Placental human papillomavirus infections and adverse pregnancy outcomes.

INTRODUCTION: Knowledge on prevalence and association of human papillomavirus (HPV) in third trimester placentae and adverse pregnancy outcomes is limited. We investigated the prevalence of placental HPV at delivery, explored urine HPV characteristics associated with placental HPV and whether placental HPV increased the risk adverse pregnancy outcomes. METHODS: Pregnant women were enrolled in the Scandinavian PreventADALL mother-child cohort study at midgestation. Human papillomavirus genotyping was performed on placental biopsies collected at delivery (n = 587) and first-void urine at midgestation and delivery (n = 556). Maternal characteristics were collected by questionnaires at gestational week 18 and 34. Adverse pregnancy outcomes were registered from chart data including hypertensive disorders of pregnancy, gestational diabetes mellitus and newborns small for gestational age. Uni- and multivariable regression models were used to investigate associations. RESULTS: Placental HPV was detected in 18/587 (3 %). Twenty-eight genotypes were identified among the 214/556 (38 %) with midgestational urine HPV. Seventeen of the 18 women with placental HPV were midgestational HPV positive with 89 % genotype concordance. Midgestational high-risk-(HR)-HPV and high viral loads of Any- or HR-HPV were associated with placental HPV. Persisting HPV infection from midgestation to delivery was not associated with placental HPV. Adverse pregnancy outcomes were seen in 2/556 (0.4 %) of women with placental HPV. DISCUSSION: In this general cohort of pregnant women, the prevalence of placental HPV was 3 %, and midgestational urinary HPV 38 %. High HPV viral load increased the risk for placental HPV infections. We observed no increased risk for adverse pregnancy outcomes in women with placental HPV.

Exhaled Volatile Organic Compounds for Asthma Control Classification in Children with Moderate to Severe Asthma: Results from the SysPharmPediA Study.

RATIONALE: Early identification of children with poorly controlled asthma is imperative for optimizing treatment strategies. The analysis of exhaled volatile organic compounds (VOCs) is an emerging approach to identify prognostic and diagnostic biomarkers in pediatric asthma. OBJECTIVES: To assess the accuracy of gas chromatography-mass spectrometry based exhaled metabolite analysis to differentiate between controlled and uncontrolled pediatric asthma. METHODS: This study encompassed a discovery (SysPharmPediA) and validation phase (U-BIOPRED, PANDA). Firstly, exhaled VOCs that discriminated asthma control levels were identified. Subsequently, outcomes were validated in two independent cohorts. Patients were classified as controlled or uncontrolled, based on asthma control test scores and number of severe attacks in the past year. Additionally, potential of VOCs in predicting two or more future severe asthma attacks in SysPharmPediA was evaluated. MEASUREMENTS AND MAIN RESULTS: Complete data were available for 196 children (SysPharmPediA=100, U-BIOPRED=49, PANDA=47). In SysPharmPediA, after randomly splitting the population into training (n=51) and test sets (n=49), three compounds (acetophenone, ethylbenzene, and styrene) distinguished between uncontrolled and controlled asthmatics. The area under the receiver operating characteristic curve (AUROCC) for training and test sets were respectively: 0.83 (95% CI: 0.65-1.00) and 0.77 (95% CI: 0.58-0.96). Combinations of these VOCs resulted in AUROCCs of 0.74 ±0.06 (UBIOPRED) and 0.68 ±0.05 (PANDA). Attacks prediction tests, resulted in AUROCCs of 0.71 (95% CI 0.51-0.91) and 0.71 (95% CI 0.52-0.90) for training and test sets. CONCLUSIONS: Exhaled metabolites analysis might enable asthma control classification in children. This should stimulate further development of exhaled metabolites-based point-of-care tests in asthma.

Recommendations for asthma monitoring in children: A PeARL document endorsed by APAPARI, EAACI, INTERASMA, REG, and WAO.

Monitoring is a major component of asthma management in children. Regular monitoring allows for diagnosis confirmation, treatment optimization, and natural history review. Numerous factors that may affect disease activity and patient well-being need to be monitored: response and adherence to treatment, disease control, disease progression, comorbidities, quality of life, medication side-effects, allergen and irritant exposures, diet and more. However, the prioritization of such factors and the selection of relevant assessment tools is an unmet need. Furthermore, rapidly developing technologies promise new opportunities for closer, or even "real-time," monitoring between visits. Following an approach that included needs assessment, evidence appraisal, and Delphi consensus, the PeARL Think Tank, in collaboration with major international professional and patient organizations, has developed a set of 24 recommendations on pediatric asthma monitoring, to support healthcare professionals in decision-making and care pathway design.

Frequent oil-baths and skin barrier during infancy in the PreventADALL study.

BACKGROUND: In the general population randomized controlled PreventADALL trial, frequent emollient bath additives from 2 weeks of age did not prevent atopic dermatitis, while the effect on skin barrier function throughout infancy is not established. OBJECTIVE: The primary aim of this exploratory substudy was to assess the effect of mineral based oil-baths on transepidermal water loss (TEWL) and dry skin through infancy, and secondarily to explore if filaggrin (FLG) mutations modified the effect. METHODS: Overall 2153 infants randomized to Skin intervention (SI)(n=995) (oil-bath 4 times/week from 2 weeks through 8 months) or No skin intervention (NSI)(n=1158) with TEWL measurements at 3, 6 and/or 12 months of age were included, of whom 1683 infants also had available FLG mutation status. Effects of the skin intervention on TEWL and dry skin through infancy were assessed by mixed effects regression modelling. Background characteristics and protocol adherence were collected from electronic questionnaires, birth records and weekly diaries. RESULTS: The TEWL (95% CI) was in average 0.42 g/m2/h (0.13-0.70, p= 0.004) higher in the SI compared to NSI group through the first year of life, with significantly higher levels at 3 months, (8.6 (8.3-9.0) versus 7.6 (7.3-7.9)), but similar at 6 and 12 months. Dry skin was significantly more often observed in the NSI group compared to the SI group at 3 months (59% versus 51%) and at 6 months of age (63% versus 53%), while at 12 months of age, the difference was no longer significant. At 3 months, the TEWL of FLG mutation carriers was similar to the TEWL in SI group. No interaction between skin intervention and FLG mutation was found in the first year of life. CONCLUSIONS: Infants with frequent oil-baths from 2 weeks of age had reduced skin barrier function through infancy compared to controls, largely attributed to higher TEWL at 3 months of age, while the skin at 3 and 6 months appeared less dry in infants subjected to the skin intervention.

Rhinovirus-induced wheeze was associated with asthma development in predisposed children.

AIM: This study explored whether early-life factors, such as rhinovirus-induced wheeze and allergic sensitisation, were related to asthma at 11 years of age. METHODS: We focused on 107 children aged 6-48 months, who attended the paediatric emergency department at Astrid Lindgren's Children's Hospital in Stockholm, Sweden, with acute wheeze in 2008-2012. They also attended follow-up visits at 11 years of age and were compared with 46 age-matched healthy controls. Odds ratios (OR) with 95% confidence intervals (CI) were calculated with logistic regression. RESULTS: We found that 62.6% of the acute wheeze cases had asthma at 11 years of age. Rhinoviruses at inclusion were the only common airway viruses associated with an increased asthma risk (OR 2.4, 95% CI 1.02-5.6). Other increased risks were parental heredity for asthma and/or allergies (adjusted OR 3.4, 95% CI 1.1-9.9) and allergic sensitisation at 2 years of age (adjusted OR 3.0, 95% CI 1.02-8.7). The highest prevalence of asthma was when children had both rhinovirus-induced wheeze at inclusion and allergic sensitisation at 7 years of age. CONCLUSION: Our findings highlight the importance of hereditary factors and allergic sensitisation on the development of asthma and suggest that rhinoviruses are associated with asthma development in predisposed children.

Infant lung function and early skin barrier impairment in the development of asthma at age 3 years.

BACKGROUND: Largely unexplored, we investigated if lower lung function, impaired skin barrier function by transepidermal water loss (TEWL), eczema, and filaggrin (FLG) mutations in infancy were associated with asthma in early childhood. METHODS: From the factorially designed randomized controlled intervention study PreventADALL, we evaluated 1337/2394 children from all randomization groups with information on asthma at age 3 years, and at age 3 months either lung function, TEWL, eczema, and/or FLG mutations. Lower lung function was defined as the time to peak tidal expiratory flow to expiratory time (tPTEF /tE ) <0.25, and skin barrier impairment as a high TEWL >9.50 g/m2 /h. Eczema was clinically observed, and DNA genotyped for FLG mutations. Asthma was defined as asthma-like symptoms (≥3 episodes of bronchial obstruction) between age 2-3 years as well as a history of doctor-diagnosed asthma and/or asthma medication use. Associations were analyzed in logistic regression models, presented with adjusted ORs (aOR) and 95% confidence intervals (CI). RESULTS: Lower lung function and skin barrier impairment were associated with asthma in general; aOR (95% CI) 5.4 (2.1, 13.7) and 1.6 (1.1, 2.5), while eczema and FLG mutations were associated with asthma in children with atopic dermatitis or allergic sensitization only. Stratifying for sex, the risk of asthma was only increased in boys with lower lung function; aOR (95% CI) 7.7 (2.5, 23.6), and in girls with FLG mutations; aOR (95% CI) 3.5 (1.5, 8.2). CONCLUSION: Lower lung function and impaired skin barrier function in infancy may increase the risk of asthma at age 3 years.

Inflammatory related plasma proteins involved in acute preschool wheeze.

BACKGROUND: Preschool wheeze is a risk factor for asthma development. However, the molecular mechanism behind a wheezing episode is not well understood. OBJECTIVE: Our aims were to assess the association of plasma proteins with acute preschool wheeze and to study the proteins with differential expression at the acute phase at revisit after 3 months. Additionally, to investigate the relationship between protein expression and clinical parameters. METHOD: We measured 92 inflammatory proteins in plasma and clinical parameters from 145 children during an episode of preschool wheeze (PW) and at the revisit after 3 months (PW-R, n = 113/145) and 101 healthy controls (HC) aged 6-48 months in the GEWAC cohort using the antibody-mediated proximity extension-based assay (Olink Proteomics, Uppsala). RESULTS: Of the 74 analysed proteins, 52 were differentially expressed between PW and HC. The expression profiles of the top 10 proteins, Oncostatin M (OSM), IL-10, IL-6, Fibroblast growth factor 21 (FGF21), AXIN1, CXCL10, SIRT2, TNFSF11, Tumour necrosis factor ß (TNF-ß) and CASP8, could almost entirely separate PW from HC. Five out of 10 proteins were associated with intake of oral corticosteroids (OCS) 24 h preceding blood sampling (OSM, CASP8, IL-10, TNF-ß and CXCL10). No differences in protein expression were seen between PWs with or without OCS in comparison to HC. At the revisit after 3 months, differential protein expressions were still seen between PW-R and HC for three (IL-10, SIRT2 and FGF21) of the 10 proteins. CONCLUSION: Our results contribute to unravelling potential immunopathological pathways shared between preschool wheeze and asthma.

Birth mode is associated with development of atopic dermatitis in infancy and early childhood.

Background: Birth by caesarean section (CS) is associated with development of allergic diseases, but its role in the development of atopic dermatitis (AD) is less convincing. Objective: Our primary aim was to determine if birth mode was associated with AD in 3-year-olds and secondarily to determine if birth mode was associated with early onset and/or persistent AD in the first 3 years of life. Methods: We included 2129 mother-child pairs from the Scandinavian population-based prospective PreventADALL cohort with information on birth mode including vaginal birth, either traditional (81.3%) or in water (4.0%), and CS before (6.3%) and after (8.5%) onset of labor. We defined early onset AD as eczema at 3 months and AD diagnosis by 3 years of age. Persistent AD was defined as eczema both in the first year and at 3 years of age, together with an AD diagnosis by 3 years of age. Results: AD was diagnosed at 3, 6, 12, 24, and/or 36 months in 531 children (25%). Compared to vaginal delivery, CS was overall associated with increased odds of AD by 3 years of age, with adjusted odds ratio (95% confidence interval) of 1.33 (1.02-1.74), and higher odds of early onset AD (1.63, 1.06-2.48). The highest odds for early onset AD were observed in infants born by CS after onset of labor (1.83, 1.09-3.07). Birth mode was not associated with persistent AD. Conclusion: CS was associated with increased odds of AD by 3 years of age, particularly in infants presenting with eczema at 3 months of age.

Infant colic and abdominal pain; associations with infant multimorbidity and maternal perceived stress up to 3 months postpartum-A cross-sectional/cohort study in the PreventADALL study.

AIMS AND OBJECTIVES: The primary aim was to explore whether infants with pain symptoms (colic, abdominal pain and visit to healthcare provider with pain or other discomforts) had increased multimorbidity (common infections, eczema and food sensitivity) compared with infants without these conditions. Secondarily, we aimed to determine whether infant pain symptoms were associated with maternal perceived stress in pregnancy and 3 months postpartum. BACKGROUND: Infant colic and abdominal pain are common concerns in early infancy. Nevertheless, to our knowledge, little research exists on the relationship between infant pain and common infant infections, eczema and food sensitization as comorbidities, and the impact of infant pain on the development of maternal perceived stress from pregnancy to infancy is inconsistent. DESIGN: This study was cross-sectional and partly prospective. METHODS: The sample consisted of mother-infant pairs (N = 1852); information regarding infant pain and multimorbidity was collected from the 3-month questionnaire and postpartum visits in the PreventADALL prospective cohort study. Chi-square tests and regression analyses were conducted. The STROBE checklist was followed. RESULTS: Our results showed a statistically significant higher proportion of respiratory and other infections in infants with pain symptoms. The odds of infant pain were higher for infants with multimorbidity compared to those with no comorbidity. Mothers of infants with colic and of infants visiting healthcare with pain and other discomforts reported statistically significant higher perceived stress by 3 months compared with mothers of infants with no reported pain. CONCLUSION: Our results indicate an association between infant pain symptoms and the presence of infections. Mothers of infants with colic and visiting healthcare had higher perceived stress compared to the no pain group. IMPLICATIONS FOR PRACTICE: Our study indicates that infant pain is associated with infant multimorbidity and maternal perceived stress, which may be useful when planning diagnostic, treatment and coping strategies in infant and family care. PATIENT OR PUBLIC CONTRIBUTION: The PreventADALL is a collaborative study with governmental and patient organisation representation. Selected infants with parents were also contributing during calibrating courses on eczema assessment for the data collectors. TRIAL REGISTRATION: The study was approved by the Regional Committee in Norway (2014/518) and Sweden (2014/2242-31/4) and registered at clinicaltrial.gov (NCT02449850). Link for clinical trials: https://clinicaltrials.gov/ct2/show/NCT02449850.

A Globally Distributed Bacteroides caccae Strain Is the Most Prevalent Mother-Child Shared Bacteroidaceae Strain in a Large Scandinavian Cohort.

Bacteroides and Phocaeicola, members of the family Bacteroidaceae, are among the first microbes to colonize the human infant gut. While it is known that these microbes can be transmitted from mother to child, our understanding of the specific strains that are shared and potentially transmitted is limited. In this study, we aimed to investigate the shared strains of Bacteroides and Phocaeicola in mothers and their infants. We analyzed fecal samples from pregnant woman recruited at 18 weeks of gestation from the PreventADALL study, as well as offspring samples from early infancy, including skin swab samples taken within 10 min after birth, the first available fecal sample (meconium), and fecal samples at 3 months of age. We screened 464 meconium samples for Bacteroidaceae, with subsequent selection of 144 mother-child pairs for longitudinal analysis, based on the presence of Bacteroidaceae, longitudinal sample availability, and delivery mode. Our results showed that Bacteroidaceae members were mainly detected in samples from vaginally delivered infants. We identified high prevalences of Phocaeicola vulgatus, Phocaeicola dorei, Bacteroides caccae, and Bacteroides thetaiotaomicron in mothers and vaginally born infants. However, at the strain level, we observed high prevalences of only two strains: a B. caccae strain and a P. vulgatus strain. Notably, the B. caccae strain was identified as a novel component of mother-child shared strains, and its high prevalence was also observed in publicly available metagenomes worldwide. Our findings suggest that mode of delivery may play a role in shaping the early colonization of the infant gut microbiota, in particular the colonization of Bacteroidaceae members. IMPORTANCE Our study provides evidence that Bacteroidaceae strains present on infants' skin within 10 min after birth, in meconium samples, and in fecal samples at 3 months of age in vaginally delivered infants are shared with their mothers. Using strain resolution analyses, we identified two strains, belonging to Bacteroides caccae and Phocaeicola vulgatus, as shared between mothers and their infants. Interestingly, the B. caccae strain showed a high prevalence worldwide, while the P. vulgatus strain was less common. Our findings also showed that vaginal delivery was associated with early colonization of Bacteroidaceae members, whereas cesarean section delivery was associated with delayed colonization. Given the potential for these microbes to influence the colonic environment, our results suggest that understanding the bacterial-host relationship at the strain level may have implications for infant health and development later in life.

Oropharyngeal Microbiota Clusters in Children with Asthma or Wheeze Associate with Allergy, Blood Transcriptomic Immune Pathways, and Exacerbation Risk.

Rationale: Children with preschool wheezing or school-age asthma are reported to have airway microbial imbalances. Objectives: To identify clusters in children with asthma or wheezing using oropharyngeal microbiota profiles. Methods: Oropharyngeal swabs from the U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes) pediatric asthma or wheezing cohort were characterized using 16S ribosomal RNA gene sequencing, and unsupervised hierarchical clustering was performed on the Bray-Curtis ß-diversity. Enrichment scores of the Molecular Signatures Database hallmark gene sets were computed from the blood transcriptome using gene set variation analysis. Children with severe asthma or severe wheezing were followed up for 12-18 months, with assessment of the frequency of exacerbations. Measurements and Main Results: Oropharyngeal samples from 241 children (age range, 1-17 years; 40% female) revealed four taxa-driven clusters dominated by Streptococcus, Veillonella, Rothia, and Haemophilus. The clusters showed significant differences in atopic dermatitis, grass pollen sensitization, FEV1% predicted after salbutamol, and annual asthma exacerbation frequency during follow-up. The Veillonella cluster was the most allergic and included the highest percentage of children with two or more exacerbations per year during follow-up. The oropharyngeal clusters were different in the enrichment scores of TGF-ß (transforming growth factor-ß) (highest in the Veillonella cluster) and Wnt/ß-catenin signaling (highest in the Haemophilus cluster) transcriptomic pathways in blood (all q values <0.05). Conclusions: Analysis of the oropharyngeal microbiota of children with asthma or wheezing identified four clusters with distinct clinical characteristics (phenotypes) that associate with risk for exacerbation and transcriptomic pathways involved in airway remodeling. This suggests that further exploration of the oropharyngeal microbiota may lead to novel pathophysiologic insights and potentially new treatment approaches.

Maternal human papillomavirus infection during pregnancy and preterm delivery: A mother-child cohort study in Norway and Sweden.

INTRODUCTION: Human papillomavirus (HPV) infection is common in women of reproductive age. Infection and inflammation are leading causes for preterm delivery (PTD), but the role of HPV infection in PTD and prelabor rupture of membranes (PROM) is unclear. We aimed to explore whether HPV infection during pregnancy in general, and high-risk-HPV (HR-HPV) infection specifically, increased the risk of PTD, preterm prelabor rupture of membranes (PPROM), PROM at term, and/or chorioamnionitis. MATERIAL AND METHODS: In pregnant women, who were participating in a prospective multicenter cohort study from a general population in Norway and Sweden (PreventADALL, ClinicalTrials.gov NCT02449850), HPV DNA was analyzed in available urine samples at mid-gestation (16-22 weeks) and at delivery, and in the placenta after delivery with Seegene Anyplex II HPV28 PCR assay. The risk of PTD, PPROM, PROM, and chorioamnionitis was analyzed using unadjusted and adjusted logistic regression analyses for any 28 HPV genotypes, including 12 HR-HPV genotypes, compared with HPV-negative women. Further, subgroups of HPV (low-risk/possibly HR-HPV, HR-HPV-non-16 and HR-HPV-16), persistence of HR-HPV from mid-gestation to delivery, HR-HPV-viral load, and presence of multiple HPV infections were analyzed for the obstetric outcomes. Samples for HPV analyses were available from 950 women with singleton pregnancies (mean age 32 years) at mid-gestation and in 753 also at delivery. RESULTS: At mid-gestation, 40% of women were positive for any HPV and 24% for HR-HPV. Of the 950 included women, 23 had PTD (2.4%), nine had PPROM (0.9%), and six had chorioamnionitis (0.6%). Of the term pregnancies, 25% involved PROM. The frequency of PTD was higher in HR-HPV-positive women (8/231, 3.5%) than in HPV-negative women (13/573, 2.3%) at mid-gestation, but the association was not statistically significant (odds ratio 1.55; 95% confidence interval 0.63-3.78). Neither any HPV nor subgroups of HPV at mid-gestation or delivery, nor persistence of HR-HPV was significantly associated with increased risk for PTD, PPROM, PROM, or chorioamnionitis. No HPV DNA was detected in placentas of women with PTD, PPROM or chorioamnionitis. CONCLUSIONS: HPV infection during pregnancy was not significantly associated with increased risk for PTD, PPROM, PROM, or chorioamnionitis among women from a general population with a low incidence of adverse obstetric outcomes.

Maternal food-avoidance diets and dietary supplements during breastfeeding.

AIMS: To identify maternal food-avoidance diets and dietary supplement use during breastfeeding, and to explore factors associated with food avoidance diets. DESIGN: A prospective mother-child birth cohort study. METHODS: Electronic questionnaires were answered by 1,462 breastfeeding mothers 6 months postpartum in the Preventing Atopic Dermatitis and Allergies in Children (PreventADALL) study from 2014-2016. Demographic and antenatal factors were analysed for associations with food avoidance diets in 1,368 women by multiple logistic regression. RESULTS: Overall, 289 breastfeeding women (19.8%) avoided at least one food item in their diet, most commonly cow's milk in 99 women (6.8%). Foods were most often avoided due to conditions in the child, maternal factors or lifestyle choice. The odds for food avoidance diets were 2.1 (95% CI: 1.3, 3.4) for food allergy (presumed or diagnosed) and 19.4 (5.4, 70.1) for celiac disease in the mother. Dietary supplements were reported by nearly 80%, most commonly cod liver oil.

Development of Core Outcome Measures sets for paediatric and adult Severe Asthma (COMSA).

BACKGROUND: Effectiveness studies with biological therapies for asthma lack standardised outcome measures. The COMSA (Core Outcome Measures sets for paediatric and adult Severe Asthma) Working Group sought to develop Core Outcome Measures (COM) sets to facilitate better synthesis of data and appraisal of biologics in paediatric and adult asthma clinical studies. METHODS: COMSA utilised a multi-stakeholder consensus process among patients with severe asthma, adult and paediatric clinicians, pharmaceutical representatives, and health regulators from across Europe. Evidence included a systematic review of development, validity and reliability of selected outcome measures plus a narrative review and a pan-European survey to better understand patients' and carers' views about outcome measures. It was discussed using a modified GRADE (Grading of Recommendations Assessment, Development and Evaluation) Evidence to Decision framework. Anonymous voting was conducted using predefined consensus criteria. RESULTS: Both adult and paediatric COM sets include forced expiratory volume in 1 s (FEV1) as z-scores, annual frequency of severe exacerbations and maintenance oral corticosteroid use. Additionally, the paediatric COM set includes the Paediatric Asthma Quality of Life Questionnaire and Asthma Control Test or Childhood Asthma Control Test, while the adult COM set includes the Severe Asthma Questionnaire and Asthma Control Questionnaire-6 (symptoms and rescue medication use reported separately). CONCLUSIONS: This patient-centred collaboration has produced two COM sets for paediatric and adult severe asthma. It is expected that they will inform the methodology of future clinical trials, enhance comparability of efficacy and effectiveness of biological therapies, and help assess their socioeconomic value. COMSA will inform definitions of non-response and response to biological therapy for severe asthma.

Infant tidal flow-volume parameters and arousal state.

Background: Infant lung function can be assessed with tidal flow-volume (TFV) loops. While TFV loops can be measured in both awake and sleeping infants, the influence of arousal state in early infancy is not established. The aim of the present study was to determine whether TFV loop parameters in healthy infants differed while awake compared to the sleeping state at 3 months of age. Methods: From the population-based Scandinavian Preventing Atopic Dermatitis and ALLergies in children (PreventADALL) birth cohort, 91 infants had reproducible TFV loops measured with Exhalyzer® D in both the awake and sleeping state at 3 months of age. The TFV loops were manually selected according to a standardised procedure. The ratio of time to peak tidal expiratory flow (t PTEF) to expiratory time (t E) and the corresponding volume ratio (V PTEF/V E), as well as tidal volume (V T) and respiratory rate were compared using nonparametric tests. Results: The mean (95% CI) t PTEF/t E was significantly higher while awake compared to the sleeping state: 0.39 (0.37-0.41) versus 0.28 (0.27-0.29); with the corresponding V PTEF/V E of 0.38 (0.36-0.40) versus 0.29 (0.28-0.30). The V T was similar, while the respiratory rate was higher while awake compared to the sleeping state: 53 (51-56) breaths·min-1 versus 38 (36-40) breaths·min-1. Conclusion: Higher t PTEF/t E, V PTEF/V E and respiratory rate, but similar V T while awake compared to the sleeping state suggests that separate normative TFV loop values according to arousal state may be required in early infancy.

Asthma and Wheeze Severity and the Oropharyngeal Microbiota in Children and Adolescents.

Rationale: There is a major unmet need for improving the care of children and adolescents with severe asthma and wheeze. Identifying factors contributing to disease severity may lead to improved diagnostics, biomarkers, or therapies. The airway microbiota may be such a key factor. Objectives: To compare the oropharyngeal airway microbiota of children and adolescents with severe and mild/moderate asthma/wheeze. Methods: Oropharyngeal swab samples from school-age and preschool children in the European U-BIOPRED (Unbiased BIOmarkers in the PREDiction of respiratory disease outcomes) multicenter study of severe asthma, all receiving severity-appropriate treatment, were examined using 16S ribosomal RNA gene sequencing. Bacterial taxa were defined as amplicon sequence variants. Results: We analyzed 241 samples from four cohorts: A) 86 school-age children with severe asthma; B) 39 school-age children with mild/moderate asthma; C) 65 preschool children with severe wheeze; and D) 51 preschool children with mild/moderate wheeze. The most common bacteria were Streptococcus (mean relative abundance, 33.5%), Veillonella (10.3%), Haemophilus (7.0%), Prevotella (5.9%), and Rothia (5.5%). Age group (school-age vs. preschool) was associated with the microbiota in ß-diversity analysis (F = 3.32, P = 0.011) and in a differential abundance analysis (28 significant amplicon sequence variants). Among all children, we found no significant difference in the microbiota between children with severe and mild/moderate asthma/wheeze in univariable ß-diversity analysis (F = 1.99, P = 0.08, N = 241), but a significant difference in a multivariable model (F = 2.66, P = 0.035), including the number of exacerbations in the previous year. Age was also significant when expressed as a microbial maturity score (Spearman Rho, 0.39; P = 4.6 × 10-10); however, this score was not associated with asthma/wheeze severity. Conclusions: There was a modest difference in the oropharyngeal airway microbiota between children with severe and mild/moderate asthma/wheeze across all children but not in individual age groups, and a strong association between the microbiota and age. This suggests the oropharyngeal airway microbiota as an interesting entity in studying asthma severity, but probably without the strength to serve as a biomarker for targeted intervention.

The effect of nicotine-containing products and fetal sex on placenta-associated circulating midpregnancy biomarkers.

BACKGROUND: In utero exposure to nicotine, largely assessed by smoking, is a risk factor for impaired offspring health, while potential effects of non-combustible nicotine use such as snus (oral moist tobacco), are less well-known. Maternal serum concentrations of placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) may be viewed as "placenta health markers", known to differ by fetal sex. Maternal smoking during pregnancy has been associated with lower levels of circulating sFlt-1, while the effect of snus on placenta-associated angiogenic factors is unknown. Our aim was to explore if snus and/or smoking exposure was associated with midpregnancy maternal levels of sFlt-1, PlGF and sFlt-1/PlGF ratio if these associations were modified by fetal sex. METHODS: Midpregnancy (16-22 gestational weeks) serum from 2603 Scandinavian women enrolled in the population-based multi-center PreventADALL (Preventing Atopic Dermatitis and ALLergies in children) study was analysed for sFlt-1 and PlGF concentrations by electrochemiluminescence, deriving the sFlt-1/PGF ratio. Nicotine use was assessed by electronic questionnaires at enrollment in 2278 of the women. Univariable and multivariable linear regression models on log transformed outcomes were used to assess the association between nicotine use and biomarker levels. Interaction terms were included to identify whether the associations were modified by fetal sex. RESULTS: Median sFlt-1, PlGF and sFlt-1/PlGF ratios among women with nicotine exposure information were similar to those of all included women and differed by fetal sex. Current snus use was significantly associated with reduced maternal circulating PlGF levels in adjusted analyses [ß - 0.12, (95% CI - 0.20; 0.00) compared to never use, p = 0.020]. A significant interaction between fetal sex and snus exposure was observed for PIGF (p = 0.031). Prior or periconceptional snus use was significantly associated with PIGF in male fetus pregnancies [ß - 0.05 (95% CI - 0.09 to (- 0.02)) and ß - 0.07 (95% CI - 0.12 to (- 0.02)) compared to never use, p = 0.002]. Smoking was not significantly associated with any circulating biomarkers levels. CONCLUSIONS: Midpregnancy maternal angiogenic profile differed by periconceptional snus use and fetal sex. Snus exposure, perceived as "safe" by users, before or during pregnancy seems to affect midpregnancy placental health in a sex dimorphic manner.

Early food intervention and skin emollients to prevent food allergy in young children (PreventADALL): a factorial, multicentre, cluster-randomised trial.

BACKGROUND: Primary prevention of food allergy by early introduction of allergenic foods seems promising. We aimed to determine whether early food introduction or the application of regular skin emollients in infants from a general population reduced the risk of food allergy. METHODS: This 2 × 2 factorial, cluster-randomised trial was done at Oslo University Hospital and Østfold Hospital Trust, Oslo, Norway, and Karolinska University Hospital, Stockholm, Sweden. Infants of women recruited antenatally at the routine 18-week ultrasound examination were cluster-randomised at birth to the following groups: (1) no intervention group; (2) the skin intervention group (skin emollients; bath additives and facial cream; from age 2 weeks to <9 months, both at least four times per week); (3) the food intervention group (early complementary feeding of peanut, cow's milk, wheat, and egg from age 3 months); or (4) combined intervention group (skin and food interventions). Participants were randomly assigned (1:1:1:1) using computer-generated randomisation based on clusters of 92 geographical areas and eight 3-month time blocks. Study personnel performing clinical assessments were masked to group allocation. The primary outcome was allergy to any interventional food at 36 months of age. The primary efficacy analysis was done by intention-to-treat analysis, which included all participants who were randomly assigned, apart from three individuals who withdrew their consent. This was a study performed within ORAACLE (the Oslo Research Group of Asthma and Allergy in Childhood; the Lung and Environment). This study is registered as ClinicalTrials.gov, NCT02449850. FINDINGS: We recruited 2697 women with 2701 pregnancies, from whom 2397 newborn infants were enrolled between April 14, 2015, and April 11, 2017. Of these infants, 597 were randomly assigned to the no intervention group, 575 to the skin intervention group, 642 to the food intervention group, and 583 to the combined intervention group. One participant in each of the no intervention, food intervention, and skin intervention groups withdrew consent and were therefore not included in any analyses. Food allergy was diagnosed in 44 children; 14 (2·3%) of 596 infants in the non-intervention group, 17 (3·0%) of 574 infants in the skin intervention group, six (0·9%) of 641 infants in the food intervention group, and seven (1·2%) of 583 infants in the combined intervention group. Peanut allergy was diagnosed in 32 children, egg allergy in 12 children, and milk allergy in four children. None had allergy to wheat. Prevalence of food allergy was reduced in the food intervention group compared with the no food intervention group (risk difference -1·6% [95% CI -2·7 to -0·5]; odds ratio [OR] 0·4 [95% CI 0·2 to 0·8]), but not compared with the skin intervention group (0·4% [95% CI -0·6 to 1· 5%]; OR 1·3 [0·7 to 2·3]), with no significant interaction effect (p=1·0). Preventing food allergy in one child required early exposure to allergenic foods in 63 children. No serious adverse events were observed. INTERPRETATION: Exposure to allergenic foods from 3 months of age reduced food allergy at 36 months in a general population. Our results support that early introduction of common allergenic foods is a safe and effective strategy to prevent food allergy. FUNDING: Full funding sources listed at end of paper (see Acknowledgments).