Pre-activated antiviral innate immunity in the upper airways controls early SARS-CoV-2 infection in children.

Children have reduced severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection rates and a substantially lower risk for developing severe coronavirus disease 2019 compared with adults. However, the molecular mechanisms underlying protection in younger age groups remain unknown. Here we characterize the single-cell transcriptional landscape in the upper airways of SARS-CoV-2-negative (n = 18) and age-matched SARS-CoV-2-positive (n = 24) children and corresponding samples from adults (n = 44), covering an age range of 4 weeks to 77 years. Children displayed higher basal expression of relevant pattern recognition receptors such as MDA5 (IFIH1) and RIG-I (DDX58) in upper airway epithelial cells, macrophages and dendritic cells, resulting in stronger innate antiviral responses upon SARS-CoV-2 infection than in adults. We further detected distinct immune cell subpopulations including KLRC1 (NKG2A)+ cytotoxic T cells and a CD8+ T cell population with a memory phenotype occurring predominantly in children. Our study provides evidence that the airway immune cells of children are primed for virus sensing, resulting in a stronger early innate antiviral response to SARS-CoV-2 infection than in adults.

Measurement of the Charge-Averaged Elastic Lepton-Proton Scattering Cross Section by the OLYMPUS Experiment.

We report the first measurement of the average of the electron-proton and positron-proton elastic scattering cross sections. This lepton charge-averaged cross section is insensitive to the leading effects of hard two-photon exchange, giving more robust access to the proton's electromagnetic form factors. The cross section was extracted from data taken by the OLYMPUS experiment at DESY, in which alternating stored electron and positron beams were scattered from a windowless gaseous hydrogen target. Elastic scattering events were identified from the coincident detection of the scattered lepton and recoil proton in a large-acceptance toroidal spectrometer. The luminosity was determined from the rates of Møller, Bhabha, and elastic scattering in forward electromagnetic calorimeters. The data provide some selectivity between existing form factor global fits and will provide valuable constraints to future fits.

Quality indicators for mental healthcare in the Danube region: results from a pilot feasibility study.

Quality indicators are vital for monitoring the transformation of institution-based mental health services towards the provision of person-centered mental healthcare. While several mental healthcare quality indicators have been identified as relevant and valid, their actual usability and utility for routine monitoring healthcare quality over time is significantly determined by the availability and trustworthiness of the underlying data. In this feasibility study, quality indicators that have been systematically identified for use in the Danube region countries of Bulgaria, the Czech Republic, Hungary, and Serbia were measured on the basis of existing mental healthcare data in the four countries. Data were collected retrospectively by means of the best available, most standardized, trustworthy, and up-to-date data in each country. Out of 21 proposed quality indicators, 18 could be measured in Hungary, 17 could be measured in Bulgaria and in the Czech Republic, and 8 could be measured in Serbia. The results demonstrate that a majority of quality indicators can be measured in most of the countries by means of already existing data, thereby demonstrating the feasibility of quality measurement and regular quality monitoring. However, data availability and usability are scattered across countries and care sectors, which leads to variations in the quality of the quality indicators themselves. Making the planning and outputs of national mental healthcare reforms more transparent and evidence-based requires (trans-)national standardization of healthcare quality data, their routine availability and standardized assessment, and the regular reporting of quality indicators.

Impact of maternal body mass index and gestational weight gain on pregnancy complications: an individual participant data meta-analysis of European, North American and Australian cohorts.

OBJECTIVE: To assess the separate and combined associations of maternal pre-pregnancy body mass index (BMI) and gestational weight gain with the risks of pregnancy complications and their population impact. DESIGN: Individual participant data meta-analysis of 39 cohorts. SETTING: Europe, North America, and Oceania. POPULATION: 265 270 births. METHODS: Information on maternal pre-pregnancy BMI, gestational weight gain, and pregnancy complications was obtained. Multilevel binary logistic regression models were used. MAIN OUTCOME MEASURES: Gestational hypertension, pre-eclampsia, gestational diabetes, preterm birth, small and large for gestational age at birth. RESULTS: Higher maternal pre-pregnancy BMI and gestational weight gain were, across their full ranges, associated with higher risks of gestational hypertensive disorders, gestational diabetes, and large for gestational age at birth. Preterm birth risk was higher at lower and higher BMI and weight gain. Compared with normal weight mothers with medium gestational weight gain, obese mothers with high gestational weight gain had the highest risk of any pregnancy complication (odds ratio 2.51, 95% CI 2.31- 2.74). We estimated that 23.9% of any pregnancy complication was attributable to maternal overweight/obesity and 31.6% of large for gestational age infants was attributable to excessive gestational weight gain. CONCLUSIONS: Maternal pre-pregnancy BMI and gestational weight gain are, across their full ranges, associated with risks of pregnancy complications. Obese mothers with high gestational weight gain are at the highest risk of pregnancy complications. Promoting a healthy pre-pregnancy BMI and gestational weight gain may reduce the burden of pregnancy complications and ultimately the risk of maternal and neonatal morbidity. TWEETABLE ABSTRACT: Promoting a healthy body mass index and gestational weight gain might reduce the population burden of pregnancy complications.

Stressful life events in childhood and allergic sensitization.

Stressful life events evidently have an impact on development of allergic diseases, but the mechanism linking stress to pathological changes of immune system function is still not fully understood. The aim of our study was to investigate the relationship between stressful life events, neuropeptide and cytokine concentrations in children as well as the association between early stressful life events and atopic eczema (AE). Within the LISA plus (Life style - Immune system - Allergy) study, blood samples from children of 6 years of age were analyzed for concentration of the neuropeptides vasoactive intestinal peptide (VIP), somatostatin (SOM), substance P (SP) and the Th1/Th2 cytokines IFN-γ and IL-4. Life events such as severe disease or death of a family member, unemployment or divorce of the parents were assessed with a questionnaire filled in by the parents. Furthermore, lifetime prevalence of AE and incidence after the assessment period of life events were compared. Our data suggest that separation/ divorce of parents increase childrens risk of developing AE later in life. Children with separated/divorced parents showed high VIP levels and high concentrations of the Th2 cytokine IL-4 in their blood. Severe diseases and death of a family member were neither associated with neuropeptide levels nor with cytokine concentrations. Unemployment of the parents was associated with decreased IFN-γ concentrations in childrens blood but not with neuropeptide levels. Thus, the neuropeptide VIP might be a mediator between stressful life events and immune regulation contributing to the Th2-shifted immune response in children with separated/divorced parents.

The sex-shift in single disease and multimorbid asthma and rhinitis during puberty - a study by MeDALL.

BACKGROUND: Cross-sectional studies suggested that allergy prevalence in childhood is higher in boys compared to girls, but it remains unclear whether this inequality changes after puberty. We examined the sex-specific prevalence of asthma and rhinitis as single and as multimorbid diseases before and after puberty onset in longitudinal cohort data. METHODS: In six European population-based birth cohorts of MeDALL, we assessed the outcomes: current rhinitis, current asthma, current allergic multimorbidity (ie, concurrent asthma and rhinitis), puberty status and allergic sensitization by specific serum antibodies (immunoglobulin E) against aero-allergens. With generalized estimating equations, we analysed the effects of sex, age, puberty (yes/no) and possible confounders on the prevalence of asthma and rhinitis, and allergic multimorbidity in each cohort separately and performed individual participant data meta-analysis. FINDINGS: We included data from 19 013 participants from birth to age 14-20 years. Current rhinitis only affected girls less often than boys before and after puberty onset: adjusted odds ratio for females vs males 0.79 (95%-confidence interval 0.73-0.86) and 0.86 (0.79-0.94), respectively (sex-puberty interaction P = .089). Similarly, for current asthma only, females were less often affected than boys both before and after puberty onset: 0.71, 0.63-0.81 and 0.81, 0.64-1.02, respectively (sex-puberty interaction P = .327). The prevalence of allergic multimorbidity showed the strongest sex effect before puberty onset (female-male-OR 0.55, 0.46-0.64) and a considerable shift towards a sex-balanced prevalence after puberty onset (0.89, 0.74-1.04); sex-puberty interaction: P < .001. INTERPRETATION: The male predominance in prevalence before puberty and the "sex-shift" towards females after puberty onset were strongest in multimorbid patients who had asthma and rhinitis concurrently.

Associations between fatty acids and low-grade inflammation in children from the LISAplus birth cohort study.

BACKGROUND/OBJECTIVES: Assessing fatty acid (FA) composition in relation to inflammatory markers can shed light on the role of different FA and their metabolism in low-grade inflammation. Existing exploratory studies in children are scarce, and findings inconsistent. We hence aim to analyse associations of FA with common inflammatory markers, high-sensitivity C-reactive protein (hs-CRP) and interleukin-6 (IL-6), in 10-year-old children. SUBJECTS/METHODS: Complete data were available for 958 participants from the 10-year follow-up of the LISAplus (Influence of Lifestyle-Related Factors on the Immune System and the Development of Allergies in Childhood plus the Influence of Traffic Emissions and Genetics) birth cohort study. FA composition was assessed in serum glycerophospholipids. Hs-CRP and IL-6 were categorised into three levels. Associations of FA with inflammatory markers were assessed using multinomial logistic regression, adjusting for potential confounders. Additionally, sex-stratified analyses were carried out. RESULTS: FA exposures associated with significantly higher low-grade inflammation, as indicated by higher hs-CRP or IL-6 levels, included: palmitic acid (PA) (IL-6: P<0.001, 95% confidence interval: 1.30; 2.43), arachidonic acid (AA) (hs-CRP: P=0.002, 1.07; 1.31), n-6 highly unsaturated FA (HUFA) (hs-CRP: P=0.002, 1.06; 1.27), ratio of AA to linoleic acid (AA/LA) (hs-CRP: P<0.001, 1.16; 1.62) and total saturated FA (SFA) (IL-6: P<0.001, 1.77; 3.15). FA exposures associated with reduced levels of inflammatory markers included LA (hs-CRP: P=0.001, 0.84; 0.96; IL-6: P<0.001, 0.69; 0.90) and total polyunsaturated FA (PUFA) (IL-6: P<0.001, 0.57; 0.78). CONCLUSIONS: These findings suggest that higher SFA and minor n-6 HUFA, namely PA and AA, are associated with increased low-grade inflammation in children, whereas the major dietary n-6 PUFA and total PUFA are associated with reduced inflammation. Elevated desaturase activity, estimated by the ratio AA/LA, may be associated with higher inflammation, particularly in boys.

Maternal cytokine status may prime the metabolic profile and increase risk of obesity in children.

BACKGROUND: The maternal inflammation status during pregnancy has been associated with metabolic imprinting and obesity development in the child. However, the influence of the maternal Th2 cytokines, interleukin-4 (IL4), IL5 and IL13, has not been studied so far. METHODS: We investigated the relationship between maternal innate (IL6, IL8, IL10 and tumor necrosis factor-α (TNFa)) and adaptive (interferon-γ, IL4, IL5 and IL13) blood cytokine levels at 34 weeks of gestation and children's overweight development until the age of 3 years in 407 children of the German longitudinal LINA (Lifestyle and Environmental Factors and their Influence on Newborns Allergy risk) cohort. Children's body weight and height were measured during the annual clinical visits or acquired from questionnaires. Body mass index (BMI) Z-scores were calculated according to the WHO reference data to adjust for child's age and gender. Cytokine secretion was stimulated with phytohemagglutinin or lipopolysaccharide and measured by cytometric bead assay. Furthermore, we assessed metabolic parameter in blood of 318 children at age 1 using the AbsoluteIDQ p180 Kit (Biocrates LIFE Science AG). RESULTS: Applying logistic regression models, we found that an increase of maternal IL4 and IL13 was associated with a decreased risk for overweight development in 1- and 2-year-old children. This effect was consistent up to the age of 3 years for IL13 and mainly concerns children without maternal history of atopy. Children's acylcarnitine concentrations at 1 year were positively correlated with maternal IL13 levels and inversely associated with the BMI Z-score at age 1. CONCLUSIONS: We were able to show for the first time that the maternal Th2 status may be linked inversely to early childhood overweight development accompanied by an altered metabolic profile of the fetus. However, our data do not support a direct mediating role of acylcarnitines on maternal IL13-induced weight development.

Hard Two-Photon Contribution to Elastic Lepton-Proton Scattering Determined by the OLYMPUS Experiment.

The OLYMPUS Collaboration reports on a precision measurement of the positron-proton to electron-proton elastic cross section ratio, R_{2γ}, a direct measure of the contribution of hard two-photon exchange to the elastic cross section. In the OLYMPUS measurement, 2.01 GeV electron and positron beams were directed through a hydrogen gas target internal to the DORIS storage ring at DESY. A toroidal magnetic spectrometer instrumented with drift chambers and time-of-flight scintillators detected elastically scattered leptons in coincidence with recoiling protons over a scattering angle range of ≈20° to 80°. The relative luminosity between the two beam species was monitored using tracking telescopes of interleaved gas electron multiplier and multiwire proportional chamber detectors at 12°, as well as symmetric Møller or Bhabha calorimeters at 1.29°. A total integrated luminosity of 4.5 fb^{-1} was collected. In the extraction of R_{2γ}, radiative effects were taken into account using a Monte Carlo generator to simulate the convolutions of internal bremsstrahlung with experiment-specific conditions such as detector acceptance and reconstruction efficiency. The resulting values of R_{2γ}, presented here for a wide range of virtual photon polarization 0.456<ε<0.978, are smaller than some hadronic two-photon exchange calculations predict, but are in reasonable agreement with a subtracted dispersion model and a phenomenological fit to the form factor data.

Early life travelling does not increase risk of atopic outcomes until 15 years: results from GINIplus and LISAplus.

BACKGROUND: Westernized lifestyle has been blamed for allergy epidemics. One of its characteristics is increased distances and frequency of travelling from early life onwards. Early life travelling to places which substantially differ from home environment in terms of climate, vegetation and food could increase the exposure to further unknown allergens and hence promote the development of allergies, but no epidemiological study has investigated this speculation. METHODS: Detailed data on travelling during the first 2 years of life as well as a range of atopic outcomes along with potential confounders up to age 15 years were collected prospectively within two large population-based multicentre German birth cohorts - GINIplus and LISAplus. Farthest travelling destination (within Germany; middle/northern/eastern Europe; southern Europe; outside Europe), total number of trips and their combination were considered as exposures. Six atopic outcomes were used: (1) doctor-diagnosed asthma, (2) doctor-diagnosed allergic rhinitis, (3) nose and eye symptoms, (4) sensitization to food allergens, (5) sensitization to indoor and (6) outdoor inhalant allergens. Longitudinal associations between each exposure and health outcome pair were analysed using generalized estimation equations (GEEs). RESULTS: The results of our longitudinal analyses of 5674 subjects do not support the research hypothesis that travelling abroad to different regions in Europe or beyond Europe and frequency of travelling increase prevalence of doctor-diagnosed asthma and allergic rhinitis, nose and eye symptoms and allergic sensitization up to 15 years of age. Furthermore, there was no indication of age-varying effects. CONCLUSIONS: Early life travelling does not seem to increase risk of atopic outcomes. Nevertheless, as we could not account for the type of visited environment or length of stay, these first findings should be interpreted with caution.

GINIplus and LISAplus - Design and selected results of two German birth cohorts about natural course of atopic diseases and their determinants.

The increasing prevalence of asthma, hay fever, and allergic sensitization in Western Germany after east-west division in 1949 and their rapid increase in East German children after re-unification in 1990 are strong indications for the role of life-style and/or environmental factors in the development of atopic diseases. Obviously, the perinatal period is crucial for priming the immune system. Therefore, explorations of determinants of atopic diseases need pregnancy or birth cohorts as the most appropriate epidemiological study designs. This review presents the design and selected results of the two German birth cohorts GINIplus and LISAplus. GINIplus and LISAplus recruited 5.991 and 3.097 healthy, term newborns, respectively, from Munich, Wesel, Leipzig, and Bad Honnef. Approximately 55% could be followed for the first 10 years. We analyzed the natural course of atopic diseases and the role of life-style, environmental, and genetic factors for disease onset, intermediate phenotypes, and genes involved in detoxification and oxidative stress. The results of these two large birth cohorts contributed substantially to the understanding of atopic diseases and their determinants.

Associations between serum 25-hydroxyvitamin D and bone turnover markers in a population based sample of German children.

Severe vitamin D deficiency is known to cause rickets, however epidemiological studies and RCTs did not reveal conclusive associations for other parameters of bone health. In our study, we aimed to investigate the association between serum levels of 25(OH) vitamin D and bone turnover markers in a population-based sample of children. 25(OH)D, calcium (Ca), osteocalcin (OC), and ß-Crosslaps (ß-CTx) were measured in 2798 ten-year-old children from the German birth cohorts GINIplus and LISAplus. Linear regression was used to determine the association between bone turnover markers and 25(OH)D levels. 25(OH)D, OC, and ß-CTx showed a clear seasonal variation. A 10 nmol/l increase in 25(OH)D was significantly associated with a 10.5 ng/l decrease (p < 0.001) in ß-CTx after adjustment for design, sex, fasting status, time of blood drawn, BMI, growth rate, and detectable testosterone/estradiol. For OC alone no significant association with 25(OH)D was observed, whereas the ß-CTx-to-OC ratio was inversely associated with 25(OH)D (-1.7% change, p < 0.001). When stratifying the analyses by serum calcium levels, associations were stronger in children with Ca levels below the median. This study in school-aged children showed a seasonal variation of 25(OH)D and the bone turnover markers OC and ß-CTx. Furthermore a negative association between 25(OH)D and the bone resorption marker ß-CTx was observed.

Early-life house dust mite allergens, childhood mite sensitization, and respiratory outcomes.

BACKGROUND: Exposure to indoor allergens during early life may play a role in the development of the immune system and inception of asthma. OBJECTIVE: To describe the house dust mite (HDM) allergen concentrations in bedroom dust during early life and to evaluate its associations with HDM sensitization, wheezing, and asthma, from birth to school age, in 5 geographically spread European birth cohorts. METHODS: We included 4334 children from INMA-Menorca (Spain), BAMSE (Sweden), LISAplus and MAS (Germany), and PIAMA-NHS (the Netherlands). Dust samples were collected from bedrooms during early life and analyzed for Dermatophagoides pteronyssinus (Der p1) and Dermatophagoides farinae (Der f1). HDM concentrations were divided into four categories. Sensitization was determined by specific IgE. Wheezing and asthma information up to 8/10 years was collected through questionnaires. We performed mixed-effects logistic regression models and expressed associations as odds ratios with 95% confidence intervals. RESULTS: House dust mite concentrations varied across cohorts. Mean allergen concentrations were highest in INMA-Menorca (geometric mean (GM) Der p1 = 3.3 µg/g) and LISAplus (GM Der f1 = 2.1 µg/g) and lowest in BAMSE (GM Der p1 = 0.1 µg/g, Der f1 = 0.3 µg/g). Moderate and high HDM concentrations were significantly (P-values < 0.05) associated with 50-90% higher prevalence of HDM sensitization. No significant associations were observed with respiratory outcomes. CONCLUSION: Our study based on geographically spread regions, a large sample size, and a wide range of allergen concentration shows that HDM allergen concentrations vary across regions and that exposure during early life plays a role in the development of allergic sensitization but not in the development of respiratory outcomes.

Parental allergic disease before and after child birth poses similar risk for childhood allergies.

Whether the strength of associations between parental and child allergic diseases differs by whether the first onset of the parental disease is before or after a child's birth has never been examined and is the aim of this study. Yearly childhood asthma, allergic rhinitis, and eczema diagnoses were longitudinally regressed against the effect of a parental disease (pre- vs post-child birth) of the same type separately for each parent using generalized estimation equations. Both a maternal and paternal history of asthma were associated with childhood asthma prevalence up to 15 years of age. Effect estimates were similar for parental asthma with first onset before and after the birth of the child. The results for allergic rhinitis and eczema were less consistent. Parental allergic diseases with first onsets before and after the birth of a child both pose risks to childhood allergic disease in the offspring, especially for asthma.

Peer problems are associated with elevated serum leptin levels in children.

BACKGROUND: Leptin is thought to act as an important mediator in stress reactions. To date, no study has examined the association between psychological stress and leptin levels in children. This study aimed to assess the association between emotional symptoms and peer problems and serum leptin levels in children aged 10 years of the two population-based GINI-plus and LISA-plus birth cohorts. METHOD: Cross-sectional data from 2827 children aged 10 years were assessed with regard to leptin concentrations in serum and behavioral problems using the parent-reported Strengths and Difficulties Questionnaire (SDQ). Linear regression modeling was applied to determine the likelihood of elevated leptin levels in children with emotional symptoms and peer problems, controlling for socio-economic status (SES), body mass index (BMI), fasting serum leptin levels, pubertal development and sex hormones. RESULTS: We found that increases in emotional symptoms (exp ß adj = 1.03, s.e. = 0.02, p < 0.04) and peer problems (exp ß adj = 1.05, s.e. = 0.01, p = 0.0001) were significantly associated with higher serum leptin levels controlled for BMI and sociodemographic factors. Similar results were found when the fasting serum leptin sample was examined (exp ß adj = 1.08, s.e. = 0.04, p = 0.0294). Gender-stratified analyses showed a significant relationship between serum leptin and peer problems in girls (exp ß adj = 1.05, s.e. = 0.02, p = 0.03), and a borderline significant association in boys (exp ß adj = 1.04, s.e. = 0.02, p = 0.05). CONCLUSIONS: Children with peer problems have higher stress and eat more, acquire a higher body fat mass and thus, through increased leptin resistance, exhibit higher leptin levels.

Epidemiology of urticaria in infants and young children in Germany--results from the German LISAplus and GINIplus Birth Cohort Studies.

BACKGROUND: Although urticaria is considered one of the most frequent skin diseases, reliable epidemiologic data are scarce. OBJECTIVE: To evaluate the incidence and cumulative prevalence of urticaria in infants and children up to age of 10, to characterize the relationship of specific IgE levels (food and inhalative allergens) with urticaria, and to monitor the joint occurrence of urticaria with other diseases, such as eczema, asthma, and hay fever. METHODS: The study population consisted of two prospective birth cohort studies: the LISAplus and GINIplus studies. Information on physician-diagnosed urticaria, asthma, eczema, or hay fever was collected using self-administered questionnaires completed by the parents. Blood samples were drawn, and specific immunoglobulin E measured at 2 (only LISAplus), 6 and 10 yr of age. RESULTS: The incidence of urticaria was approximately 1% per year of age. The cumulative prevalence of urticaria in children up to the age of 10 yr was 14.5% for boys and 16.2% for girls. Cumulative prevalence of urticaria at the age of ten was significantly (p < 0.05) associated with allergic sensitization to peanut, soy, and wheat flour, but not with inhalant allergens. Both a parental history of atopy/urticaria and the children's diagnosis of asthma, eczema, and hay fever were strongly related (p < 0.0001) to the occurrence of urticaria. CONCLUSIONS: Urticaria is a frequent event during childhood, with highest incidence in infants and preschool children. Comorbidity with atopic disease is high.