Urinary eicosanoid levels in early life and risk of atopic disease in childhood.

BACKGROUND: Eicosanoids are lipid mediators including thromboxanes (TXs), prostaglandins (PGs), and leukotrienes with a pathophysiological role in established atopic disease. However, their role in the inception of disease is unclear. This study aimed to investigate the association between urinary eicosanoids in early life and development of atopic disease. METHODS: This study quantified the levels of 21 eicosanoids in urine from children from the COPSAC2010 (Copenhagen Prospective Studies on Asthma in Childhood 2010) (age 1 year, n = 450) and VDAART (Vitamin D Antenatal Asthma Reduction Trial) (age 3 years, n = 575) mother-child cohorts and analyzed the associations with development of wheeze/asthma, atopic dermatitis, and biomarkers of type-2 inflammation, applying false discovery rate of 5% (FDR5%) multiple testing correction. RESULTS: In both cohorts, analyses adjusted for environmental determinants showed that higher TXA2 eicosanoids in early life were associated with increased risk of developing atopic dermatitis (P < FDR5%) and type-2 inflammation (P < .05). In VDAART, lower PGE2 and PGI2 eicosanoids and higher isoprostanes were also associated with increased risk of atopic dermatitis (P < FDR5%). For wheeze/asthma, analyses in COPSAC2010 showed that lower isoprostanes and PGF2 eicosanoids and higher PGD2 eicosanoids at age 1 year associated with an increased risk at age 1-10 years (P < .05), whereas analyses in VDAART showed that lower PGE2 and higher TXA2 eicosanoids at age 3 years associated with an increased risk at 6 years (P < FDR5%). CONCLUSIONS: This study suggests that early life perturbations in the eicosanoid metabolism are present before the onset of atopic disease in childhood, which provides pathophysiological insight in the inception of atopic diseases.

Analyzing postprandial metabolomics data using multiway models: a simulation study.

BACKGROUND: Analysis of time-resolved postprandial metabolomics data can improve the understanding of metabolic mechanisms, potentially revealing biomarkers for early diagnosis of metabolic diseases and advancing precision nutrition and medicine. Postprandial metabolomics measurements at several time points from multiple subjects can be arranged as a subjects by metabolites by time points array. Traditional analysis methods are limited in terms of revealing subject groups, related metabolites, and temporal patterns simultaneously from such three-way data. RESULTS: We introduce an unsupervised multiway analysis approach based on the CANDECOMP/PARAFAC (CP) model for improved analysis of postprandial metabolomics data guided by a simulation study. Because of the lack of ground truth in real data, we generate simulated data using a comprehensive human metabolic model. This allows us to assess the performance of CP models in terms of revealing subject groups and underlying metabolic processes. We study three analysis approaches: analysis of fasting-state data using principal component analysis, T0-corrected data (i.e., data corrected by subtracting fasting-state data) using a CP model and full-dynamic (i.e., full postprandial) data using CP. Through extensive simulations, we demonstrate that CP models capture meaningful and stable patterns from simulated meal challenge data, revealing underlying mechanisms and differences between diseased versus healthy groups. CONCLUSIONS: Our experiments show that it is crucial to analyze both fasting-state and T0-corrected data for understanding metabolic differences among subject groups. Depending on the nature of the subject group structure, the best group separation may be achieved by CP models of T0-corrected or full-dynamic data. This study introduces an improved analysis approach for postprandial metabolomics data while also shedding light on the debate about correcting baseline values in longitudinal data analysis.

Characterizing human postprandial metabolic response using multiway data analysis.

INTRODUCTION: Analysis of time-resolved postprandial metabolomics data can improve our understanding of the human metabolism by revealing similarities and differences in postprandial responses of individuals. Traditional data analysis methods often rely on data summaries or univariate approaches focusing on one metabolite at a time. OBJECTIVES: Our goal is to provide a comprehensive picture in terms of the changes in the human metabolism in response to a meal challenge test, by revealing static and dynamic markers of phenotypes, i.e., subject stratifications, related clusters of metabolites, and their temporal profiles. METHODS: We analyze Nuclear Magnetic Resonance (NMR) spectroscopy measurements of plasma samples collected during a meal challenge test from 299 individuals from the COPSAC2000 cohort using a Nightingale NMR panel at the fasting and postprandial states (15, 30, 60, 90, 120, 150, 240 min). We investigate the postprandial dynamics of the metabolism as reflected in the dynamic behaviour of the measured metabolites. The data is arranged as a three-way array: subjects by metabolites by time. We analyze the fasting state data to reveal static patterns of subject group differences using principal component analysis (PCA), and fasting state-corrected postprandial data using the CANDECOMP/PARAFAC (CP) tensor factorization to reveal dynamic markers of group differences. RESULTS: Our analysis reveals dynamic markers consisting of certain metabolite groups and their temporal profiles showing differences among males according to their body mass index (BMI) in response to the meal challenge. We also show that certain lipoproteins relate to the group difference differently in the fasting vs. dynamic state. Furthermore, while similar dynamic patterns are observed in males and females, the BMI-related group difference is observed only in males in the dynamic state. CONCLUSION: The CP model is an effective approach to analyze time-resolved postprandial metabolomics data, and provides a compact but a comprehensive summary of the postprandial data revealing replicable and interpretable dynamic markers crucial to advance our understanding of changes in the metabolism in response to a meal challenge.

Prenatal exposure to ambient air pollution is associated with early life immune perturbations.

BACKGROUND: Exposure to ambient air pollution has been linked to asthma, allergic rhinitis, and other inflammatory disorders, but little is known about the underlying mechanisms. OBJECTIVE: We studied the potential mechanisms leading from prenatal ambient air pollution exposure to asthma and allergy in childhood. METHODS: Long-term exposure to nitrogen dioxide (NO2) as well as to particulate matter with a diameter of ≤2.5 and ≤10 µm (PM2.5 and PM10) were modeled at the residence level from conception to 6 years of age in 700 Danish children followed clinically for development of asthma and allergy. Nasal mucosal immune mediators were assessed at age 4 weeks and 6 years, inflammatory markers in blood at 6 months, and nasal epithelial DNA methylation and gene expression at age 6 years. RESULTS: Higher prenatal air pollution exposure with NO2, PM2.5, and PM10 was associated with an altered nasal mucosal immune profile at 4 weeks, conferring an increased odds ratio [95% confidence interval] of 2.68 [1.58, 4.62] for allergic sensitization and 2.63 [1.18, 5.81] for allergic rhinitis at age 6 years, and with an altered immune profile in blood at age 6 months conferring increased risk of asthma at age 6 years (1.80 [1.18, 2.76]). Prenatal exposure to ambient air pollution was not robustly associated with immune mediator, epithelial DNA methylation, or gene expression changes in nasal cells at age 6 years. CONCLUSION: Prenatal exposure to ambient air pollution was associated with early life immune perturbations conferring risk of allergic rhinitis and asthma. These findings suggest potential mechanisms of prenatal exposure to ambient air pollution on the developing immune system.

Diet-associated vertically transferred metabolites and risk of asthma, allergy, eczema, and infections in early childhood.

BACKGROUND: Evidence suggests maternal pregnancy dietary intake and nutrition in the early postnatal period to be of importance for the newborn child's health. However, studies investigating diet-related metabolites transferred from mother to child on disease risk in childhood are lacking. We sought to investigate the influence of vertically transferred metabolites on risk of atopic diseases and infections during preschool age. METHODS: In the Danish population-based COPSAC2010 mother-child cohort, information on 10 diet-related vertically transferred metabolites from metabolomics profiles of dried blood spots (DBS) at age 2-3 days was analyzed in relation to the risk of childhood asthma, allergy, eczema, and infections using principal component and single metabolite analyses. RESULTS: In 678 children with DBS measurements, a coffee-related metabolite profile reflected by principal component 1 was inversely associated with risk of asthma (odds ratio (95% CI) 0.78 (0.64; 0.95), p = .014) and eczema at age 6 years (0.79 (0.65; 0.97), p = .022). Furthermore, increasing stachydrine (fruit-related), 3-carboxy-4-methyl-5-propyl-2-furanpropanoate (fish-related), and ergothioneine (fruit-, green vegetables-, and fish-related) levels were all significantly associated with reduced risks of infections at age 0-3 years (p < .05). CONCLUSION: This study demonstrates associations between pregnancy diet-related vertically transferred metabolites measured in children in early life and risk of atopic diseases and infections in childhood. The specific metabolites associated with a reduced disease risk in children may contribute to the characterization of a healthy nutritional profile in pregnancy using a metabolomics-based unbiased tool for predicting childhood health.

Genome-wide study of early and severe childhood asthma identifies interaction between CDHR3 and GSDMB.

BACKGROUND: Asthma with severe exacerbation is one of the most common causes of hospitalization among young children. Exacerbations are typically triggered by respiratory infections, but the host factors causing recurrent infections and exacerbations in some children are poorly understood. As a result, current treatment options and preventive measures are inadequate. OBJECTIVE: We sought to identify genetic interaction associated with the development of childhood asthma. METHODS: We performed an exhaustive search for pairwise interaction between genetic single nucleotide polymorphisms using 1204 cases of a specific phenotype of early childhood asthma with severe exacerbations in patients aged 2 to 6 years combined with 5328 nonasthmatic controls. Replication was attempted in 3 independent populations, and potential underlying immune mechanisms were investigated in the COPSAC2010 and COPSAC2000 birth cohorts. RESULTS: We found evidence of interaction, including replication in independent populations, between the known childhood asthma loci CDHR3 and GSDMB. The effect of CDHR3 was dependent on the GSDMB genotype, and this interaction was more pronounced for severe and early onset of disease. Blood immune analyses suggested a mechanism related to increased IL-17A production after viral stimulation. CONCLUSIONS: We found evidence of interaction between CDHR3 and GSDMB in development of early childhood asthma, possibly related to increased IL-17A response to viral infections. This study demonstrates the importance of focusing on specific disease subtypes for understanding the genetic mechanisms of asthma.

Changes in Muscle Mass and Strength During Follow-Up After One-Year Resistance Training Interventions in Older Adults.

ABSTRACT: Mertz, KH, Reitelseder, S, Rasmussen, MA, Bülow, J, Højfeldt, G, Jensen, M, Hjulmand, M, Lindberg, J, Kramer, MU, Bechshøft, R, and Holm, L. Changes in muscle mass and strength during follow-up after one-year resistance training interventions in older adults. J Strength Cond Res 37(10): 2064-2070, 2023-The aim of this study was to investigate if home-based resistance training compared with center-based resistance training was associated with better preservation of muscle mass and strength in older individuals, 6 months after the interventions ended. One hundred four healthy older individuals (>65 years) who had completed 1 year of either home-based light-intensity training with daily whey protein supplementation (LITW), center-based heavy resistance training with whey protein supplementation (HRTW), or daily whey protein supplementation alone (WHEY) returned for follow-up measurement 6 months after the interventions. Measures of muscle mass, strength, and power were assessed at the end of intervention as well as at follow-up. Furthermore, we compared changes in these parameters between subjects who continued resistance training (≥1 weekly training session) during follow-up (CONT) with those who stopped (STOP). Resistance training continuation during follow-up did not differ between HRTW and LITW (41 vs. 41%, P = 1.0) but was higher for both groups compared with WHEY (18%, P = 0.04-0.05). However, no between-group differences were observed between LITW/HRTW/WHEY in changes in muscle mass, strength, or power during follow-up. STOP was associated with a poorer preservation of quadriceps cross-sectional area compared with CONT (-1.7 cm 2 [-0.4 to -3.0], P = 0.01, effect size: 0.79). No effect of training continuation was observed on changes in muscle strength and power. In conclusion, maintenance of muscle mass and strength is not superior after home-based resistance training compared with center-based training. However, training continuation seems crucial for the maintenance of muscle mass, irrespective of the training intervention.

Characteristics and Mechanisms of a Sphingolipid-associated Childhood Asthma Endotype.

Rationale: A link among sphingolipids, 17q21 genetic variants, and childhood asthma has been suggested, but the underlying mechanisms and characteristics of such an asthma endotype remain to be elucidated.Objectives: To study the sphingolipid-associated childhood asthma endotype using multiomic data.Methods: We used untargeted liquid chromatography-mass spectrometry plasma metabolomic profiles at the ages of 6 months and 6 years from more than 500 children in the COPSAC2010 (Copenhagen Prospective Studies on Asthma in Childhood) birth cohort focusing on sphingolipids, and we integrated the 17q21 genotype and nasal gene expression of SPT (serine palmitoyl-CoA transferase) (i.e., the rate-limiting enzyme in de novo sphingolipid synthesis) in relation to asthma development and lung function traits from infancy until the age 6 years. Replication was sought in the independent VDAART (Vitamin D Antenatal Asthma Reduction Trial) cohort.Measurements and Main Results: Lower concentrations of ceramides and sphingomyelins at the age of 6 months were associated with an increased risk of developing asthma before age 3, which was also observed in VDAART. At the age of 6 years, lower concentrations of key phosphosphingolipids (e.g., sphinganine-1-phosphate) were associated with increased airway resistance. This relationship was dependent on the 17q21 genotype and nasal SPT gene expression, with significant interactions occurring between the genotype and the phosphosphingolipid concentrations and between the genotype and SPT expression, in which lower phosphosphingolipid concentrations and reduced SPT expression were associated with increasing numbers of at-risk alleles. However, the findings did not pass the false discovery rate threshold of <0.05.Conclusions: This exploratory study suggests the existence of a childhood asthma endotype with early onset and increased airway resistance that is characterized by reduced sphingolipid concentrations, which are associated with 17q21 genetic variants and expression of the SPT enzyme.

Influence of Age, Sex, and Diet on the Human Fecal Metabolome Investigated by 1H NMR Spectroscopy.

The human fecal metabolome is increasingly studied to explore the impact of diet and lifestyle on health and the gut microbiome. However, systematic differences and confounding factors related to age, sex, and diet remain largely unknown. In this study, absolute concentrations of fecal metabolites from 205 healthy Danes (105 males and 100 females, 49 ± 31 years old) were quantified using 1H NMR spectroscopy and the newly developed SigMa software. The largest systemic variation was found to be highly related to age. Fecal concentrations of short-chain fatty acids (SCFA) were higher in the 18 years old group, while amino acids (AA) were higher in the elderly. Sex-related metabolic differences were weak but significant and mainly related to changes in SCFA. The concentrations of butyric, valeric, propionic, and isovaleric acids were found to be higher in males compared to females. Sex differences were associated with a stronger, possibly masking, effect from differential intake of macronutrients. Dietary fat intake decreased levels of SCFA and AA of both sexes, while carbohydrate intake showed weak correlations with valeric and isovaleric acids in females. This study highlights some possible demographic confounders linked to diet, disease, lifestyle, and microbiota that have to be taken into account when analyzing fecal metabolome data.

Innate IL-23/Type 17 immune responses mediate the effect of the 17q21 locus on childhood asthma.

BACKGROUND: Several childhood asthma risk loci that relate to immune function have been identified by genome-wide association studies (GWAS), but the underlying mechanisms remain unknown. OBJECTIVE: Here, we examined whether perturbed innate immune responses mediate the association between known genetic risk variants and development of childhood asthma. METHODS: Peripheral blood mononuclear cells from 336 six-month-old infants from the Copenhagen Prospective Studies on Asthma in Childhood (COPSAC2000 ) cohort were stimulated in vitro with six different innate ligands (LPS, CpG, poly(I:C), R848, HDMAPP and aluminium hydroxide together with low levels of LPS) followed by quantification of 18 released cytokines and chemokines 40 h after the stimulations. The innate immune response profiles were decomposed by principal component (PC) analysis, and PC1-5 were used in mediation analyses of the effect of 25 known genetic risk variants on childhood asthma until age 7. RESULTS: The effects of two variants from the 17q21 locus (rs7216389, rs2305480) on asthma and exacerbation risk were significantly mediated by immune parameters induced in response to ligands mimicking intracellular colonization; bacterial DNA (CpG) and double-stranded viral RNA (poly(I:C)). The Th17 and innate lymphoid cell type 3-amplifying cytokine IL-23 was the most prominent cytokine involved. CONCLUSION: The 17q21 effect on childhood asthma and exacerbations was partly mediated by deregulation of IL-23 in response to intracellular microbial ligands, which may suggest ineffective clearance of intracellular pathogens in the lungs.

Airway immune mediator levels during asthma-like symptoms in young children and their possible role in response to azithromycin.

BACKGROUND: Asthma-like symptoms in young children are orchestrated by the local airway immune response, but current knowledge largely relies on in vitro airway models. Azithromycin has been shown to reduce the duration of episodes with asthma-like symptoms, but efficacy may depend on the individual child's immune response. OBJECTIVES: To investigate in vivo upper airway immune mediator levels during episodes with asthma-like symptoms in young children and their ability to predict the clinical response to azithromycin treatment. METHODS: A total of 535 children aged 0-3 years from the Copenhagen Prospective Studies of Asthma in Childhood-2010 mother-child cohort were examined for immune mediator levels in samples of nasal epithelial lining fluid during episodes with asthma-like symptoms as well as in the asymptomatic state. In a sub-study, children with recurrent asthma-like symptoms were randomized to either a 3-day course of oral azithromycin (10 mg/kg; n = 32) or placebo (n = 38). In the current study, we compared the pretreatment immune mediator levels with the clinical response to treatment with azithromycin in an exploratory post hoc analysis. RESULTS: The immune mediator concentrations during vs outside episodes were significantly upregulated for IFN-É£ (ratio 1.73), TNF-α (ratio 2.05), IL-1ß (ratio 1.45), IL-10 (ratio 1.97), while CCL22 (ratio 0.65) was downregulated. Low levels of TNF-α and IL-10 and high levels of CCL22 predicted better treatment response to azithromycin (P-values < .05). CONCLUSION: Upper airway immune mediator levels were altered during episodes of asthma-like symptoms, and levels of TNF-α, CCL22, and IL-10 may predict the response to azithromycin treatment.

Neonatal airway immune profiles and asthma and allergy endpoints in childhood.

BACKGROUND: The immune system plays a key role in the pathogenesis of asthma and allergy, but the role of the airway cytokine and chemokine composition in vivo in early life prior to symptom development has not been described previously. Here, we aimed to examine whether the neonatal airway immune composition associates with development of allergy and asthma in childhood. METHODS: We measured unstimulated levels of 20 immune mediators related to the Type 1, Type 2, Type 17, or regulatory immune pathways in the airway mucosal lining fluid of 620 one-month-old healthy neonates from the COPSAC2010 birth cohort. Allergy and asthma were diagnosed at our research clinic by predefined algorithms and objective assessments at age 6 years. Principal component analyses were used to describe the airway cytokine and chemokine composition. RESULTS: A neonatal airway immune profile particularly characterized by enhanced IL-1ß and reduced CCL26 was significantly associated with later development of elevated specific IgE to inhaled allergens, a positive skin prick test, and allergic rhinitis, but not with food sensitization. Conversely, reduced Type 17 immune-associated markers, including IL-1ß and CXCL8, showed trend of association with development of early asthma endpoints. CONCLUSIONS: Development of early asthma endpoints and inhalant allergy during the first 6 years of life seems associated with distinctly perturbed airway immune profiles in neonatal life, which is suggestive of an early origin and different pathogenesis of childhood asthma and allergy. These exploratory findings suggest pre- and perinatal life as an important window of opportunity for prevention of asthma and inhalant allergy.

Fish Oil-Derived Fatty Acids in Pregnancy and Wheeze and Asthma in Offspring.

BACKGROUND: Reduced intake of n-3 long-chain polyunsaturated fatty acids (LCPUFAs) may be a contributing factor to the increasing prevalence of wheezing disorders. We assessed the effect of supplementation with n-3 LCPUFAs in pregnant women on the risk of persistent wheeze and asthma in their offspring. METHODS: We randomly assigned 736 pregnant women at 24 weeks of gestation to receive 2.4 g of n-3 LCPUFA (fish oil) or placebo (olive oil) per day. Their children formed the Copenhagen Prospective Studies on Asthma in Childhood2010 (COPSAC2010) cohort and were followed prospectively with extensive clinical phenotyping. Neither the investigators nor the participants were aware of group assignments during follow-up for the first 3 years of the children's lives, after which there was a 2-year follow-up period during which only the investigators were unaware of group assignments. The primary end point was persistent wheeze or asthma, and the secondary end points included lower respiratory tract infections, asthma exacerbations, eczema, and allergic sensitization. RESULTS: A total of 695 children were included in the trial, and 95.5% completed the 3-year, double-blind follow-up period. The risk of persistent wheeze or asthma in the treatment group was 16.9%, versus 23.7% in the control group (hazard ratio, 0.69; 95% confidence interval [CI], 0.49 to 0.97; P=0.035), corresponding to a relative reduction of 30.7%. Prespecified subgroup analyses suggested that the effect was strongest in the children of women whose blood levels of eicosapentaenoic acid and docosahexaenoic acid were in the lowest third of the trial population at randomization: 17.5% versus 34.1% (hazard ratio, 0.46; 95% CI, 0.25 to 0.83; P=0.011). Analyses of secondary end points showed that supplementation with n-3 LCPUFA was associated with a reduced risk of infections of the lower respiratory tract (31.7% vs. 39.1%; hazard ratio, 0.75; 95% CI, 0.58 to 0.98; P=0.033), but there was no statistically significant association between supplementation and asthma exacerbations, eczema, or allergic sensitization. CONCLUSIONS: Supplementation with n-3 LCPUFA in the third trimester of pregnancy reduced the absolute risk of persistent wheeze or asthma and infections of the lower respiratory tract in offspring by approximately 7 percentage points, or one third. (Funded by the Lundbeck Foundation and others; ClinicalTrials.gov number, NCT00798226 .).

Sensitization trajectories in childhood revealed by using a cluster analysis.

BACKGROUND: Assessment of sensitization at a single time point during childhood provides limited clinical information. We hypothesized that sensitization develops as specific patterns with respect to age at debut, development over time, and involved allergens and that such patterns might be more biologically and clinically relevant. OBJECTIVE: We sought to explore latent patterns of sensitization during the first 6 years of life and investigate whether such patterns associate with the development of asthma, rhinitis, and eczema. METHODS: We investigated 398 children from the at-risk Copenhagen Prospective Studies on Asthma in Childhood 2000 (COPSAC2000) birth cohort with specific IgE against 13 common food and inhalant allergens at the ages of ½, 1½, 4, and 6 years. An unsupervised cluster analysis for 3-dimensional data (nonnegative sparse parallel factor analysis) was used to extract latent patterns explicitly characterizing temporal development of sensitization while clustering allergens and children. Subsequently, these patterns were investigated in relation to asthma, rhinitis, and eczema. Verification was sought in an independent unselected birth cohort (BAMSE) constituting 3051 children with specific IgE against the same allergens at 4 and 8 years of age. RESULTS: The nonnegative sparse parallel factor analysis indicated a complex latent structure involving 7 age- and allergen-specific patterns in the COPSAC2000 birth cohort data: (1) dog/cat/horse, (2) timothy grass/birch, (3) molds, (4) house dust mites, (5) peanut/wheat flour/mugwort, (6) peanut/soybean, and (7) egg/milk/wheat flour. Asthma was solely associated with pattern 1 (odds ratio [OR], 3.3; 95% CI, 1.5-7.2), rhinitis with patterns 1 to 4 and 6 (OR, 2.2-4.3), and eczema with patterns 1 to 3 and 5 to 7 (OR, 1.6-2.5). All 7 patterns were verified in the independent BAMSE cohort (R2 > 0.89). CONCLUSION: This study suggests the presence of specific sensitization patterns in early childhood differentially associated with development of clinical outcomes. Using such patterns in future research might provide more robust and clinically relevant results.

Effect of Vitamin D3 Supplementation During Pregnancy on Risk of Persistent Wheeze in the Offspring: A Randomized Clinical Trial.

IMPORTANCE: Observational studies have suggested that increased dietary vitamin D intake during pregnancy may protect against wheezing in the offspring, but the preventive effect of vitamin D supplementation to pregnant women is unknown. OBJECTIVE: To determine whether supplementation of vitamin D3 during the third trimester of pregnancy reduces the risk of persistent wheeze in the offspring. DESIGN, SETTING, AND PARTICIPANTS: A double-blind, single-center, randomized clinical trial conducted within the Copenhagen Prospective Studies on Asthma in Childhood 2010 cohort. Enrollment began March 2009 with a goal of 708 participants, but due to delayed ethical approval, only 623 women were recruited at 24 weeks of pregnancy. Follow-up of the children (N = 581) was completed when the youngest child reached age 3 years in March 2014. INTERVENTIONS: Vitamin D3 (2400 IU/d; n = 315) or matching placebo tablets (n = 308) from pregnancy week 24 to 1 week postpartum. All women received 400 IU/d of vitamin D3 as part of usual pregnancy care. MAIN OUTCOMES AND MEASURES: Age at onset of persistent wheeze in the first 3 years of life. Secondary outcomes included number of episodes of troublesome lung symptoms, asthma, respiratory tract infections, and neonatal airway immunology. Adverse events were assessed. RESULTS: Of the 581 children, persistent wheeze was diagnosed during the first 3 years of life in 47 children (16%) in the vitamin D3 group and 57 children (20%) in the control group. Vitamin D3 supplementation was not associated with the risk of persistent wheeze, but the number of episodes of troublesome lung symptoms was reduced, and the airway immune profile was up-regulated (principal component analysis, P = .04). There was no effect on additional end points. Intrauterine death was observed in 1 fetus (<1%) in the vitamin D3 group vs 3 fetuses (1%) in the control group and congenital malformations in 17 neonates (5%) in the vitamin D3 group vs 23 neonates (8%) in the control group. [table: see text]. CONCLUSIONS AND RELEVANCE: The use of 2800 IU/d of vitamin D3 during the third trimester of pregnancy compared with 400 IU/d did not result in a statistically significant reduced risk of persistent wheeze in the offspring through age 3 years. However, interpretation of the study is limited by a wide CI that includes a clinically important protective effect. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00856947.

Structure-revealing data fusion.

BACKGROUND: Analysis of data from multiple sources has the potential to enhance knowledge discovery by capturing underlying structures, which are, otherwise, difficult to extract. Fusing data from multiple sources has already proved useful in many applications in social network analysis, signal processing and bioinformatics. However, data fusion is challenging since data from multiple sources are often (i) heterogeneous (i.e., in the form of higher-order tensors and matrices), (ii) incomplete, and (iii) have both shared and unshared components. In order to address these challenges, in this paper, we introduce a novel unsupervised data fusion model based on joint factorization of matrices and higher-order tensors. RESULTS: While the traditional formulation of coupled matrix and tensor factorizations modeling only shared factors fails to capture the underlying structures in the presence of both shared and unshared factors, the proposed data fusion model has the potential to automatically reveal shared and unshared components through modeling constraints. Using numerical experiments, we demonstrate the effectiveness of the proposed approach in terms of identifying shared and unshared components. Furthermore, we measure a set of mixtures with known chemical composition using both LC-MS (Liquid Chromatography - Mass Spectrometry) and NMR (Nuclear Magnetic Resonance) and demonstrate that the structure-revealing data fusion model can (i) successfully capture the chemicals in the mixtures and extract the relative concentrations of the chemicals accurately, (ii) provide promising results in terms of identifying shared and unshared chemicals, and (iii) reveal the relevant patterns in LC-MS by coupling with the diffusion NMR data. CONCLUSIONS: We have proposed a structure-revealing data fusion model that can jointly analyze heterogeneous, incomplete data sets with shared and unshared components and demonstrated its promising performance as well as potential limitations on both simulated and real data.

Pathogenic bacteria colonizing the airways in asymptomatic neonates stimulates topical inflammatory mediator release.

RATIONALE: Bacterial colonization of neonatal airways with the pathogenic bacterial species, Moraxella catarrhalis, Streptococcus pneumoniae, and Haemophilus influenzae, is associated with later development of childhood asthma. OBJECTIVES: To study a possible association between colonization with pathogenic bacterial strains and the immune signature of the upper airways in healthy neonates. METHODS: A total of 20 cytokines and chemokines were quantified in vivo in the airway mucosal lining fluid of 662 neonates from the Copenhagen Prospective Study of Asthma in Childhood 2010 birth cohort. Colonization of the hypopharynx with M. catarrhalis, S. pneumoniae, H. influenzae, and Staphylococcus aureus was assessed simultaneously. The association between immune signatures and bacterial colonization or noncolonized controls was analyzed using conventional statistical methods supplemented by a multivariate approach for pattern identification. MEASUREMENTS AND MAIN RESULTS: Colonization with M. catarrhalis and H. influenzae induced a mixed T helper cell (Th) type 1/Th2/Th17 response with high levels of IL-1ß (M. catarrhalis, P = 2.2 × 10(-12); H. influenzae, P = 7.1 × 10(-10)), TNF-α (M. catarrhalis, P = 1.5 × 10(-9); H. influenzae, P = 5.9 × 10(-7)), and macrophage inflammatory protein-1ß (M. catarrhalis, P = 1.6 × 10(-11); H. influenzae, P = 2.7 × 10(-7)). S. aureus colonization demonstrated a Th17-promoting profile with elevated IL-17 levels (P = 1.6 × 10(-24)). S. pneumoniae colonization was not significantly associated with any of the mediators. CONCLUSIONS: M. catarrhalis and H. influenzae colonization of the airways of asymptomatic neonates is associated with an inflammatory immune response of the airway mucosa, which may result in chronic inflammation.

Metabolic maturation in the infant urine during the first 3 months of life.

The infant urine metabolome provides a body metabolic snapshot, and the sample collection can be done without stressing the fragile infant. 424 infant urine samples from 157 infants were sampled longitudinally at 1-, 2-, and 3 months of age. 49 metabolites were detected using proton nuclear magnetic resonance spectroscopy. Data were analyzed with multi- and univariate statistical methods to detect differences related to infant age-stage, gestational age, mother's pre-pregnancy BMI, C-section, infant birth weight, and infant sex. Significant differences were identified between age-stage (pbonferoni < 0.05) in 30% (15/49) of the detected metabolites. Urine creatinine increased significantly from 1 to 3 months. In addition, myo-inositol, taurine, methionine, and glucose seem to have conserved levels within the individual over time. We calculated a urine metabolic maturation age and found that the metabolic age at 3 months is negatively correlated to weight at 1 year. These results demonstrate that the metabolic maturation can be observed in urine metabolome with implications on infant growth and specifically suggesting that the systematic age effect on creatinine promotes caution in using this as normalization of other urine metabolites.

Randomised, Placebo-Controlled Investigation of the Impact of Probiotic Consumption on Gut Microbiota Diversity and the Faecal Metabolome in Seniors.

Aging has been associated with a changed composition and function of the gut microbiota (GM). Here, we investigate the effects of the multi-strain probiotic HOWARU® Restore on GM composition and function in seniors. Ninety-eight healthy adult volunteers aged ≥75 years were enrolled in a randomised, double-blinded intervention (NCT02207140), where they received HOWARU Restore (1010 CFU) or the placebo daily for 24 weeks, with 45 volunteers from each group completing the intervention. Questionnaires monitoring the effects on gastro-intestinal discomfort and bowel movements were collected. Faecal samples for GM characterisation (qPCR, 16S rRNA gene amplicon sequencing) and metabolomics (GC-FID, 1H NMR) were collected at the baseline and after 24 weeks. In the probiotic group, self-reported gastro-intestinal discomfort in the form of flatulence was significantly decreased during the intervention. At the baseline, 151 'core species' (present in ≥95% of samples) were identified. Most core species belonged to the Lachnospiraceae and Ruminococcaceae families. Neither alpha diversity nor beta diversity or faecal metabolites was affected by probiotic intake. On the contrary, we observed high intra-individual GM stability, with 'individual' accounting for 72-75% of variation. In conclusion, 24 weeks of HOWARU Restore intake reduced gastro-intestinal discomfort in the form of flatulence in healthy seniors without significantly influencing GM composition or activity.

Sociodemographic characteristics and food habits of organic consumers--a study from the Danish National Birth Cohort.

OBJECTIVE: To develop a basis for building models that can examine the impact of organic food (OF) choices on maternal and offspring health, including identification of factors associated with OF consumption and underlying dietary patterns. DESIGN: Dietary intake was collected for the preceding month from an FFQ in mid-pregnancy and information on sociodemographic characteristics was collected from telephone interviews during pregnancy. From a question about OF consumption in the FFQ, including six food categories, an OF preference index was calculated. Latent variables that captured the variability in OF choices in relation to dietary intake were defined. SETTING: The Danish National Birth Cohort (DNBC), 1996-2002. SUBJECTS: Pregnant women from DNBC (n 60,773). RESULTS: We found that frequent OF use was highly associated with age, occupational status, urbanization, smoking and vegetarianism. By principal components analysis we identified two eating patterns, a 'Western dietary pattern' and a 'Prudent dietary pattern', that explained 14.2% of the variability in data. Frequent OF users consumed a more 'prudent' diet compared with non-users and had significantly higher intakes of vegetables (167%), fibre (113%) and n-3 fatty acids (111%) and less saturated fat (28%). CONCLUSIONS: Frequent OF users seemed to have a healthier lifestyle than non-users. These findings highlight a major challenge in observational studies examining the impact of OF consumption on health due to potentially irremediable confounding factors.