Centre for genomics and child health

PM 2.5 , mass concentration of particles less than 2.5 mm in size; PM 2.5 absorbance, measurement of the blackness of PM 2.5 filters, this is a proxy for elemental carbon, which is the dominant light absorbing substance; PM 10 , mass concentration of particles less than 10 mm in size; PM coarse , mass concentration of the coarse fraction of particles between 2.5 mm and 10 mm in size; RB, regional background; RH, relative humidity; ST, Street; TRAPCA, Traffic-Related Air Pollution and Childhood Asthma; UB, urban background; US EPA, United States Environmental Protection Agency.

PM 2.5 : mass concentration of particles less than 2.5 µm in size PM 10 : mass concentration of particles less than 10 µm in size RB: Regional Background site SOP: Standard Operating Procedure ST: Street site TRAPCA: Traffic-Related Air Pollution and Childhood Asthma UB: Urban Background site ABSTRACT The ESCAPE study (European Study of Cohorts for Air Pollution Effects) investigates long-term effects on human health of exposure to air pollution in Europe. Various health endpoints are analysed by using prospective cohort studies in the study areas. This paper documents the spatial variation of measured NO 2 and NO x concentrations between and within 36 study areas across Europe. In 36 study areas NO 2 and NO x were measured using standardized methods between October 2008 and April 2011. In each study area 14 to 80 sites were selected, which represented a wide range of regional, urban and nearby traffic related pollution contrast. The measurements were conducted for two weeks per site in three different seasons, using Ogawa badges. Results for each site were adjusted for temporal variation using data obtained from a routine monitor background site, which operated continuously, and averaged. Substantial spatial variability was found in NO 2 and NO x concentrations between and within study areas. Analysis of variance showed that 40% of the overall NO 2 variance is attributable to the variability between the study areas and 60% is caused by the variability within the study areas. The corresponding values for NO x are 30% (between the study areas) and 70% (within the study areas). The within-area spatial variability was mostly determined by the differences between traffic and urban background concentrations. The traffic/urban background concentration ratio varied between 1.09 and 3.16 across Europe. The NO 2 / NO x ratio varied between 0.47 (Verona) and 0.72 (Heraklion) across study areas. In study areas in southern Europe the highest median concentrations were observed (Barcelona: NO 2 55 µg/m³), followed by densely populated areas in Western Europe (Ruhr area, The Netherlands). The lowest concentrations were observed in all areas in Northern Europe (e.g. Umeå: NO 2 7 µg/m³). In conclusion, we found significant contrast in annual average NO 2 and NO x concentration between and especially within 36 study areas across Europe. Epidemiological studies should therefore characterize intra-urban contrasts. The use of traffic indicators such as "living close to major road" as an exposure variable in epidemiological studies results in different actual NO 2 contrasts. We would like to thank Kees Meliefste, Geert de Vrieze, Marjan Tewis (IRAS, Utrecht University, The Netherlands) for the sampler preparation, analysis and data management. Furthermore, we thank all those who were responsible for air pollution measurements, data management and project supervision in all study areas and especially:

Background: The Household Air Pollution Intervention Network (HAPIN) trial is a randomized controlled trial to assess the health impact of providing a clean cooking intervention to households using solid cooking fuel in Guatemala, India, Peru, and Rwanda. The intervention-a liquefied petroleum gas (LPG) stove and 18 months of free LPG-has significant value in these communities, where it is seen as aspirational, yet unaffordable. Although control households in randomized trials often receive the intervention at the trial conclusion, in HAPIN this was logistically unfeasible. It was therefore necessary to develop a tailored compensation strategy for control households that would be comparable across four distinct settings. Methods: Investigators generated a set of underlying ethical principles to guide development of compensation packages. Field staff conducted interviews, surveys, and focus groups to obtain input on appropriate compensation for control participants in each setting. This feedback was compared across the four sites and evaluated against initial underlying principles. Results: In Guatemala, control compensation consists of coupons equivalent to the LPG stove value that can be redeemed for the participant's choice of household items, which could include an LPG stove. In Peru, control households receive several small items during the trial plus the intervention stove and one month of fuel at the conclusion. Rwandan participants are given small items during the trial and a choice of a solar kit, LPG stove, or cash equivalent at the end. India is the only setting in which control participants receive the intervention (stove and 18 months of fuel) at the trial's end, in accordance with local ethics committee requirements. Conclusions: Applying common principles that are adaptable to different settings can generate ethical and contextually appropriate compensation packages in trials with highly valued interventions. The approach presented here could inform future randomized trials in multi-country settings.

Land use regression models (LUR) frequently use leave-one-out-cross-validation (LOOCV) to assess model fit, but recent studies suggested that this may overestimate predictive ability in independent data sets. Our aim was to evaluate LUR models for nitrogen dioxide (NO 2) and particulate matter (PM) components exploiting the high correlation between concentrations of PM metrics and NO 2. LUR models have been developed for NO 2 , PM 2.5 absorbance, and copper (Cu) in PM 10 based on 20 sites in each of the 20 study areas of the ESCAPE project. Models were evaluated with LOOCV and "hold-out evaluation (HEV)" using the correlation of predicted NO 2 or PM concentrations with measured NO 2 concentrations at the 20 additional NO 2 sites in each area. For NO 2 , PM 2.5 absorbance and PM 10 Cu, the median LOOCV R 2 s were 0.83, 0.81, and 0.76 whereas the median HEV R 2 were 0.52, 0.44, and 0.40. There was a positive association between the LOOCV R 2 and HEV R 2 for PM 2.5 absorbance and PM 10 Cu. Our results confirm that the predictive ability of LUR models based on relatively small training sets is overestimated by the LOOCV R 2 s. Nevertheless, in most areas LUR models still explained a substantial fraction of the variation of concentrations measured at independent sites.

The role of air pollution in chronic obstructive pulmonary disease (COPD) remains uncertain. The aim was to assess the impact of chronic exposure to air pollution on COPD in four cohorts using the standardised ESCAPE exposure estimates. Annual average particulate matter (PM), nitrogen oxides (NO x) and road traffic exposure were assigned to home addresses using land-use regression models. COPD was defined by NHANES reference equation (forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) less than the lower limit of normal) and the Global Initiative for Chronic Obstructive Lung Disease criterion (FEV1/FVC ,0.70) and categorised by severity in non-asthmatics. We included 6550 subjects with assigned NO x and 3692 with PM measures. COPD was not associated with NO 2 or PM10 in any individual cohort. In meta-analyses only NO 2 , NO x , PM10 and the traffic indicators were positively, although not significantly, associated with COPD. The only statistically significant associations were seen in females (COPD prevalence using GOLD: OR 1.57, 95% CI 1.11-2.23; and incidence: OR 1.79, 95% CI 1.21-2.68). None of the principal results were statistically significant, the weak positive associations of exposure with COPD and the significant subgroup findings need to be evaluated in further well standardised cohorts followed up for longer time, and with time-matched exposure assignments.

PM 2.5 , mass concentration of particles less than 2.5 μm in size; PM 2.5 , absorbance measurement of the blackness of PM 2.5 filters, this is a proxy for elemental carbon, which is the dominant light absorbing substance; PM 10 , mass concentration of particles less than 10 μm in size; PM coarse , mass concentration of the coarse fraction of particles between 2.5 μm and 10 μm in size; ST, street site; UB, urban background site; RB, regional background site;

Objective: The asthma control test (ACT) is a validated tool for assessing control in asthmatic children aged 12 years and older. Using the ACT, we sought to assess asthma control and knowledge in London secondary school children. Methods: Secondary schools in London, UK, participated in this study. Children with doctor-diagnosed asthma were invited to complete an online questionnaire that included the ACT and questions about asthma. Suboptimal asthma control was defined as an ACT score of ࣘ 19 out of a maximum score of 25. Data are summarised as median and interquartile range (IQR), and were analysed by either Mann-Whitney test, or chi-square test. A p value of < 0.05 was considered significant. Results: A total of 799 children completed the questionnaire; 689 (86.2%) were included for analysis. Suboptimal asthma control was reported by 49.6% of students. Over a third (42.4%) of students prescribed a short-acting β2-agonist inhaler felt uncomfortable using it at school, and 29.2% (n = 173) reported not using this inhaler when wheezy. 56.4% (n = 220) of those with regular inhaled corticosteroids did not take them as prescribed, and 41.7% did not know what this inhaler was for. Suboptimal control was associated with a greater proportion of students reporting that they were 'somewhat' , 'hardly' or 'not at all' comfortable using inhalers at school (52.7% vs 29.1%, p < 0.01) and outside school (22.8% vs. 14.8%, p < 0.01). Conclusions: Suboptimal asthma control and poor asthma knowledge are common in London schoolchildren.

IntroductionAsthma-related morbidity and mortality in the UK is higher than elsewhere in Europe. Although the reasons for this are largely unclear, one explanation could be a higher prevalence of poorly controlled asthma in the UK. Findings from our earlier study found that, in a sample of 766 children with asthma, 45.7% had poorly controlled asthma. Our earlier study also showed that adherence to inhaled corticosteroids was low. Subsequent focus groups identified concerns regarding embarrassment and bullying as barriers to adherence, as well as forgetfulness and incorrect medication beliefs. Following this, a school-based self-management intervention has been developed, aimed to improve asthma control and self-management behaviours.Methods and analysisThe theory-based cluster randomised controlled trial tests an intervention comprising two components: (1) a theatre workshop for all children in years 7 and 8, and (2) self-management workshops for children with asthma. The COM-B mode...

Background Asthma control in adolescents is low with half of the young people in a London study identified as having suboptimal control when measured using the Asthma Control Test. Control of asthma symptoms can be improved by addressing barriers to good self-management, such as poor understanding of asthma and adherence to medication. The aim of this study was therefore to develop the My Asthma in School (MAIS) intervention for the improvement of asthma control and self-management in adolescents and to test its initial feasibility. The intervention intended to combine a strong focus on theory with a design specifically aimed to engage adolescents. Methods The intervention development was based on previous qualitative and quantitative findings, and on guidelines from the Medical Research Council for the development of complex interventions. The COM-B (Capability, Opportunity, Motivation–Behaviour) model was applied to inform the design of intervention elements. Behavioural targets w...

Background Children with poorly controlled asthma have higher rates of unplanned healthcare use and school absences, as well as lower rates of medication adherence and knowledge. They also feel less comfortable using their medication at school, due to social fears and bullying. In this study, this was addressed through two school-based self-management interventions piloted to determine which one to use in a full trial. Methods We sought to assess the feasibility and acceptability of two school-based self-management intervention aimed at improving asthma control. Schools in London were randomised to (i) a theatre workshop for the whole year group aimed at raising awareness of asthma in schools, followed by self-management workshops for children (full intervention), (ii) theatre workshop alone (theatre only), or (iii) usual care (controls). Opt-out consent was obtained from parents. The study was a cluster randomised pilot trial, using London schools as the unit of allocation. Our pri...

Background Asthma is the most common chronic respiratory disease among children and adolescents worldwide. However, the burden of severe asthma is highest in Sub-Saharan Africa. This study aimed to explore teachers&#39; perceptions of asthma care across six African countries. Methods We conducted focus group discussions (FGDs) using a semi-structured interview guide. Interviews were audio-recorded, transcribed verbatim and analysed thematically. FGDs were conducted in Accra (Ghana), Blantyre (Malawi), Lagos (Nigeria), Durban (South Africa), Kampala (Uganda), and Harare (Zimbabwe) between 01 November 2020 and 30 June 2021. Results We identified two key themes related to asthma care: (1) barriers to asthma care and (2) suggestions to improve the care of asthma learners. Teachers reported a lack of knowledge and skills among themselves, learners, and caregivers. Some teachers believed that myths about asthma and restrictions on themselves administering care exacerbated challenges faced...

Asthma is the most common chronic respiratory disease among school-going adolescents worldwide. However, the burden of severe asthma is highest in Sub-Saharan Africa. This study aimed to explore teachers’ perceptions of asthma care across six African countries. We conducted focus group discussions (FGDs) using a semi-structured interview guide. Interviews were audio-recorded, transcribed verbatim and analysed thematically. FGDs were conducted in Kumasi(Ghana), Blantyre (Malawi), Lagos (Nigeria), Durban (South Africa), Kampala (Uganda), and Harare (Zimbabwe) between 01 November 2020 and 30 June 2021. We identified two key themes related to asthma care; barriers to asthma care and suggestions to improve the care of adolescents with asthma. Barriers reported by teachers included a lack of knowledge and skills among themselves, adolescents, and caregivers. In addition, some traditional beliefs of teachers on asthma exacerbated challenges with asthma care in schools. Regarding suggestion...

Objectives This study identifies barriers and provides recommendations to improve asthma care in children across sub-Saharan Africa, where qualitative data is lacking despite high rates. Design One of the aims of our National Institute for Health Research global health research group 'Achieving Control of Asthma in Children in Africa' was to use qualitative thematic analysis of transcribed audio recordings from focus group discussions (FGDs) to describe barriers to achieving good asthma control. Setting Schools in Blantyre (Malawi), Lagos (Nigeria), Durban (South Africa), Kampala (Uganda) and Harare (Zimbabwe). Participants Children (n=136), 12-14 years with either asthma symptoms or a diagnosis and their caregivers participated in 39 FGDs. All were recruited using asthma control questions from the Global Asthma Network survey. Results There were four key themes identified: (1) Poor understanding, (2) difficulties experienced with being diagnosed, (3) challenges with caring for children experiencing an acute asthma episode and (4) suboptimal uptake and use of prescribed medicines. An inadequate understanding of environmental triggers, a hesitancy in using metred dose inhalers and a preference for oral and alternate medications were identified as barriers. In addition, limited access to healthcare with delays in diagnosis and an inability to cope with expected lifestyle changes was reported. Based on these findings, we recommend tailored education to promote access to and acceptance of metred dose inhalers, including advocating for access to a single therapeutic, preventative and treatment option. Furthermore, healthcare systems should have simpler diagnostic pathways and easier emergency access for asthma. Conclusions In a continent with rapidly increasing levels of poorly controlled asthma, we identified multiple barriers to achieving good asthma control along the trajectory of care. Exploration of these barriers reveals several generalisable recommendations that should modify asthma care plans and potentially transform asthma care in Africa. Trial registration number 269211. ⇒ This is the first multicountry African qualitative study that used thematic analysis to identify barriers to asthma care. ⇒ Perspectives of both adolescents and their caregivers on asthma diagnosis and management are included. ⇒ Views of both children with a physician diagnosis of asthma and those with symptoms of asthma and not formally diagnosed are included.

Dyskeratosis congenita (DC) is an inherited bone-marrow-failure disorder characterized by a triad of mucocutaneous features that include abnormal skin pigmentation, nail dystrophy, and oral leucoplakia. Despite the identification of several genetic variants that cause DC, a significant proportion of probands remain without a molecular diagnosis. In a cohort of eight independent DC-affected families, we have identified a remarkable series of heterozygous germline variants in the gene encoding thymidylate synthase (TYMS). Although the inheritance appeared to be autosomal recessive, one parent in each family had a wild-type TYMS coding sequence. Targeted genomic sequencing identified a specific haplotype and rare variants in the naturally occurring TYMS antisense regulator ENOSF1 (enolase super family 1) inherited from the other parent. Lymphoblastoid cells from affected probands have severe TYMS deficiency, altered cellular deoxyribonucleotide triphosphate pools, and hypersensitivity to the TYMS-specific inhibitor 5-fluorouracil. These defects in the nucleotide metabolism pathway resulted in genotoxic stress, defective transcription, and abnormal telomere maintenance. Generescue studies in cells from affected probands revealed that post-transcriptional epistatic silencing of TYMS is occurring via elevated ENOSF1. These cell and molecular abnormalities generated by the combination of germline digenic variants at the TYMS-ENOSF1 locus represent a unique pathogenetic pathway for DC causation in these affected individuals, whereas the parents who are carriers of either of these variants in a singular fashion remain unaffected.

Telomere biology disorders are complex clinical conditions that arise due to mutations in genes required for telomere maintenance. Telomere length has been utilised as part of the diagnostic work-up of patients with these diseases; here, we have tested the utility of high-throughput STELA (HT-STELA) for this purpose. HT-STELA was applied to a cohort of unaffected individuals (n = 171) and a retrospective cohort of mutation carriers (n = 172). HT-STELA displayed a low measurement error with inter-and intra-assay coefficient of variance of 2.3% and 1.8%, respectively. Whilst telomere length in unaffected individuals declined as a function of age, telomere length in mutation carriers appeared to increase due to a preponderance of shorter telomeres detected in younger individuals (< 20 years of age). These individuals were more severely affected, and age-adjusted telomere length differentials could be used to stratify the cohort for overall survival (Hazard Ratio = 5.6 (1.5-20.5); p < 0.0001). Telomere lengths of asymptomatic mutation carriers were shorter than controls (p < 0.0001), but longer than symptomatic mutation carriers (p < 0.0001) and telomere length heterogeneity was dependent on the diagnosis and mutational status. Our data show that the ability of HT-STELA to detect short telomere lengths, that are not readily detected with other methods, means it can provide powerful diagnostic discrimination and prognostic information. The rapid format, with a low measurement error, demonstrates that HT-STELA is a new high-quality laboratory test for the clinical diagnosis of an underlying telomeropathy.

for the shorter RFS prediction, the contribution of MRD data to the multivariable model's accuracy was more pronounced than for the RFS model built initially (C-statistics of 0.78 and 0.65 for 6-and 12-month RFS without MRD data). As a caveat, there were only 18 events in the 6-month RFS analysis, limiting the inference that can be drawn from the multivariable models; larger cohorts will be needed to test this idea further. If confirmed, our studies may form the basis for the development of relatively accurate shorter-term RFS prediction models in which MRD data should be included.