Aim To identify the common factors in serious case reviews (SCRs) where a child has died of a medical cause. Design Qualitative thematic analysis. Background SCRs take place when neglect or abuse results in children dying or being seriously harmed. Known key factors within SCRs include parental substance misuse, mental health problems and domestic abuse. To date, there has been no investigation of children who die of a medical cause where there are concerns about child maltreatment. Data sources A list of SCRs relating to deaths through medical causes was provided from previous coded studies and accessed from the National Society for the Prevention of Cruelty to Children National Case Review Repository. Twenty-three SCRs with a medical cause of death from 1 April 2009 to 31 March 2017 were sourced. Results 20 children died of an acute condition and 12 of a chronic condition; 20 of the deaths were unexpected and maltreatment contributed to the deaths of 18 children. Most children were aged either 16 years at the time of death. Many parents were caring for a child with additional vulnerabilities including behavioural issues (6/23), learning difficulties (6/23), mental health issues (5/23) or a chronic medical condition (12/23). Common parental experiences included domestic violence/abuse (13/23), drug/alcohol misuse (10/23), mental ill health or struggling to cope (7/23), criminal history (11/23) and caring for another vulnerable individual (8/23). Most children lived in a chaotic household characterised by missed medical appointments (18/23), poor school attendance (11/23), poor physical home environment (7/23) and disguised compliance (12/23). All 23 SCRs reported elements of abusive or neglectful parenting. In most, there was an evidence of cumulative harm, where multiple factors contributed to their premature death. At the time of death, 11 children were receiving social care support. Conclusion Although the underlying medical cause of the child’s death was often incurable, the maltreatment that often exacerbated the medical issue could have been prevented.

Background: Preserved ratio impaired spirometry (PRISm) is defined as a forced expiratory volume in 1 s (FEV₁) <80% predicted and FEV₁/forced vital capacity ≥0.70. PRISm is associated with respiratory symptoms and comorbidities. Our objective was to discover novel genetic signals for PRISm and see if they provide insight into the pathogenesis of PRISm and associated comorbidities.Methods: We undertook a genome-wide association study (GWAS) of PRISm in UK Biobank participants (Stage 1), and selected single nucleotide polymorphisms (SNPs) reaching genome-wide significance for replication in 13 cohorts (Stage 2). A combined meta-analysis of Stage 1 and Stage 2 was done to determine top SNPs. We used cross-trait linkage disequilibrium score regression to estimate genome-wide genetic correlation between PRISm and pulmonary and extrapulmonary traits. Phenome-wide association studies of top SNPs were performed.Results: 22 signals reached significance in the joint meta-analysis, including four signals novel for lung function. A strong genome-wide genetic correlation (r_g) between PRISm and spirometric COPD (r_g=0.62, p<0.001) was observed, and genetic correlation with type 2 diabetes (r_g=0.12, p=0.007). Phenome-wide association studies showed that 18 of 22 signals were associated with diabetic traits and seven with blood pressure traits.Conclusion: This is the first GWAS to successfully identify SNPs associated with PRISm. Four of the signals, rs7652391 (nearest geneMECOM), rs9431040 (HLX), rs62018863 (TMEM114) and rs185937162 (HLA-B), have not been described in association with lung function before, demonstrating the utility of using different lung function phenotypes in GWAS. Genetic factors associated with PRISm are strongly correlated with risk of both other lung diseases and extrapulmonary comorbidity.

Background: Patients with chronic obstructive pulmonary disease (COPD) are commonly treated with inhaled corticosteroid/long-acting ß2-agonist combination therapy. While previous studies have investigated the host–microbiome interactions in COPD, the effects of specific steroid formulations on this complex cross-talk remain obscure. Methods: We collected and evaluated data from the Study to Investigate the Differential Effects of Inhaled Symbicort and Advair on Lung Microbiota (DISARM), a randomized controlled trial. Bronchoscopy was performed on COPD patients before and after treatment with salmeterol/fluticasone, formoterol/budesonide or formoterol-only. Bronchial brush samples were processed for microbial 16S rRNA gene sequencing and host mRNA sequencing. Longitudinal changes in the microbiome at a community, phylum and genus level were correlated with changes in host gene expression using a Spearman’s rank correlation test. Findings: In COPD patients treated with salmeterol/fluticasone, the expression levels of 676 host genes were significantly correlated to changes in the alpha diversity of the small airways. At a genus level, the expression levels of 122 host genes were significantly related to changes in the relative abundance of Haemophilus. Gene enrichment analyses revealed the enrichment of pathways and biological processes related to innate and adaptive immunity and inflammation. None of these changes were evident in patients treated with formoterol/budesonide or formoterol alone. Interpretation: Changes in the microbiome following salmeterol/fluticasone treatment are related to alterations in the host transcriptome in the small airways of patients with COPD. These data may provide insights into why some COPD patients treated with inhaled corticosteroids may be at an increased risk for airway infection, including pneumonia. Funding: The Canadian Institute of Health Research, the British Columbia Lung Association, and an investigator-initiated grant from AstraZeneca.

Background: The role of epigenetic ageing in the environmental pathogenesis and prognosis of fibrotic interstitial lung disease (fILD) is unclear. We evaluated whether ambient particulate matter with diameter ≤2.5 μm (PM_2.5) and neighbourhood disadvantage exposures are associated with accelerated epigenetic ageing, and whether epigenetic age is associated with adverse clinical outcomes in patients with fILD.Methods: This multicentre, international, cohort study included patients with fILD from the University of Pittsburgh (UPitt, n=306) and University of British Columbia (UBC, n=170). 5-year PM_2.5exposures were estimated using satellite-derived hybrid models. Neighbourhood disadvantage was calculated using US and Canadian census-based metrics. Epigenetic age difference (EAD=epigenetic age−chronological age) was calculated using GrimAge analysis of blood DNA methylation data. Linear models assessed associations of exposures with EAD. Cox models assessed associations of EAD with transplant-free survival. Causal mediation analysis evaluated EAD mediation of exposure–survival relationships.Results: Median epigenetic age was 11.7 years older than chronological age in patients with fILD. In combined cohort analysis, each interquartile range (IQR) increase in PM_2.5was associated with 2.88 years (95% CI 1.39–4.38; p<0.001) increased EAD. In UPitt, each IQR neighbourhood disadvantage increase was associated with 1.16 years (95% CI 0.22–2.09; p=0.02) increased EAD. Increased EAD was associated with worse transplant-free survival (hazard ratio 1.17 per 1-year increase in EAD, 95% CI 1.10–1.24; p<0.001), with EAD mediating 40% of the PM_2.5–survival relationship and 59% of the neighbourhood disadvantage–survival relationship. Epigenetic age was also more strongly associated with transplant-free survival than chronological age.Conclusions: Epigenetic age acceleration is associated with worse survival and mediates adverse exposure impacts in fILD.

One key feature of Chronic Obstructive Pulmonary Disease (COPD) is that its prevalence increases exponentially with age. DNA methylation clocks have become powerful biomarkers to detect accelerated aging in a variety of diseases and can help prognose outcomes in severe COPD. This study investigated which DNA methylation clock could best reflect airway epigenetic age when used in more accessible blood samples. Our analyses showed that out of six DNA methylation clocks investigated, DNAmGrimAge demonstrated the strongest correlation and the smallest difference between the airway epithelium and blood. Our findings suggests that blood DNAmGrimAge accurately reflects airway epigenetic age of individuals and that its elevation is highly associated with COPD.