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Objectives To investigate the associations of physical activity (PA) and sedentary behaviour in early childhood with asthma and reduced lung function in later childhood within a large collaborative study.Design Pooling of longitudinal data from collaborating birth cohorts using meta-analysis of separate cohort-specific estimates and analysis of individual participant data of all cohorts combined.Setting Children aged 0–18 years from 26 European birth cohorts.Participants 136 071 individual children from 26 cohorts, with information on PA and/or sedentary behaviour in early childhood and asthma assessment in later childhood.Main outcome measure Questionnaire-based current asthma and lung function measured by spirometry (forced expiratory volume in 1 s (FEV1), FEV1/forced vital capacity) at age 6–18 years.Results Questionnaire-based and accelerometry-based PA and sedentary behaviour at age 3–5 years was not associated with asthma at age 6–18 years (PA in hours/day adjusted OR 1.01, 95% CI 0.98 to 1.04; sedentary behaviour in hours/day adjusted OR 1.03, 95% CI 0.99 to 1.07). PA was not associated with lung function at any age. Analyses of sedentary behaviour and lung function showed inconsistent results.Conclusions Reduced PA and increased sedentary behaviour before 6 years of age were not associated with the presence of asthma later in childhood.

This retrospective population-based analysis assessed variations in urgent healthcare use by children and young people (CYP) across UK nations (England, Scotland and Wales) between 2007 and 2017. The study focused on urgent hospital admissions, short stay urgent admissions (SSUA) and Emergency Department (ED) attendances among CYP aged

Abstract Benefits of breastfeeding for both the mother and the child are well established, but a comprehensive and robust study to investigate the protective effect of breastfeeding and attenuated time effect stratified by cause of morbidity are lacking. This study is based on the nationwide birth cohort in Korea that includes data on all infants born from 2009 to 2015. Of 1,608,540 children, the median follow-up period was 8.41 years (interquartile range, 6.76-10.06). When compared to children with fully formula feeding, the hospital admission rate was 12% lower in those with partially breastfeeding and 15% lower in those with exclusive breastfeeding. The apparent protective effect of breastfeeding was reduced with increasing age. Our study provides potential evidence of the beneficial association of breastfeeding on subsequent hospital admissions. The protective effect declined over time as the children grew older. Encouraging any breastfeeding for at least the first 6 months among infants is an important public health strategy to improve overall child health.

Summary: Background: Spirometric obstruction and restriction are two patterns of impaired lung function which are predictive of poor health. We investigated the development of these phenotypes and their transitions through childhood to early adulthood. Methods: In this study, we analysed pooled data from three UK population−based birth cohorts established between 1989 and 1995. We applied descriptive statistics, regression modelling and data-driven modelling to data from three population−based birth cohorts with at least three spirometry measures from childhood to adulthood (mid-school: 8–10 years, n = 8404; adolescence: 15–18, n = 5764; and early adulthood: 20–26, n = 4680). Participants were assigned to normal, restrictive, and obstructive spirometry based on adjusted regression residuals. We considered two transitions: from 8–10 to 15–18 and from 15–18 to 20–26 years. Findings: Obstructive phenotype was observed in ∼10%, and restrictive in ∼9%. A substantial proportion of children with impaired lung function in school age (between one third in obstructive and a half in restricted phenotype) improved and achieved normal and stable lung function to early adulthood. Of those with normal lung function in school-age,

Asthma is a common condition in children. This review describes the evidence from the literature and international asthma guidelines for using fractional exhaled nitric oxide (FENO) in the diagnosis and monitoring of childhood asthma. The accuracy of FENO measuring devices could be further improved, the difference in FENO results between devices are equivalent to what is considered a clinically important difference. For diagnosing asthma no guideline currently recommends FENO is used as the first test, but many recommend FENO as part of a series of tests. A cut-off of 35 ppb is widely recommended as being supportive of an asthma diagnosis, but evidence from children at risk of asthma suggests that a lower threshold of 25 ppb may be more appropriate. Nine randomised clinical trials including 1885 children have added FENO to usual asthma care and find that exacerbations are reduced when care is guided by FENO (OR for exacerbation compared to usual care 0.77, 95% CI 0.62–0.94). What is not clear is what cut-off(s) of FENO should be used to trigger a change in treatment. After 30 years of intensive research there is not sufficient evidence to recommend FENO for routine diagnosing and monitoring asthma in children. Educational aims To give the reader an overview of literature that supports and does not support the role of FENO in diagnosing asthma in children. To give the reader an overview of literature that supports and does not support the role of FENO in monitoring asthma in children. To give the reader an understanding of the role of FENO in international guidelines for diagnosing and monitoring asthma in children.

Childhood asthma is a common condition in children. This review describes the evidence from seven asthma guidelines for using spirometry in the diagnosis and monitoring of childhood asthma. All guidelines recommend spirometry as the primary test to be performed for diagnosing asthma in children aged >5 years. Spirometry is often normal in children with asthma. Guidelines are not consistent with respect to whether forced expiratory volume in 1 s (FEV1) or FEV1/forced vital capacity (FVC) should be measured, or their threshold for “abnormal” spirometry, and we describe the sensitivity and specificity for these different cut-offs. The role of spirometry in monitoring asthma is less clear in the guidelines, and some do not suggest spirometry should be done. There is no consensus on what spirometric measurement should be used, how often it should be measured and what is a minimum clinically important change in spirometry. The role of spirometry in diagnosing asthma is more clearly established when compared to its role in monitoring asthma. The potential of spirometry to aid decision making for asthma diagnosis and monitoring in children remains to be fully evaluated. Educational aims To provide knowledge of the commonly used guidelines for asthma diagnosis and management. To give insight into the opportunities and challenges in using spirometry to diagnose and monitor asthma in children. To provide an understanding of the precision of spirometry for diagnosing asthma.

Abstract Background There is increasing evidence that the airway microbiome plays a key role in the establishment of respiratory health by interacting with the developing immune system early in life. While it has become clear that bacteria are involved in this process, there is a knowledge gap concerning the role of fungi. Moreover, the inter-kingdom interactions that influence immune development remain unknown. In this prospective exploratory human study, we aimed to determine early post-natal microbial and immunological features of the upper airways in 121 healthy newborns. Results We found that the oropharynx and nasal cavity represent distinct ecological niches for bacteria and fungi. Breastfeeding correlated with changes in microbiota composition of oropharyngeal samples with the greatest impact upon the relative abundance of Streptococcus species and Candida. Host transcriptome profiling revealed that genes with the highest expression variation were immunological in nature. Multi-omics factor analysis of host and microbial data revealed unique co-variation patterns. Conclusion These data provide evidence of a diverse multi-kingdom microbiota linked with local immunological characteristics in the first week of life that could represent distinct trajectories for future respiratory health. Trial registration NHS Health Research Authority, IRAS ID 199053. Registered 5 Oct 2016. https://www.hra.nhs.uk/planning-and-improving-research/application-summaries/research-summaries/breathing-together/ Video abstract

Abstract Background Factors contributing to decisions to refer children for scheduled appointments at medical paediatric outpatient clinics are not well understood. Our aim was to describe practice-level characteristics associated with referrals to general paediatric clinics. Methods In this cross-sectional study the setting was general practices in three health boards in Scotland, NHS Grampian, NHS Highland and NHS Tayside The outcome was average annual number of referrals per 1000 children between 2011 and 2017. Univariate and multivariate analyses related the outcome to practice characteristics. For each practice the following characteristics were determined: distance from hospital; area deprivation; number of children registered; presence of ≥ 1 general practitioner with a child health interest and practice ownership. Results There were 62 practices in NHS Grampian, 63 in NHS Highland, and 65 in NHS Tayside; representative annual number of referrals to paediatric clinics per capita were 22, 34, and 35/1000 respectively. In the multivariate model, the number of referrals was inversely related to number of children in the practice (0.8 % fall per 1000 children [95 % confidence interval, CI, 0.5, 1.1]) and was higher from practices in the more deprived areas by a mean 55 % [95 % CI 9, 121] compared to less deprived areas. The number of referrals from a practice rose by 0.91 % [95 % CI 0.86, 0.97] for each additional partner in the practice. Conclusion Some practice-level characteristics were related to the standardised number of referrals, and associations differed between regions.

Acute exacerbations are common in children and potentially preventable. Currently, a past exacerbation is the best predictor of a future exacerbation. We undertook a systematic review of the literature describing the relationship between past and future exacerbations. Our analysis considered whether the odds ratios for one exacerbation to predict a recurrence were different across different categories of exacerbation. Four databases were searched systematically (MEDLINE, Embase, the Cumulative Index to Nursing and Allied Health and PsycInfo). Exacerbations were categorised by severity as: presentation to emergency department (ED); hospital admission; paediatric intensive care unit (PICU) admission; and “unspecified severity” (i.e. no distinction between severity categories was made). Meta-analysis was performed for studies where sufficient data were provided for inclusion. There were 26 eligible articles from 9185 identified. There was significant heterogeneity in duration of follow-up, healthcare system and exacerbation definition between studies. For the unspecified severity definition, the odds ratio for an exacerbation after a previous exacerbation was 9.87 (95% CI 5.02–19.39; six studies, 162 583 individuals). PICU admission was also associated with increased risk of future admission (OR 5.87, 95% CI 2.96–11.64; two studies, 730 individuals). Meta-analysis was not possible for ED visits or hospitalisation. The median odds ratio (range) for past ED visit predicting future ED visit was 6.27 (3.3–8.26) and for past hospitalisation predicting future hospitalisation was 3.37 (1.89–5.36). The odds for a second asthma exacerbation do not necessarily increase with increasing severity of an initial exacerbation.

Abstract Background Many inpatient facilities in Scotland have opened short stay paediatric assessment units (SSPAU) which are clinical areas separate from the usual inpatient ward area and these are where most short stay (also called zero day) admissions are accommodated. Here we describe the effect of opening short stay paediatric assessment units (SSPAU) on the proportion of zero day admissions relative to all emergency admissions. Methods Details of all emergency medical paediatric admissions to Scottish hospitals between 2000 and 2013 were obtained, including the number of zero day admissions per month and health board (i.e. geographic region). The month and year that an SSPAU opened in each health board was provided by local clinicians. Results SSPAUs opened in 7 health boards, between 2004 and 2012. Health boards with an SSPAU had a slower rise in zero day admissions compared to those without SSPAU (0.6% per month [95% CI 0.04, 0.09]. Across all 7 health boards, opening an SSPAU was associated with a 13% [95% CI 10, 15] increase in the proportion of zero day admissions. When considered individually, zero day admissions rose in four health boards after their SSPAU opened, were unchanged in one and fell in two health boards. Independent of SSPAUs opening, there was an increase in the proportion of all admissions which were zero day admissions (0.1% per month), and this accelerated after SSPAUs opened. Conclusion Opening an SSPAU has heterogeneous outcomes on the proportion of zero day admissions in different settings. Zero day admissions could be reduced in some health boards by understanding differences in clinical referral pathways between health boards with contrasting trends in zero day admissions after their SSPAU opens.

Abstract Background Service reconfiguration of inpatient services in a hospital includes complete and partial closure of all emergency inpatient facilities. The “natural experiment” of service reconfiguration may give insight into drivers for emergency admissions to hospital. This study addressed the question does the prevalence of emergency admission to hospital for children change after reconfiguration of inpatient services? Methods There were five service reconfigurations in Scottish hospitals between 2004 and 2018 where emergency admissions to one “reconfigured” hospital were halted (permanently or temporarily) and directed to a second “adjacent” hospital. The number of emergency admissions (standardised to /1000 children in the regional population) per month to the “reconfigured” and “adjacent” hospitals was obtained for five years prior to reconfiguration and up to five years afterwards. An interrupted time series analysis considered the association between reconfiguration and admissions across pairs comprised of “reconfigured” and “adjacent” hospitals, with adjustment for seasonality and an overall rising trend in admissions. Results Of the five episodes of reconfiguration, two were immediate closure, two involved closure only to overnight admissions and one with overnight closure for a period and then closure. In “reconfigured” hospitals there was an average fall of 117 admissions/month [95% CI 78, 156] in the year after reconfiguration compared to the year before, and in “adjacent” hospitals admissions rose by 82/month [32, 131]. Across paired reconfigured and adjacent hospitals, in the months post reconfiguration, the overall number of admissions to one hospital pair slowed, in another pair admissions accelerated, and admission prevalence was unchanged in three pairs. After reconfiguration in one hospital, there was a rise in admissions to a third hospital which was closer than the named “adjacent” hospital. Conclusions There are diverse outcomes for the number of emergency admissions post reconfiguration of inpatient facilities. Factors including resources placed in the community after local reconfiguration, distance to the “adjacent” hospital and local deprivation may be important drivers for admission pathways after reconfiguration. Policy makers considering reconfiguration might consider a number of factors which may be important determinants of admissions post reconfiguration.

Background: The role of fractional exhaled nitric oxide in guiding asthma treatment in children is uncertain. Objective: To compare treatment guided by both fractional exhaled nitric oxide and symptoms (intervention) with treatment guided by symptoms alone (standard care) in children with asthma who are at risk of an asthma exacerbation, in terms of the number of asthma exacerbations over 12 months. Design: This was a pragmatic, multicentre, randomised controlled trial with embedded cost-effectiveness and qualitative process evaluations. Randomisation (1 : 1) was carried out using a remote web-based system and was minimised on recruitment centre, age, sex and British Thoracic Society treatment step. Clinical teams and participants were not blind to treatment allocation. Setting: The trial took place in 35 hospitals and seven primary care practices in the UK. Participants: Children aged 6–15 years with a diagnosis of asthma who were currently prescribed inhaled corticosteroids and who had one or more parent-/patient-reported asthma exacerbation treated with oral corticosteroids in the 12 months prior to recruitment. Interventions: Asthma treatment guided by symptoms alone (standard care) and asthma treatment guided by symptoms plus fractional exhaled nitric oxide (intervention). Treatment recommendations in both groups were protocolised within a web-based algorithm, incorporating inhaled corticosteroid adherence (objectively measured using an electronic logging device) and current treatment. Main outcome measures: The primary outcome measure was asthma exacerbations treated with oral corticosteroids in the year post randomisation. Secondary outcomes included time to first exacerbation, number of exacerbations, lung function, fractional exhaled nitric oxide, daily dose of inhaled corticosteroid, asthma control and quality of life. Results: In total, 509 eligible participants were recruited and the primary outcome was available for 506 participants. The primary outcome occurred in 123 out of 255 (48.2%) participants in the intervention group and 129 out of 251 (51.4%) participants in the standard-care group (adjusted odds ratio 0.88, 95% confidence interval 0.61 to 1.27). There was algorithm non-compliance on 21% of assessments. Per-protocol and complier-average causal effect analysis did not change the interpretation. This non-statistically significant estimate was consistent across predefined subgroups. There were no differences between the groups in secondary outcomes. There were no serious adverse events or deaths. No meaningful differences in health service costs, direct patient costs or indirect costs to society were identified between the groups. The economic evaluation does not provide evidence to support the cost-effectiveness of the intervention. In the qualitative process evaluation, 15 trial staff and six families were interviewed. Overall, their experiences were positive. The intervention was broadly acceptable, with caveats around clinicians using the algorithm recommendation as a guide and wariness around extreme step ups/downs in treatment in the light of contextual factors not being taken into account by the algorithm. Limitations: Potential limitations included the choice of cut-off point to define uncontrolled asthma and the change in fractional exhaled nitric oxide to trigger a change in treatment. Furthermore, the treatment decisions in the two groups may not have been sufficiently different to create a difference in outcomes. Conclusions: The RAACENO (Reducing Asthma Attacks in Children using Exhaled Nitric Oxide) trial findings do not support the routine use of fractional exhaled nitric oxide measurements as part of asthma management in a secondary care setting. The potential for other objective markers to guide asthma management in children needs to be evaluated. Trial registration: This trial was registered as ISRCTN67875351. Funding: This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a MRC and National Institute for Health and Care Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 9, No. 4. See the NIHR Journals Library website for further project information.

BackgroundIn 2020, the SARS-CoV-2 (COVID-19) pandemic and lockdown control measures threatened to disrupt routine childhood immunisation programmes with early reports suggesting uptake would fall. In response, public health bodies in Scotland and England collected national data for childhood immunisations on a weekly or monthly basis to allow for rapid analysis of trends. The aim of this study was to use these data to assess the impact of different phases of the pandemic on infant and preschool immunisation uptake rates.Methods and findingsWe conducted an observational study using routinely collected data for the year prior to the pandemic (2019) and immediately before (22 January to March 2020), during (23 March to 26 July), and after (27 July to 4 October) the first UK "lockdown". Data were obtained for Scotland from the Public Health Scotland "COVID19 wider impacts on the health care system" dashboard and for England from ImmForm. Five vaccinations delivered at different ages were evaluated; 3 doses of "6-in-1" diphtheria, tetanus, pertussis, polio, Haemophilus influenzae type b, and hepatitis B vaccine (DTaP/IPV/Hib/HepB) and 2 doses of measles, mumps, and rubella (MMR) vaccine. This represented 439,754 invitations to be vaccinated in Scotland and 4.1 million for England. Uptake during the 2020 periods was compared to the previous year (2019) using binary logistic regression analysis. For Scotland, uptake within 4 weeks of a child becoming eligible by age was analysed along with geographical region and indices of deprivation. For Scotland and England, we assessed whether immunisations were up-to-date at approximately 6 months (all doses 6-in-1) and 16 to 18 months (first MMR) of age. We found that uptake within 4 weeks of eligibility in Scotland for all the 5 vaccines was higher during lockdown than in 2019. Differences ranged from 1.3% for first dose 6-in-1 vaccine (95.3 versus 94%, odds ratio [OR] compared to 2019 1.28, 95% confidence intervals [CIs] 1.18 to 1.39) to 14.3% for second MMR dose (66.1 versus 51.8%, OR compared to 2019 1.8, 95% CI 1.74 to 1.87). Significant increases in uptake were seen across all deprivation levels. In England, fewer children due to receive their immunisations during the lockdown period were up to date at 6 months (6-in-1) or 18 months (first dose MMR). The fall in percentage uptake ranged from 0.5% for first 6-in-1 (95.8 versus 96.3%, OR compared to 2019 0.89, 95% CI 0.86- to 0.91) to 2.1% for third 6-in-1 (86.6 versus 88.7%, OR compared to 2019 0.82, 95% CI 0.81 to 0.83). The use of routinely collected data used in this study was a limiting factor as detailed information on potential confounding factors were not available and we were unable to eliminate the possibility of seasonal trends in immunisation uptake.ConclusionsIn this study, we observed that the national lockdown in Scotland was associated with an increase in timely childhood immunisation uptake; however, in England, uptake fell slightly. Reasons for the improved uptake in Scotland may include active measures taken to promote immunisation at local and national levels during this period and should be explored further. Promoting immunisation uptake and addressing potential vaccine hesitancy is particularly important given the ongoing pandemic and COVID-19 vaccination campaigns.

Leukotrienes play a central pathophysiological role in both paediatric and adult asthma. However, 35% to 78% of asthmatics do not respond to leukotriene inhibitors. In this study we tested the role of the LTA4H regulatory variant rs2660845 and age of asthma onset in response to montelukast in ethnically diverse populations. We identified and genotyped 3,594 asthma patients treated with montelukast (2,514 late-onset and 1,080 early-onset) from seven cohorts (UKBiobank, GoSHARE, BREATHE, Tayside RCT, PAGES, GALA II and SAGE). Individuals under montelukast treatment experiencing at least one exacerbation in a 12-month period were compared against individuals with no exacerbation, using logistic regression for each cohort and meta-analysis. While no significant association was found with European late-onset subjects, a meta-analysis of 523 early-onset individuals from European ancestry demonstrated the odds of experiencing asthma exacerbations by carriers of at least one G allele, despite montelukast treatment, were increased (odds-ratio = 2.92, 95%confidence interval (CI): 1.04-8.18, I2 = 62%, p = 0.0412) compared to those in the AA group. When meta-analysing with other ethnic groups, no significant increased risk of asthma exacerbations was found (OR = 1.60, 95% CI: 0.61-4.19, I2 = 85%, p = 0.342). Our study demonstrates that genetic variation in LTA4H, together with timing of asthma onset, may contribute to variability in montelukast response. European individuals with early-onset (≤18y) carrying at least one copy of rs2660845 have increased odd of exacerbation under montelukast treatment, presumably due to the up-regulation of LTA4H activity. These findings support a precision medicine approach for the treatment of asthma with montelukast.

Background: Accurately diagnosing asthma can be challenging. Uncertainty about the best combination of clinical features and investigations for asthma diagnosis is reflected in conflicting recommendations from international guidelines. One solution could be a clinical prediction model to support health professionals estimate the probability of an asthma diagnosis. However, systematic review evidence identifies that existing models for asthma diagnosis are at high risk of bias and unsuitable for clinical use. Being mindful of previous limitations, this protocol describes plans to derive and validate a prediction model for use by healthcare professionals to aid diagnostic decision making during assessment of a child or young person with symptoms suggestive of asthma in primary care. Methods: A prediction model will be derived using data from the Avon Longitudinal Study of Parents and Children (ALSPAC) and linked primary care electronic health records (EHR). Data will be included from study participants up to 25 years of age where permissions exist to use their linked EHR. Participants will be identified as having asthma if they received at least three prescriptions for an inhaled corticosteroid within a one-year period and have an asthma code in their EHR. To deal with missing data we will consider conducting a complete case analysis. However, if the exclusion of cases with missing data substantially reduces the total sample size, multiple imputation will be used. A multivariable logistic regression model will be fitted with backward stepwise selection of candidate predictors. Apparent model performance will be assessed before internal validation using bootstrapping techniques. The model will be adjusted for optimism before external validation in a dataset created from the Optimum Patient Care Research Database. Discussion: This protocol describes a robust strategy for the derivation and validation of a prediction model to support the diagnosis of asthma in children and young people in primary care.

The culture of differentiated human airway epithelial cells allows the study of pathogen-host interactions and innate immune responses in a physiologically relevant in vitro model. As the use of primary cell culture has gained popularity the availability of the reagents needed to generate these cultures has increased. In this study we assessed two different media, Promocell and PneumaCult, during the differentiation and maintenance of well-differentiated primary nasal epithelial cell cultures (WD-PNECs). We compared and contrasted the consequences of these media on WD-PNEC morphological and physiological characteristics and their responses to respiratory syncytial virus (RSV) infection. We found that cultures generated using PneumaCult resulted in greater total numbers of smaller, tightly packed, pseudostratified cells. However, cultures from both media resulted in similar proportions of ciliated and goblet cells. There were no differences in RSV growth kinetics, although more ciliated cells were infected in the PneumaCult cultures. There was also significantly more IL-29/IFNλ1 secreted from PneumaCult compared to Promocell cultures following infection. In conclusion, the type of medium used for the differentiation of primary human airway epithelial cells may impact experimental results.

There are many common and incurable conditions diagnosed in the elderly, such as dementia and chronic obstructive pulmonary disease (COPD). Understanding the earliest signs of these conditions may lead to early interventions aimed at prevention or cure. A challenge to studying the relationship between childhood factors diseases of the elderly is being able to follow up individuals over the lifecourse. This review describes a series of cohorts of children attending schools in Aberdeen since the mid-1930s have been followed up and where measurements made in childhood have been related to cognitive and respiratory outcomes in later life. Low birth weight combined with premature delivery are associated with low cognition scores during childhood and this persists to the sixth decade. Childhood asthma and non-asthmatic wheezing symptoms were associated with abnormal breathing tests which persists to the seventh decade and is associated with increased risk of COPD. Deprivation in early life is associated with relatively poor cognitive ability in childhood and adulthood but not with childhood asthma. Together, these findings demonstrate that conditions traditionally considered to affect the elderly are potentially detectable in childhood. What remains to be determined is what might be done in early life to prevent or lessen the burden of disease after retirement

Background: Maternal ambient air pollution exposure is associated with reduced birthweight. Few studies have examined the effect on growth in utero and none have examined the effect of exposure to particulates less than 2.5µm (PM2.5) and possible effect modification by smoking status. Objectives: Examine the effect of maternal exposure to ambient concentrations of PM10, PM2.5 and nitrogen dioxide (NO2) for in utero fetal growth, size at birth and effect modification by smoking status. Methods: Administratively acquired second and third trimester fetal measurements (bi-parietal diameter, femur length and abdominal circumference), birth outcomes (weight, crown heel length and occipito-frontal circumference) and maternal details were obtained from routine fetal ultrasound scans and maternity records (period 1994–2009). These were modelled against residential annual pollution concentrations (calendar year mean) adjusting for covariates and stratifying by smoking status. Results: In the whole sample (n=13,775 pregnancies), exposure to PM10, PM2.5 and NO2 was associated with reductions in measurements at birth and biparietal diameter from late second trimester onwards. Among mothers who did not smoke at all during pregnancy (n=11,075), associations between biparietal diameter and pollution exposure remained significant but were insignificant among those who did smoke (n=2700). Femur length and abdominal circumference were not significantly associated with pollution exposure. Conclusions: Fetal growth is strongly associated with particulates exposure from later in second trimester onwards but the effect appears to be subsumed by smoking. Typical ambient exposures in this study were relatively low compared to other studies and given these results, it may be necessary to consider reducing recommended “safe” ambient air exposures. Keywords: Fetal growth, Ambient air pollution, Maternal health, In utero, Scotland

BackgroundMaternal obesity and excessive gestational weight gain may have persistent effects on offspring fat development. However, it remains unclear whether these effects differ by severity of obesity, and whether these effects are restricted to the extremes of maternal body mass index (BMI) and gestational weight gain. We aimed to assess the separate and combined associations of maternal BMI and gestational weight gain with the risk of overweight/obesity throughout childhood, and their population impact.Methods and findingsWe conducted an individual participant data meta-analysis of data from 162,129 mothers and their children from 37 pregnancy and birth cohort studies from Europe, North America, and Australia. We assessed the individual and combined associations of maternal pre-pregnancy BMI and gestational weight gain, both in clinical categories and across their full ranges, with the risks of overweight/obesity in early (2.0-5.0 years), mid (5.0-10.0 years) and late childhood (10.0-18.0 years), using multilevel binary logistic regression models with a random intercept at cohort level adjusted for maternal sociodemographic and lifestyle-related characteristics. We observed that higher maternal pre-pregnancy BMI and gestational weight gain both in clinical categories and across their full ranges were associated with higher risks of childhood overweight/obesity, with the strongest effects in late childhood (odds ratios [ORs] for overweight/obesity in early, mid, and late childhood, respectively: OR 1.66 [95% CI: 1.56, 1.78], OR 1.91 [95% CI: 1.85, 1.98], and OR 2.28 [95% CI: 2.08, 2.50] for maternal overweight; OR 2.43 [95% CI: 2.24, 2.64], OR 3.12 [95% CI: 2.98, 3.27], and OR 4.47 [95% CI: 3.99, 5.23] for maternal obesity; and OR 1.39 [95% CI: 1.30, 1.49], OR 1.55 [95% CI: 1.49, 1.60], and OR 1.72 [95% CI: 1.56, 1.91] for excessive gestational weight gain). The proportions of childhood overweight/obesity prevalence attributable to maternal overweight, maternal obesity, and excessive gestational weight gain ranged from 10.2% to 21.6%. Relative to the effect of maternal BMI, excessive gestational weight gain only slightly increased the risk of childhood overweight/obesity within each clinical BMI category (p-values for interactions of maternal BMI with gestational weight gain: p = 0.038, p < 0.001, and p = 0.637 in early, mid, and late childhood, respectively). Limitations of this study include the self-report of maternal BMI and gestational weight gain for some of the cohorts, and the potential of residual confounding. Also, as this study only included participants from Europe, North America, and Australia, results need to be interpreted with caution with respect to other populations.ConclusionsIn this study, higher maternal pre-pregnancy BMI and gestational weight gain were associated with an increased risk of childhood overweight/obesity, with the strongest effects at later ages. The additional effect of gestational weight gain in women who are overweight or obese before pregnancy is small. Given the large population impact, future intervention trials aiming to reduce the prevalence of childhood overweight and obesity should focus on maternal weight status before pregnancy, in addition to weight gain during pregnancy.

Background. Childhood asthma is a common complex condition whose aetiology is thought to involve gene-environment interactions in early life occurring at the airway epithelium, associated with immune dysmaturation. It is not clear if abnormal airway epithelium cell (AEC) and cellular immune system functions associated with asthma are primary or secondary. To explore this, we will (i) recruit a birth cohort and observe the evolution of respiratory symptoms; (ii) recruit children with and without asthma symptoms; and (iii) use existing data from children in established STELAR birth cohorts. Novel pathways identified in the birth cohort will be sought in the children with established disease. Our over-arching hypothesis is that epithelium function is abnormal at birth in babies who subsequently develop asthma and progression is driven by abnormal interactions between the epithelium, genetic factors, the developing immune system, and the microbiome in the first years of life. Methods. One thousand babies will be recruited and nasal AEC collected at 5-10 days after birth for culture. Transcriptomes in AEC and blood leukocytes and the upper airway microbiome will be determined in babies and again at one and three years of age. In a subset of 100 individuals, AEC transcriptomes and microbiomes will also be assessed at three and six months. Individuals will be assigned a wheeze category at age three years. In a cross sectional study, 300 asthmatic and healthy children aged 1 to 16 years will have nasal and bronchial AEC collected for culture and transcriptome analysis, leukocyte transcriptome analysis, and upper and lower airway microbiomes ascertained. Genetic variants associated with asthma symptoms will be confirmed in the STELAR cohorts. Conclusions. This study is the first to comprehensively study the temporal relationship between aberrant AEC and immune cell function and asthma symptoms in the context of early gene-microbiome interactions.

Mortality is higher for adults admitted to hospital and for babies born on weekends compared to weekdays. This study compares in-hospital mortality and in children admitted to hospital on weekends and weekdays. Details for all acute medical admissions to hospitals in Scotland for children aged ≤16 years between 1st January 2000 and 31st December 2013 were obtained. Death was linked to day of admission. There were 570,403 acute medical admissions and 334 children died, including 83 who died after an admission on Saturday or Sunday and 251 who died following admission between Monday and Friday. The adjusted odds ratio (aOR) for a child dying after admission on a weekend compared to weekday was 1.03 [95% CI 0.80 to 1.32]. The OR for a child admitted over the weekend requiring intensive care unit (ICU) or high dependency unit (HDU) care was 1.24 [1.16 to 1.32], but the absolute number of admissions to HDU and ICU per day were similar on weekends and weekdays. We see no evidence of increased in-hospital paediatric mortality after admission on a weekend. The increased risk for admission to ITU or HDU with more serious illness over weekends is explained by fewer less serious admissions.

Management-related issues are an important aspect of monitoring asthma in children in clinical practice. This review summarises the literature on practical aspects of monitoring including adherence to treatment, inhalation technique, ongoing exposure to allergens and irritants, comorbid conditions and side-effects of treatment, as agreed by the European Respiratory Society Task Force on Monitoring Asthma in Childhood. The evidence indicates that it is important to discuss adherence to treatment in a non-confrontational way at every clinic visit, and take into account a patient's illness and medication beliefs. All task force members teach inhalation techniques at least twice when introducing a new inhalation device and then at least annually. Exposure to second-hand tobacco smoke, combustion-derived air pollutants, house dust mites, fungal spores, pollens and pet dander deserve regular attention during follow-up according to most task force members. In addition, allergic rhinitis should be considered as a cause for poor asthma control. Task force members do not screen for gastro-oesophageal reflux and food allergy. Height and weight are generally measured at least annually to identify individuals who are susceptible to adrenal suppression and to calculate body mass index, even though causality between obesity and asthma has not been established. In cases of poor asthma control, before stepping up treatment the above aspects of monitoring deserve closer attention.

Asthma is a common condition, which is associated with atopy and allergic conditions including hay fever, eczema, and food allergies. Asthma and atopy are both complex conditions where genetic and environmental factors are implicated in causation. Interactions between genetic and environmental factors, likely via epigenetic mechanisms, are widely thought to be important in determining the risk for developing asthma and atopy. The nature of the relationship between asthma and atopy is unclear and the answer to the question “does atopy cause asthma?” remains unknown. This review explores the relationship between asthma and atopy from a gene–environment interaction perspective and tackles the question “are similar gene–environment interactions present for asthma and atopy?” The main finding is that gene–environment interactions are described for asthma and atopy in children but these interactions are seldom sought for both asthma and atopy in the same population. In the few instances where a gene–environment interaction is related to both asthma and atopy, there is no consistent evidence that similar interactions are common to asthma and atopy. Many plausible gene–environment interactions for asthma and atopy are yet to be explored. Overall, from the gene–environment interaction perspective, there is absence of evidence to better understand the complex relationship between asthma and atopy.

ABSTRACT Objective Maternal obesity during pregnancy is a risk factor for increased childhood body mass index (BMI) and the mechanism may be causal or confounded by lifestyle common to mother and child. We studied BMI in siblings and their mothers to test the hypothesis that siblings born after maternal weight gain will have increased BMI compared to older siblings. Approach This was a whole population data linkage study using data from North East Scotland, UK. Databases containing details from pregnant mothers and their five-year-old children born between 1997 and 2005 were linked using the community health index number. Childhood BMI and the difference between siblings BMI were related to maternal weight gain between pregnancies. Covariates included maternal obesity, smoking, socioeconomic status and the child’s birth weight. Results Maternal weight gain between pregnancies was determined for 5,863 mothers in whom 718 had >2 pregnancies. Childhood BMI z score was increased in association with maternal obesity (mean increase 0.47 [95% CI 0.39, 0.56]) and with ≥10% maternal weight gain between pregnancies (mean increase 0.14 [95% CI 0.06, 0.21]), independent of covariates. In contrast, increased BMI z score for younger siblings, compared to older siblings, was not associated with maternal obesity in the earlier pregnancy or maternal weight gain between pregnancies. BMI z score was higher in younger compared to older siblings in association with deprivation (mean difference between most and least affluent categories 0.29 [0.08, 0.37]), persistent or new onset maternal smoking (increased by mean of 0.10[0.00, 0.19] for always smokers and 0.20[0.03, 0.38] for those starting compared to never smoked) and increased birth weight (BMI z score increased by 0.11 for each increase in birth weight z score [0.07, 0.14]). Conclusion When within-family confounding is considered, poverty, persistent and new onset maternal smoking during pregnancy and increased birth weight, but not maternal obesity or weight gain, are independent predictors of increased BMI in young children.

BACKGROUND:Maternal smoking during pregnancy is linked to reduced birth weight but the gestation at onset of this relationship is not certain. We present a systematic review of the literature describing associations between maternal smoking during pregnancy and ultrasound measurements of fetal size, together with an accompanying meta-analysis. METHODS:Studies were selected from electronic databases (OVID, EMBASE and Google Scholar) that examined associations between maternal smoking or smoke exposure and antenatal fetal ultrasound measurements. Outcome measures were first, second or third trimester fetal measurements. RESULTS:There were 284 abstracts identified, 16 papers were included in the review and the meta-analysis included data from eight populations. Maternal smoking was associated with reduced second trimester head size (mean reduction 0.09 standard deviation (SD) [95% CI 0.01, 0.16]) and femur length (0.06 [0.01, 0.10]) and reduced third trimester head size (0.18 SD [0.13, 0.23]), femur length (0.27 SD [0.21, 0.32]) and estimated fetal weight (0.18 SD [0.11, 0.24]). Higher maternal cigarette consumption was associated with a lower z score for head size in the second (mean difference 0.09 SD [0, 0.19]) and third (0.15 SD [0.03, 0.26]) trimesters compared to lower consumption. Fetal measurements were not reduced for those whose mothers quit before or after becoming pregnant compared to mothers who had never smoked. CONCLUSIONS:Maternal smoking during pregnancy is associated with reduced fetal measurements after the first trimester, particularly reduced head size and femur length. These effects may be attenuated if mothers quit or reduce cigarette consumption during pregnancy.

Background: The number of acute medical paediatric emergency admissions is rising. We undertook qualitative interviews with parents and clinicians to better understand what factors, other than the health status of the child, may influence decision making leading to emergency admission. Methods: Semi-structured interviews were conducted with parents; clinicians working in general practice, out-of-hours or the emergency department (referring clinicians); and doctors working in acute medical paediatrics (receiving clinicians). Results: Ten parents, 7 referring clinicians and 10 receiving clinicians were interviewed. Parents described “erring on the side of caution” when seeking medical opinion and one mentioned anxiety. Among themes seen among referring clinicians, “erring on the side of caution” was also identified as was managing “parental anxiety” and acting on “gut instinct”. Among receiving clinicians, themes included managing parental anxiety and increasing parental expectations of the health service. Conclusions: The study of parent and referring clinician decision-making prior to a hospital admission can identify “teachable moments” where interventions might be delivered to slow or even arrest the rise in short-stay acute medical admissions in Britain and other countries. Interventions could assure parents or referring clinicians that hospital referral is not required and help clinicians understand what they perceive as “parental anxiety”.

The “fetal origins hypothesis” or concept of “developmental programming” suggests that faltering fetal growth and subsequent catch-up growth are implicated in the aetiology of cardiovascular disease. Associations between reduced birth weight, rapid postnatal weight gain, and asthma suggest that there are fetal origins to respiratory disease. The present paper first summarises the literature relating birth weight and post natal growth trajectories to asthma outcomes. Second, issues regarding the interpretation of antenatal fetal ultrasound measurements are discussed. Finally, recent reports linking antenatal measurement and growth trajectory to early childhood asthma outcomes are discussed. Understanding the nature and timing of factors which influence antenatal growth may give important insight into the antecedents of early-onset asthma with implications for interventions.

Previous studies of congenital hypothyroidism have suggested an increasing incidence and seasonal variation in incidence, which may suggest nongenetic factors involved in aetiology. This study describes the incidence of elevated thyroid stimulating hormone (TSH) values in newborns, a surrogate for congenital hypothyroidism, measured as part of the screening programme for congenital hypothyroidism, over an eleven-year period (1994–2005), and assesses whether seasonal variation exists. All infants born in the Northern Region of England are screened by measuring levels of circulating TSH using a blood spot assay. Data on all 213 cases born from 1994 to 2005 inclusive were available. Annual incidence increased significantly from 37 per 100,000 in 1994 to a peak of 92.8 per 100,000 in 2003. There was no evidence of seasonal variation in incidence. The reasons for the increasing incidence are unclear, but do not appear to involve increasing exposure to seasonally varying factors or changes in measurements methods.