Common genetic variants associated with urinary phthalate levels in children: A genome-wide study.

INTRODUCTION: Phthalates, or dieters of phthalic acid, are a ubiquitous type of plasticizer used in a variety of common consumer and industrial products. They act as endocrine disruptors and are associated with increased risk for several diseases. Once in the body, phthalates are metabolized through partially known mechanisms, involving phase I and phase II enzymes. OBJECTIVE: In this study we aimed to identify common single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) associated with the metabolism of phthalate compounds in children through genome-wide association studies (GWAS). METHODS: The study used data from 1,044 children with European ancestry from the Human Early Life Exposome (HELIX) cohort. Ten phthalate metabolites were assessed in a two-void pooled urine collected at the mean age of 8 years. Six ratios between secondary and primary phthalate metabolites were calculated. Genome-wide genotyping was done with the Infinium Global Screening Array (GSA) and imputation with the Haplotype Reference Consortium (HRC) panel. PennCNV was used to estimate copy number variants (CNVs) and CNVRanger to identify consensus regions. GWAS of SNPs and CNVs were conducted using PLINK and SNPassoc, respectively. Subsequently, functional annotation of suggestive SNPs (p-value < 1E-05) was done with the FUMA web-tool. RESULTS: We identified four genome-wide significant (p-value < 5E-08) loci at chromosome (chr) 3 (FECHP1 for oxo-MiNP_oh-MiNP ratio), chr6 (SLC17A1 for MECPP_MEHHP ratio), chr9 (RAPGEF1 for MBzP), and chr10 (CYP2C9 for MECPP_MEHHP ratio). Moreover, 115 additional loci were found at suggestive significance (p-value < 1E-05). Two CNVs located at chr11 (MRGPRX1 for oh-MiNP and SLC35F2 for MEP) were also identified. Functional annotation pointed to genes involved in phase I and phase II detoxification, molecular transfer across membranes, and renal excretion. CONCLUSION: Through genome-wide screenings we identified known and novel loci implicated in phthalate metabolism in children. Genes annotated to these loci participate in detoxification, transmembrane transfer, and renal excretion.

Green space exposure and blood DNA methylation at birth and in childhood - A multi-cohort study.

Green space exposure has been associated with improved mental, physical and general health. However, the underlying biological mechanisms remain largely unknown. The aim of this study was to investigate the association between green space exposure and cord and child blood DNA methylation. Data from eight European birth cohorts with a total of 2,988 newborns and 1,849 children were used. Two indicators of residential green space exposure were assessed: (i) surrounding greenness (satellite-based Normalized Difference Vegetation Index (NDVI) in buffers of 100 m and 300 m) and (ii) proximity to green space (having a green space ≥ 5,000 m2 within a distance of 300 m). For these indicators we assessed two exposure windows: (i) pregnancy, and (ii) the period from pregnancy to child blood DNA methylation assessment, named as cumulative exposure. DNA methylation was measured with the Illumina 450K or EPIC arrays. To identify differentially methylated positions (DMPs) we fitted robust linear regression models between pregnancy green space exposure and cord blood DNA methylation and between cumulative green space exposure and child blood DNA methylation. Two sensitivity analyses were conducted: (i) without adjusting for cellular composition, and (ii) adjusting for air pollution. Cohort results were combined through fixed-effect inverse variance weighted meta-analyses. Differentially methylated regions (DMRs) were identified from meta-analysed results using the Enmix-combp and DMRcate methods. There was no statistical evidence of pregnancy or cumulative exposures associating with any DMP (False Discovery Rate, FDR, p-value < 0.05). However, surrounding greenness exposure was inversely associated with four DMRs (three in cord blood and one in child blood) annotated to ADAMTS2, KCNQ1DN, SLC6A12 and SDK1 genes. Results did not change substantially in the sensitivity analyses. Overall, we found little evidence of the association between green space exposure and blood DNA methylation. Although we identified associations between surrounding greenness exposure with four DMRs, these findings require replication.

Early educational attainment in children with major congenital anomaly in the UK.

OBJECTIVE: To describe early educational attainment and special educational needs (SEN) provision in children with major congenital anomaly (CA) compared with peers. DESIGN: Analysis of educational data linked to the ongoing Born in Bradford cohort study. Confounders were identified via causal inference methods and multivariable logistic regression performed. SETTING: Children born in Bradford Royal Infirmary (BRI), West Yorkshire. PATIENTS: All women planning to give birth at BRI and attending antenatal clinic from March 2007 to December 2010 were eligible. 12 453 women with 13 776 pregnancies (>80% of those attending) were recruited. Records of 555 children with major CA and 11 188 without were linked to primary education records. OUTCOMES: Key Stage 1 (KS1) attainment at age 6-7 years in Maths, Reading, Writing and Science. SEN provision from age 4 to 7 years. RESULTS: 41% of children with major CA received SEN provision (compared with 14% without), and 48% performed below expected standards in at least one KS1 domain (compared with 29% without). The adjusted odds of children with CA receiving SEN provision and failing to achieve the expected standard at KS1 were, respectively, 4.30 (95% CI 3.49 to 5.31) and 3.06 (95% CI 2.47 to 3.79) times greater than their peers. Those with genetic, heart, neurological, urinary, gastrointestinal and limb anomalies had significantly poorer academic achievement. CONCLUSIONS: These novel results demonstrate that poor educational attainment extends to children with urinary, limb and gastrointestinal CAs. We demonstrate the need for collaboration between health and education services to assess and support children with major CA, so every CA survivor can maximise their potential.

Educational attainment of children with congenital Heart disease in the United Kingdom.

BACKGROUND: Educational attainment in children with congenital heart disease (CHD) within the UK has not been reported, despite the possibility of school absences and disease-specific factors creating educational barriers. METHODS: Children were prospectively recruited to the Born in Bradford birth cohort between March 2007 and December 2010. Diagnoses of CHD were identified through linkage to the congenital anomaly register and independently verified by clinicians. Multivariable regression accounted for relevant confounders. Our primary outcome was the odds of 'below expected' attainment in Maths, Reading and Writing at ages 4-11 years. RESULTS: Educational records of 139 children with non-genetic CHD were compared to 11 188 age-matched children with no major congenital anomaly. Children with CHD had significantly higher odds of 'below expected' attainment in Maths at age 4-5 years (Odds Ratio 1.64, 95% CI 1.07-2.52), age 6-7 (OR 2.03, 95% CI 1.32-3.12), and age 10-11 (OR 2.28, 95% CI 1.01-5.14). Odds worsened with age, with similar results for Reading and Writing. The odds of receiving special educational needs support reduced with age for children with CHD relative to controls (age 4-5: OR 4.84 (2.06-11.40); age 6-7: OR 3.65 (2.41-5.53); age 10-11: OR 2.73 (1.84-4.06)). Attainment was similar for children with and without exposure to cardio-pulmonary bypass. Lower attainment was strongly associated with the number of pre-school hospital admissions. CONCLUSIONS: Children with CHD have lower educational attainment compared to their peers. Deficits are evident from school entry and increase throughout primary school.

Health care utilisation and education outcomes of children with rare diseases: a born in Bradford cohort study.

The purpose of this study is to describe the burden of health care utilisation and early education outcomes of children with and without rare diseases. Using the Born in Bradford birth cohort and its linked routine health care and education data, we looked at cumulative primary care episodes, hospital admissions and medication prescriptions. We assessed education outcomes using Early Years Foundation Stage Profile and the National Curriculum Tests-Key Stage 1 results. Among analytical sample of 13,858, 1711 or 12.3% children were identified with a rare disease by an average age of 14 years. Children with rare diseases were twice more likely to be admitted to hospital compared to children without. Average length of stay was around 5 days in those with rare diseases group compared to less than 1 day in those without. The average number of primary care episodes was 45.4 in children with rare diseases and 28.2 visits in those without. These children were over three times more likely to be on multiple medications. Children with rare diseases had 30% higher risk of being below academic expectations at Foundation Year and, depending on subject, between 50 and 60% higher risks at KS1 tests.  Conclusions: Children with rare diseases are significantly more likely to have increased primary care episodes and to have more regular medications. They are likely to have more hospital admissions with a longer stay also. Educationally, they are at higher risk of failing to achieve expected standards in early-year settings. What is Known: • Existing studies of rare diseases have used cross sectional data to describe secondary care data. Previous research has not explored the impact of rare diseases on academic outcomes in children. What is New: • Using Born in Bradford birth cohort and its linked primary and secondary care data, this study provides the most comprehensive estimate of prevalence of rare diseases in any study to date. Children with rare diseases were not only significantly more likely to have contact with primary care and to be admitted to hospitals; they were also more like to be on more regular medications and had higher risk of not achieving expected standards in early-year education outcomes. • Our study is unusual in being able to access linked health and education data and reinforces the importance of adopting a whole system approach to children's health and wellbeing that recognises the close links between health and education.

Stillbirths and neonatal deaths among 18 942 women with postpartum hemorrhage: Analysis of perinatal outcomes in the WOMAN trial.

OBJECTIVE: To describe the rates and risk factors for stillbirth and pre-discharge neonatal mortality (PDNM), and impact on quality of life (QoL) among women with postpartum hemorrhage (PPH). METHODS: A secondary analysis was conducted of the WOMAN trial, which evaluated the use of tranexamic acid for PPH and collected infant outcome data to assess drug safety. The analysis was restricted to singletons (n=18 942). Overall and country-level rates of stillbirth and PDNM were calculated. Multilevel logistic regression models examined the association of stillbirth and PDNM with selected risks, and the association of mother's QoL at discharge after stillbirth or PDNM. RESULTS: For women with PPH, the rate of stillbirths was 104.42 per 1000 births (n=1978) and the rate of PDNM was 15.56 per 1000 live births (n=264). Cesarean delivery, increasing blood loss, maternal complications, and maternal death were strongly associated with these adverse outcomes. Women with stillbirth and PDNM were significantly more likely to report poorer QoL. CONCLUSION: Women with PPH experience an extremely high rate of stillbirth and slightly elevated PDNM, which is associated with markers of the severity of their condition and impacts on their QoL.

Beyond the mask: a multidisciplinary reflection on palliating patients with COVID-19 receiving continuous positive airway pressure ventilation.

This narrative describes the experiences of an inner city respiratory unit that was transformed to treat COVID-19 patients with continuous positive airway pressure (CPAP) ventilation who were not scheduled for any further escalation in treatment. The high mortality rate and unconventional way of dying led to the creation of local guidance for removing assisted ventilation when the treatment ceased to be effective. We reflect on the specific challenges that caring for these patients holistically has presented and how we have learnt to deliver good palliative care in a unique set of circumstances. We also consider the impact of the pandemic on our team and how the development of a multidisciplinary support system has improved team dynamics and ultimately patient care.