.

Growth in Infants with Cow's Milk Protein Allergy Fed an Amino Acid-Based Formula.

PURPOSE: The present study assessed the role of an amino acid-based formula (AAF) in the growth of infants with cow's milk protein allergy (CMPA). METHODS: Non-breastfed, term infants aged 0-6 months with symptoms suggestive of CMPA were recruited from 10 pediatric centers in China. After enrollment, infants were started on AAF for two weeks, followed by an open food challenge (OFC) with cow's milk-based formula (CMF). Infants with confirmed CMPA remained on AAF until 9 months of age, in conjunction with a cow's milk protein-free complementary diet. Body weight, length, and head circumference were measured at enrollment and 9 months of age. Measurements were converted to weight-for-age, length-for-age, and head circumference-for-age Z scores (WAZ, LAZ, HCAZ), based on the World Health Organization growth reference. RESULTS: Of 254 infants (median age 16.1 weeks, 50.9% male), 218 (85.8%) were diagnosed with non-IgE-mediated CMPA, 33 (13.0%) tolerated CMF, and 3 (1.2%) did not complete the OFC. The mean WAZ decreased from 0.119 to -0.029 between birth and enrollment (p=0.067), with significant catch-up growth to 0.178 at 9 months of age (p=0.012) while being fed the AAF. There were no significant changes in LAZ (0.400 vs. 0.552; p=0.214) or HCAZ (-0.356 vs. -0.284; p=0.705) from the time of enrollment to age 9 months, suggesting normal linear and head growth velocity. CONCLUSION: The amino acid-based study formula, in conjunction with a cow's milk protein-free complementary diet, supported normal growth till 9 months of age in a cohort of Chinese infants with challenge-confirmed non-IgE-mediated CMPA.

Dietary Macronutrient Composition in Relation to Circulating HDL and Non-HDL Cholesterol: A Federated Individual-Level Analysis of Cross-Sectional Data from Adolescents and Adults in 8 European Studies.

BACKGROUND: Associations between increased dietary fat and decreased carbohydrate intake with circulating HDL and non-HDL cholesterol have not been conclusively determined. OBJECTIVE: We assessed these relations in 8 European observational human studies participating in the European Nutritional Phenotype Assessment and Data Sharing Initiative (ENPADASI) using harmonized data. METHODS: Dietary macronutrient intake was recorded using study-specific dietary assessment tools. Main outcome measures were lipoprotein cholesterol concentrations: HDL cholesterol (mg/dL) and non-HDL cholesterol (mg/dL). A cross-sectional analysis on 5919 participants (54% female) aged 13-80 y was undertaken using the statistical platform DataSHIELD that allows remote/federated nondisclosive analysis of individual-level data. Generalized linear models (GLM) were fitted to assess associations between replacing 5% of energy from carbohydrates with equivalent energy from total fats, SFAs, MUFAs, or PUFAs with circulating HDL cholesterol and non-HDL cholesterol. GLM were adjusted for study source, age, sex, smoking status, alcohol intake and BMI. RESULTS: The replacement of 5% of energy from carbohydrates with total fats or MUFAs was statistically significantly associated with 0.67 mg/dL (95% CI: 0.40, 0.94) or 0.99 mg/dL (95% CI: 0.37, 1.60) higher HDL cholesterol, respectively, but not with non-HDL cholesterol concentrations. The replacement of 5% of energy from carbohydrates with SFAs or PUFAs was not associated with HDL cholesterol, but SFAs were statistically significantly associated with 1.94 mg/dL (95% CI: 0.08, 3.79) higher non-HDL cholesterol, and PUFAs with -3.91 mg/dL (95% CI: -6.98, -0.84) lower non-HDL cholesterol concentrations. A statistically significant interaction by sex for the association of replacing carbohydrates with MUFAs and non-HDL cholesterol was observed, showing a statistically significant inverse association in males and no statistically significant association in females. We observed no statistically significant interaction by age. CONCLUSIONS: The replacement of dietary carbohydrates with fats had favorable effects on lipoprotein cholesterol concentrations in European adolescents and adults when fats were consumed as MUFAs or PUFAs but not as SFAs.

Outdoor air pollution and hormone-assessed pubertal development in children: Results from the GINIplus and LISA birth cohorts.

BACKGROUND: Air pollution is hypothesized to affect pubertal development. However, the few studies on this topic yielded overall mixed results. These studies did not consider important pollutants like ozone, and none of them involved pubertal development assessed by estradiol and testosterone measurements. We aimed to analyze associations between long-term exposure to four pollutants and pubertal development based on sex hormone concentrations among 10-year-old children. METHODS: These cross-sectional analyses were based on the 10-year follow-up medical examinations of 1945 children from the Munich and Wesel centers of the GINIplus and LISA German birth cohorts. Female and male pubertal development was assessed by dichotomizing the concentration of hormones in serum at 18.4 pmol/L and 0.087 nmol/L using the lower limits of quantification for estradiol and testosterone, respectively. Land-use regression models derived annual average concentrations of particulate matter with an aerodynamic diameter < 2.5 and 10 µm (PM2.5 and PM10), as well as spatial models assessed yearly average concentrations of nitrogen dioxide (NO2) and ozone, were calculated at the 10-year residential addresses. To evaluate associations, we utilized logistic regressions adjusted for potential covariates. The analyses were stratified by area and sex. RESULTS: Around 73% of the 943 females and 25% of the 1002 males had a high level of hormones and had already started puberty at the age of 10. Overall, we found no statistically significant associations between exposure to particles (PM2.5 or PM10) and pubertal development. Results on NO2 and ozone were not significant as well; for instance, per 10 µg/m3 increase in ozone concentration, odds ratios and 95% confidence intervals were 0.900 (0.605, 1.339) and 0.830 (0.573, 1.203) for females and males, respectively. Stratified by area, the aforementioned results did not reveal any associations either. CONCLUSIONS: Our study did not observe the associations between ambient air pollutants and pubertal development determined by estradiol and testosterone levels in children. However, due to the current limited number of studies on this topic, our results should be cautiously interpreted. Future longitudinal studies are needed to assess the association.

Long-term Air Pollution Exposure Under European Union Limits and Adolescents' Lung Function: Modifying Effect of Abnormal Weight in the GINIplus and LISA Birth Cohorts.

BACKGROUND: Abnormal weights, eg, obesity, has shown a strong modifying effect on the association between air pollution exposure and lung function impairment in adults. RESEARCH QUESTION: How might weight status modify the effects of long-term air pollution exposure on adolescents' lung function, particularly in areas with pollution levels much lower than the current European Union (EU) air quality standards? STUDY DESIGN AND METHODS: In this observational study, we investigated 2,224 adolescents from the German Infant Study on the Influence of Nutrition Intervention Plus Environmental and Genetic Influences on Allergy Development and the Influence of Life Style Factors on the Development of the Immune System and Allergies in East and West Germany birth cohorts. Lung function was measured at age 15 years. Underweight, normal weight, and overweight or obese were defined using percentiles of BMI. Average concentrations of air pollution were modelled at residential addresses at four exposure windows between 0 and 15 years. Multivariate linear regression models were fitted by weight group on lung function with exposure at each window or cumulative exposure since birth. RESULTS: The median air pollution concentrations were half to two-thirds of the EU standards. Significant associations were observed only for individuals who were underweight and overweight or obese. For example, per interquartile range increase in nitrogen dioxide at the 15-year exposure window, FEV1 declined by -2.9% (95% CI, -5.2% to -0.5%) for the underweight group and -3.4% (95% CI, -5.4% to -1.2%) for the overweight or obese group. Similarly, longer exposure to moderate-level air pollution since birth was associated significantly with lung function impairment for groups with abnormal weight. INTERPRETATION: Exposure to low to moderate levels of air pollution was associated with lung function impairment for adolescents with abnormal weight. Longer exposure aggravated the adverse effect. Whether a critical exposure window since birth exists warrants further exploration.

Air pollution during infancy and lung function development into adolescence: The GINIplus/LISA birth cohorts study.

BACKGROUND: Limited evidence exists on how air pollution exposure during infancy, i.e. the first year of life, may affect lung function development into adolescence. OBJECTIVES: To investigate the association between exposure to air pollution during the first-year of life and lung function development up to the age of 15 in Germany. METHODS: We investigated 915 children from the GINIplus and LISA birth cohorts from Munich (n = 181) and Wesel (n = 734), who had at least two spirometric measurements at ages 6, 10 and 15. Z-scores of forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) were calculated. Annual average concentrations of nitrogen dioxide, particulate matter with diameters <2.5, <10 and 2.5-10 µm (PM2.5/10/coarse), and PM2.5 absorbance at home addresses during the first-year of life, were estimated by land-use regression models. Associations between infancy exposure and lung function changes were fitted using multivariable linear mixed models with adjustment for potential confounders. RESULTS: For per interquartile range increase in air pollutants during the first-year life, FEV1 z-scores declined annually by -0.012 (95% confidence interval (CI): -0.014, -0.009) for PM2.5 to -0.023 (95%CI: -0.028, -0.018) for PMcoarse. The declines in FVC were lower than FEV1 [-0.006 (95%CI: -0.008, -0.003) to -0.011 (95%CI: -0.019, -0.003)]. In Munich, the attenuations were only significant for FEV1. Effect estimates of infancy exposure for certain air pollutants were higher for groups with asthma, older maternal age, and breastfeeding <12 weeks than their counterparts. DISCUSSION: Infancy exposure to higher air pollution may reduce lung function development up to adolescence, with airway size more affected than lung volume restriction. The potential modifying effects of maternal age, asthmatic status of children and breastfeeding warrant further exploration.

Air pollution and IgE sensitization in 4 European birth cohorts-the MeDALL project.

BACKGROUND: Whether long-term exposure air to pollution has effects on allergic sensitization is controversial. OBJECTIVE: Our aim was to investigate associations of air pollution exposure at birth and at the time of later biosampling with IgE sensitization against common food and inhalant allergens, or specific allergen molecules, in children aged up to 16 years. METHODS: A total of 6163 children from 4 European birth cohorts participating in the Mechanisms of the Development of ALLergy [MeDALL] consortium were included in this meta-analysis of the following studies: Children, Allergy, Milieu, Stockholm, Epidemiology (BAMSE) (Sweden), Influences of Lifestyle-Related Factors on the Human Immune System and Development of Allergies in Childhood (LISA)/German Infant Study on the Influence of Nutrition Intervention PLUS Environmental and Genetic Influences on Allergy Development (GINIplus) (Germany), and Prevention and Incidence of Asthma and Mite Allergy (PIAMA) (The Netherlands). The following indicators were modeled by land use regression: individual residential outdoor levels of particulate matter with aerodynamic diameters less than 2.5 µm, less than 10 µm, and between 2.5 and 10 µm; PM2.5 absorbance (a measurement of the blackness of PM2.5 filters); and nitrogen oxides levels. Blood samples drawn at ages 4 to 6 (n = 5989), 8 to 10 (n = 6603), and 15 to 16 (n = 5825) years were analyzed for IgE sensitization to allergen extracts by ImmunoCAP. Additionally, IgE against 132 allergen molecules was measured by using the MedALL microarray chip (n = 1021). RESULTS: Air pollution was not consistently associated with IgE sensitization to any common allergen extract up to age 16 years. However, allergen-specific analyses suggested increased risks of sensitization to birch (odds ratio [OR] = 1.12 [95% CI = 1.01-1.25] per 10-µg/m3 increase in NO2 exposure). In a subpopulation with microarray data, IgE to the major timothy grass allergen Phleum pratense 1 (Phl p 1) and the cat allergen Felis domesticus 1 (Fel d 1) greater than 3.5 Immuno Solid-phase Allergen Chip standardized units for detection of IgE antibodies were related to PM2.5 exposure at birth (OR = 3.33 [95% CI = 1.40-7.94] and OR = 4.98 [95% CI = 1.59-15.60], respectively, per 5-µg/m3 increase in exposure). CONCLUSION: Air pollution exposure does not seem to increase the overall risk of allergic sensitization; however, sensitization to birch as well as grass pollen Phl p 1 and cat Fel d 1 allergen molecules may be related to specific pollutants.