ERS technical standard: Global Lung Function Initiative reference values for exhaled nitric oxide fraction (F ENO50 ).

BACKGROUND: Elevated exhaled nitric oxide fraction at a flow rate of 50 mL·s-1 (F ENO50 ) is an important indicator of T-helper 2-driven airway inflammation and may aid clinicians in the diagnosis and monitoring of asthma. This study aimed to derive Global Lung Function Initiative reference equations and the upper limit of normal for F ENO50 . METHODS: Available individual F ENO50 data were collated and harmonised using consensus-derived variables and definitions. Data collected from individuals who met the harmonised definition of "healthy" were analysed using the generalised additive models of location, scale and shape (GAMLSS) technique. RESULTS: Data were retrospectively collated from 34 782 individuals from 34 sites in 15 countries, of whom 8022 met the definition of healthy (19 sites, 11 countries). Overall, height, age and sex only explained 12% of the between-subject variability of F ENO50 (R2=0.12). F ENO device was neccessary as a predictor of F ENO50 , such that the healthy range of values and the upper limit of normal varied depending on which device was used. The range of F ENO50 values observed in healthy individuals was also very wide, and the heterogeneity was partially explained by the device used. When analysing a subset of data in which F ENO50 was measured using the same device and a stricter definition of health (n=1027), between-site heterogeneity remained. CONCLUSION: Available F ENO50 data collected from different sites using different protocols and devices were too variable to develop a single all-age reference equation. Further standardisation of F ENO devices and measurement are required before population reference values might be derived.

Parents underestimate fatigue in younger children aged 5-7 years with asthma but not in older children.

AIM: To assess fatigue in children aged 2-17 years with asthma from both child and parent perspectives and describe associated factors. METHODS: Fatigue scores were self-reported by children aged 5-17 years old and proxy-reported by parents or carers for all children. The Pediatric Quality of Life Inventory Multidimensional Fatigue Scale was used. Fatigue scores ranged from 0 to 100, higher scores meant less fatigue. RESULTS: There were 527 children and parents enrolled. The mean overall fatigue score by self-report was 72.7 ± 15.8 and by proxy report was 75.8 ± 16.3. Self-reported fatigue score was lower in children aged 5-7 years (71.5 ± 15.9) compared to proxy-reported score (76.3 ± 15.5). Proxy and self-reported fatigue scores were similar between parents and older children. Fatigue scores were lower in association with poor asthma control and receipt of social support. Lower self-reported, but not proxy-reported, fatigue score was related to asthma severity. Lower proxy-reported, but not self-reported, fatigue score was related to the child being older and having shortness of breath. CONCLUSION: Parents underestimated the fatigue of younger children aged 5-7 years, but fatigue scores were similar between parents and older children. Both clinical and social factors are associated with fatigue in children with asthma.

Uptake of infant and preschool immunisations in Scotland and England during the COVID-19 pandemic: An observational study of routinely collected data.

BACKGROUND: In 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 FINDINGS: We 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. CONCLUSIONS: In 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.

A real-life comparative effectiveness study into the addition of antibiotics to the management of asthma exacerbations in primary care.

BACKGROUND: Asthma exacerbations are major contributors to asthma morbidity and mortality. They are usually managed with bronchodilators and oral corticosteroids (OCS), but clinical trial evidence suggests that antibiotics could be beneficial. We aimed to assess whether treatment of asthma exacerbations with antibiotics in addition to OCS improved outcomes in larger, more representative routine-care populations. METHOD: A retrospective comparative effectiveness study into managing asthma exacerbations with OCS alone versus OCS plus antibiotics was conducted using the Optimum Patient Care Research Database. The dataset included 28 637 patients; following propensity score matching 20 024 adults and 4184 children were analysed. RESULTS: Antibiotics in addition to OCS were prescribed for the treatment of asthma exacerbations in 45% of adults and 32% of children. Compared to OCS alone, OCS plus antibiotics was associated with reduced risk of having an asthma/wheeze consultation in the following 2 weeks (children hazard ratio (HR) 0.84 (95% CI 0.73-0.96), p=0.012; adults HR 0.86 (95% CI 0.81-0.91), p<0.001), but an increase in risk of a further OCS prescription for a new/ongoing exacerbation within 6 weeks in adults (HR 1.11 (95% CI 1.01-1.21), p=0.030), but not children. Penicillins, but not macrolides, were associated with a reduction in the odds of a subsequent asthma/wheeze consultation compared to OCS alone, in both adults and children. CONCLUSION: Antibiotics were frequently prescribed in relation to asthma exacerbations, contrary to guideline recommendations. Overall, the routine addition of antibiotics to OCS in the management of asthma exacerbations appeared to confer little clinical benefit, especially when considering the risks of antibiotic overuse.

Asthma prescribing according to Arg16Gly beta-2 genotype: a randomised trial in adolescents.

INTRODUCTION: The A allele of rs1042713 (Arg16 amino acid) in the ß2-adrenoreceptor is associated with poor response to long-acting ß2-agonist (LABA) in young people with asthma. Our aim was to assess whether the prescribing of second-line controller with LABA or a leukotriene receptor antagonist according to Arg16Gly genotype would result in improvements in Pediatric Asthma-Related Quality of Life Questionnaire (PAQLQ). METHODS: We performed a pragmatic randomised controlled trial (RCT) via a primary care clinical research network covering England and Scotland. We enrolled participants aged 12-18 years with asthma taking inhaled corticosteroids. 241 participants (mean±sd age 14.7±1.91 years) were randomised (1:1) to receive personalised care (genotype directed prescribing) or standard guideline care. Following a 4-week run-in participants were followed for 12 months. The primary outcome measure was change in PAQLQ. Asthma control, asthma exacerbation frequency and healthcare utilisation were secondary outcomes. RESULTS: Genotype-directed prescribing resulted in an improvement in PAQLQ compared to standard care (0.16, 95% CI 0.00-0.31; p=0.049), although this improvement was below the pre-determined clinical threshold of 0.25. The AA genotype was associated with a larger improvement in PAQLQ with personalised versus standard care (0.42, 95% CI 0.02-0.81; p=0.041). CONCLUSION: This is the first RCT demonstrating that genotype-driven asthma prescribing is associated with a significant improvement in a clinical outcome compared to standard care. Adolescents with the AA homozygous genotype benefited most. The potential role of such ß2-adrenoceptor genotype directed therapy in younger and more severe childhood asthma warrants further exploration.

European Respiratory Society clinical practice guidelines for the diagnosis of asthma in children aged 5-16†years.

BACKGROUND: Diagnosing asthma in children represents an important clinical challenge. There is no single gold-standard test to confirm the diagnosis. Consequently, over- and under-diagnosis of asthma is frequent in children. METHODS: A task force supported by the European Respiratory Society has developed these evidence-based clinical practice guidelines for the diagnosis of asthma in children aged 5-16 years using nine Population, Intervention, Comparator and Outcome (PICO) questions. The task force conducted systematic literature searches for all PICO questions and screened the outputs from these, including relevant full-text articles. All task force members approved the final decision for inclusion of research papers. The task force assessed the quality of the evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. RESULTS: The task force then developed a diagnostic algorithm based on the critical appraisal of the PICO questions, preferences expressed by lay members and test availability. Proposed cut-offs were determined based on the best available evidence. The task force formulated recommendations using the GRADE Evidence to Decision framework. CONCLUSION: Based on the critical appraisal of the evidence and the Evidence to Decision framework, the task force recommends spirometry, bronchodilator reversibility testing and exhaled nitric oxide fraction as first-line diagnostic tests in children under investigation for asthma. The task force recommends against diagnosing asthma in children based on clinical history alone or following a single abnormal objective test. Finally, this guideline also proposes a set of research priorities to improve asthma diagnosis in children in the future.

Genome-wide association study of asthma exacerbations despite inhaled corticosteroid use.

RATIONALE: Substantial variability in response to asthma treatment with inhaled corticosteroids (ICS) has been described among individuals and populations, suggesting the contribution of genetic factors. Nonetheless, only a few genes have been identified to date. We aimed to identify genetic variants associated with asthma exacerbations despite ICS use in European children and young adults and to validate the findings in non-Europeans. Moreover, we explored whether a gene-set enrichment analysis could suggest potential novel asthma therapies. METHODS: A genome-wide association study (GWAS) of asthma exacerbations was tested in 2681 children of European descent treated with ICS from eight studies. Suggestive association signals were followed up for replication in 538 European asthma patients. Further evaluation was performed in 1773 non-Europeans. Variants revealed by published GWAS were assessed for replication. Additionally, gene-set enrichment analysis focused on drugs was performed. RESULTS: 10 independent variants were associated with asthma exacerbations despite ICS treatment in the discovery phase (p≤5×10-6). Of those, one variant at the CACNA2D3-WNT5A locus was nominally replicated in Europeans (rs67026078; p=0.010), but this was not validated in non-European populations. Five other genes associated with ICS response in previous studies were replicated. Additionally, an enrichment of associations in genes regulated by trichostatin A treatment was found. CONCLUSIONS: The intergenic region of CACNA2D3 and WNT5A was revealed as a novel locus for asthma exacerbations despite ICS treatment in European populations. Genes associated were related to trichostatin A, suggesting that this drug could regulate the molecular mechanisms involved in treatment response.

ADRB2 haplotypes and asthma exacerbations in children and young adults: An individual participant data meta-analysis.

BACKGROUND: The polymorphism Arg16 in ß2 -adrenergic receptor (ADRB2) gene has been associated with an increased risk of exacerbations in asthmatic children treated with long-acting ß2 -agonists (LABA). However, it remains unclear whether this increased risk is mainly attributed to this single variant or the combined effect of the haplotypes of polymorphisms at codons 16 and 27. OBJECTIVE: We assessed whether the haplotype analysis could explain the association between the polymorphisms at codons 16 (Arg16Gly) and 27 (Gln27Glu) in ADRB2 and risk of asthma exacerbations in patients treated with inhaled corticosteroids (ICS) plus LABA. METHODS: The study was undertaken using data from 10 independent studies (n = 5903) participating in the multi-ethnic Pharmacogenomics in Childhood Asthma (PiCA) consortium. Asthma exacerbations were defined as asthma-related use of oral corticosteroids or hospitalizations/emergency department visits in the past 6 or 12 months prior to the study visit/enrolment. The association between the haplotypes and the risk of asthma exacerbations was performed per study using haplo.stats package adjusted for age and sex. Results were meta-analysed using the inverse variance weighting method assuming random-effects. RESULTS: In subjects treated with ICS and LABA (n = 832, age: 3-21 years), Arg16/Gln27 versus Gly16/Glu27 (OR: 1.40, 95% CI: 1.05-1.87, I2  = 0.0%) and Arg16/Gln27 versus Gly16/Gln27 (OR: 1.43, 95% CI: 1.05-1.94, I2  = 0.0%), but not Gly16/Gln27 versus Gly16/Glu27 (OR: 0.99, 95% CI: 0.71-1.39, I2  = 0.0%), were significantly associated with an increased risk of asthma exacerbations. The sensitivity analyses indicated no significant association between the ADRB2 haplotypes and asthma exacerbations in the other treatment categories, namely as-required short-acting ß2 -agonists (n = 973), ICS monotherapy (n = 2623), ICS plus leukotriene receptor antagonists (LTRA; n = 338), or ICS plus LABA plus LTRA (n = 686). CONCLUSION AND CLINICAL RELEVANCE: The ADRB2 Arg16 haplotype, presumably mainly driven by the Arg16, increased the risk of asthma exacerbations in patients treated with ICS plus LABA. This finding could be beneficial in ADRB2 genotype-guided treatment which might improve clinical outcomes in asthmatic patients.

Does lung function change in the months after an asthma exacerbation in children?

BACKGROUND: There are limited data describing lung function changes in children after an asthma exacerbation. Our hypothesis was that lung function does not fully recover in children in the months following an asthma exacerbation. METHODS: We used a data set of children with asthma where lung function (including FEV1 , FEV1 /FVC ratio and FEF25-75 ) was measured at 3-month intervals over a year. Mixed-level models compared spirometry measured on two occasions 3 months apart before a single exacerbation (assessments 1 and 2) with measurements made on two occasions after the exacerbation (assessments 3 and 4), with adjustment for covariates. Changes in spirometry over a year were also analysed across those with exacerbations in no, one or more than one 3-month periods. RESULTS: For the 113 children who had a single exacerbation, spirometry measured at assessments 1 or 2 did not differ from measurements at assessments 3 or 4 when the whole population was considered. When stratified into tertiles by change in %FEV1 between assessments 2 and 3, those with the greater reduction were more likely to be treated with long-acting beta-agonist, but in this category, %FEV1 at assessment 4 had returned to the value at assessment 1. %FEV1 did not change over a 12-month period within and between the three exacerbation categories (n = 809). CONCLUSION: One or more asthma exacerbation was not associated with a fall in lung function for the whole population. In a subset of individuals, lung function does fall after an exacerbation but returns to pre-exacerbation values after a period of months.

Genome-wide association studies of exacerbations in children using long-acting beta2-agonists.

BACKGROUND: Some children with asthma experience exacerbations despite long-acting beta2-agonist (LABA) treatment. While this variability is partly caused by genetic variation, no genome-wide study until now has investigated which genetic factors associated with risk of exacerbations despite LABA use in children with asthma. We aimed to assess whether genetic variation was associated with exacerbations in children treated with LABA from a global consortium. METHODS: A meta-analysis of genome-wide association studies (meta-GWAS) was performed in 1,425 children and young adults with asthma (age 6-21 years) with reported regular use of LABA from six studies within the PiCA consortium using a random effects model. The primary outcome of each study was defined as any exacerbation within the past 6 or 12 months, including at least one of the following: 1) hospital admissions for asthma, 2) a course of oral corticosteroids or 3) emergency room visits because of asthma. RESULTS: Genome-wide association results for a total of 82 996 common single nucleotide polymorphisms (SNPs, MAF ≥1%) with high imputation quality were meta-analysed. Eight independent variants were suggestively (P-value threshold ≤5 × 10-6 ) associated with exacerbations despite LABA use. CONCLUSION: No strong effects of single nucleotide polymorphisms (SNPs) on exacerbations during LABA use were identified. We identified two loci (TBX3 and EPHA7) that were previously implicated in the response to short-acting beta2-agonists (SABA). These loci merit further investigation in response to LABA and SABA use.

The association between opening a short stay paediatric assessment unit and trends in short stay hospital admissions.

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.

Does admission prevalence change after reconfiguration of inpatient services? An interrupted time series analysis of the impact of reconfiguration in five centres.

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.

Variation in referrals from primary care to scheduled paediatric services in North and East Scotland -a cross-sectional study.

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.

Does treatment guided by exhaled nitric oxide fraction improve outcomes in subgroups of children with asthma?

INTRODUCTION: Exhaled nitric oxide fraction (F ENO), a biomarker of eosinophilic airway inflammation, may be useful to guide asthma treatment. F ENO-guided treatment may be more effective in certain subgroups for improving asthma outcomes compared to standard treatment. METHODS: An individual patient data analysis was performed using data from seven randomised clinical trials (RCTs) which used F ENO to guide asthma treatment. The incidence of an asthma exacerbation and loss of control, and the time to first exacerbation and loss of control were described between five subgroups of RCT participants. RESULTS: Data were available in 1112 RCT participants. Among those not treated with leukotriene receptor antagonists (LTRA), but not among those who were treated with LTRA, F ENO-guided treatment was associated with reduced exacerbation risk (OR 0.68, 95% CI 0.49-0.94), longer time to first exacerbation (hazard ratio (HR) 0.76, 95% CI 0.57-0.99) and borderline reduced risk for loss of control (OR 0.70, 95% CI 0.49-1.00). Nonobese children, compared to obese children, were less likely to lose asthma control when treatment was guided by F ENO (OR 0.69, 95% CI 0.48-0.99) and time to loss of control was longer (HR 0.77, 95% CI 0.61-0.99). CONCLUSIONS: Asthma treatment guided by F ENO may be more effective in achieving better asthma outcomes for patients who are not treated with LTRA and who are not obese, compared to standard practice.

Glutathione S-Transferase Genotype Protects against In Utero Tobacco-linked Lung Function Deficits.

Rationale:In utero tobacco exposure is associated with reduced lung function from infancy. Antioxidant enzymes from the glutathione S-transferase (GST) family may protect against these lung function deficits.Objectives: To assess the long-term effect of in utero smoke exposure on lung function into adulthood, and to assess whether GSTT1 and GSTM1 active genotypes have long-term protective effects on lung function.Methods: In this longitudinal study based on a general population (n = 253), lung function was measured during infancy and at 6, 11, 18, and 24 years. GSTM1 and GSTT1 genotype was analyzed in a subgroup (n = 179). Lung function was assessed longitudinally from 6 to 24 years (n = 199).Measurements and Main Results: Exposure to maternal in utero tobacco was associated with lower FEV1 and FVC longitudinally from 6 to 24 years (mean difference, -3.87% predicted, P = 0.021; -3.35% predicted, P = 0.035, respectively). Among those homozygous for the GSTM1-null genotype, in utero tobacco exposure was associated with lower FEV1 and FVC compared with those with no in utero tobacco exposure (mean difference, -6.2% predicted, P = 0.01; -4.7% predicted, P = 0.043, respectively). For those with GSTM1 active genotype, there was no difference in lung function whether exposed to maternal in utero tobacco or not. In utero tobacco exposure was associated with deficits in lung function among those with both GSTT1-null and GSTT1-active genotypes.Conclusions: Certain GST genotypes may have protective effects against the long-term deficits in lung function associated with in utero tobacco exposure. This offers potential preventative targets in antioxidant pathways for at-risk infants of smoking mothers.

A systematic review of associations between maternal exposures during pregnancy other than smoking and antenatal fetal measurements.

BACKGROUND: Reduced birth weight is associated with many maternal environmental exposures during pregnancy, but the gestational age at onset of this association is unknown. We have previously reported associations between maternal smoking and fetal size. OBJECTIVE: To report on our systematic review of the literature describing associations between antenatal size and growth and maternal exposures during pregnancy. DATA SOURCES: Electronic databases (OVID and EMBASE) and web sites for cohort studies were searched. Studies were eligible if they examined associations between maternal environmental exposures (including ambient air exposure, diet and alcohol) and antenatal fetal ultrasound measurements. The Navigation Guide was used to assess the strength of evidence. RESULTS: There were 451 abstracts identified and 36 papers were included of which maternal diet was the exposure of interest in 15, maternal ambient air exposure in 10, maternal alcohol in 3 and other exposures in 8. The first paper was published in 2006. Associations were present between exposures and fetal measurements in 18% of comparisons with second trimester measurements and in 46% of comparisons with third trimester measurements. In the third trimester, when an association was present, reduced head size was most commonly (58%) associated with current or previous maternal exposure, with reduced length being least commonly (32%) associated and reduced weight being intermediate (52%). In the third trimester, increased maternal nitrogen dioxide exposure was associated with reduced head size was associated with in all seven studies identified and reduced fetal weight in five out of six studies. CONCLUSION: There is sufficient evidence of toxicity in the context of maternal exposure to nitrogen dioxide and reduced third trimester fetal head size. There is currently insufficient evidence of toxicity with regard to maternal exposures to dietary factors, alcohol and environmental chemicals and reduced fetal size.

Quality of life of the family of children with asthma is not related to asthma severity.

The quality of life for the family is an important outcome of childhood asthma. The aim of the study was to describe the quality of life in families who have a child with asthma. The Pediatric Quality of Life Inventory Family Impact Module was completed by the parents of 527 children with asthma. The median overall score was 75.0 (interquartile range 63.9, 87.5). The following factors were independently associated with lower quality of life: additional difficulties such as anxiety and financial hardship (3.81 [2.45, 5.93]), waking with asthma symptoms one or more nights a week (odds ratio 2.53 [1.34, 4.75]), regular use of symptoms reliever medication (2.47 [1.57, 3.87]), and female gender (1.97 [1.27, 3.05]). Lower socioeconomic status of the family and exposure to molds at home doubled the odds for lower quality of life. Physician's diagnosed asthma severity and control were associated with quality of life in univariate, but not multivariate analysis.Conclusion: Multiple factors, several of which are not related to asthma, contribute to the family burden of having a child with asthma. Clinicians should be mindful of the impact of asthma on the child and the family, and consider exploring factors not directly related to childhood asthma. What is Known: • Childhood asthma as a chronic disease impacts the quality of life of the patient, but there is also an impact on the immediate family. • There are relatively few studies exploring the quality of life of parents of a child with asthma; the results are heterogeneous and none has been carried out in an Eastern European country. What is New: • This is the first study to describe caregiver's quality of life in an Eastern European population in the context of childhood asthma. • The quality of life of the family of asthmatic child depends not only on factors related to asthma, but also non-asthma related factors such as poverty which play even more important role.

First trimester fetal size and prescribed asthma medication at 15†years of age.

There is increasing evidence that antenatal factors predispose to childhood asthma. We tested the hypothesis that reduced first trimester fetal size is associated with increased risk for asthma at 15 years of age.Fetal size in the first and second trimester was ascertained by ultrasound scan. The primary outcome of being dispensed one or more asthma medications by the family doctor in the year before the 15th birthday was determined from routinely acquired dispensing data.Dispensing data were available for 1699 (88% of the original cohort) participants at 15 years of age and questionnaire data for 750 (39%). Each reduction in z-score for first trimester size was associated with increased odds for dispensed asthma medication at 15 years of age (OR 1.26, 95% CI 1.03-1.54) and self-reported use of asthma medications (OR 1.55, 95% CI 1.16-2.08). Overall, first and second trimester size and forced expiratory volume in 1 s at ages 5, 10 and 15 years were reduced for those dispensed asthma medications compared with those not dispensed asthma medications (p=0.003).Antenatal factors that are active by the first trimester may contribute to respiratory well-being throughout childhood. Dropout from a birth cohort study can overestimate of the magnitude of any true association.

Changing characteristics of hospital admissions but not the children admitted-a whole population study between 2000 and 2013.

There are increasing numbers of emergency medical paediatric admissions. Our hypothesis was that characteristics of children and details of their emergency admissions are also changing over time. Details of emergency admissions in Scotland 2000-2013 were analysed. There were 574,403 emergency admissions, median age 2.3 years. The age distribution, proportion of boys and socioeconomic status of children admitted were essentially unchanged. Emergency admissions rose by 49% from 36/1000 children per annum to 54/1000 between 2000 and 2013. Emergency admissions that were discharged on the same day rose by 186% from 8.6/1000 to 24.6/1000. The mean duration of emergency admission fell from 1.7 to 1.0 days. The odds for an emergency admission with upper respiratory infection, "viral infection", tonsillitis, bronchiolitis and lower respiratory tract infection all rose. In contrast the odds for an emergency admission with asthma and gastroenteritis fell. CONCLUSIONS: The demographics of children with emergency admissions have not changed substantially but characteristics of admissions have changed considerably, in particular admissions which are short stay and due to respiratory infection are much more common. The fall in the absolute number of children with some acute medical diagnoses suggests that the rise in admissions is not necessarily inexorable. What is Known: • Emergency admission prevalence is rising in many countries across Europe. What is New: • Our paper is the first to comprehensively analyse emergency medical paediatric admissions by exploring how characteristics of admissions and the children admitted have changed over time for a whole population. • The "take home message" is that whilst characteristics of emergency admissions have changed (e.g. number, duration of stay, readmissions, diagnoses), the characteristics of the children have not changed.

ChEBI in 2016: Improved services and an expanding collection of metabolites.

ChEBI is a database and ontology containing information about chemical entities of biological interest. It currently includes over 46,000 entries, each of which is classified within the ontology and assigned multiple annotations including (where relevant) a chemical structure, database cross-references, synonyms and literature citations. All content is freely available and can be accessed online at http://www.ebi.ac.uk/chebi. In this update paper, we describe recent improvements and additions to the ChEBI offering. We have substantially extended our collection of endogenous metabolites for several organisms including human, mouse, Escherichia coli and yeast. Our front-end has also been reworked and updated, improving the user experience, removing our dependency on Java applets in favour of embedded JavaScript components and moving from a monthly release update to a 'live' website. Programmatic access has been improved by the introduction of a library, libChEBI, in Java, Python and Matlab. Furthermore, we have added two new tools, namely an analysis tool, BiNChE, and a query tool for the ontology, OntoQuery.