Genetic risk of obesity as a modifier of associations between neighbourhood environment and body mass index: an observational study of 335 046 UK Biobank participants.

BackgroundThere is growing recognition that recent global increases in obesity are the product of a complex interplay between genetic and environmental factors. However, in gene-environment studies of obesity, 'environment' usually refers to individual behavioural factors that influence energy balance, whereas more upstream environmental factors are overlooked. We examined gene-environment interactions between genetic risk of obesity and two neighbourhood characteristics likely to be associated with obesity (proximity to takeaway/fast-food outlets and availability of physical activity facilities).MethodsWe used data from 335 046 adults aged 40-70 in the UK Biobank cohort to conduct a population-based cross-sectional study of interactions between neighbourhood characteristics and genetic risk of obesity, in relation to body mass index (BMI). Proximity to a fast-food outlet was defined as distance from home address to nearest takeaway/fast-food outlet, and availability of physical activity facilities as the number of formal physical activity facilities within 1 km of home address. Genetic risk of obesity was operationalised by weighted Genetic Risk Scores of 91 or 69 single nucleotide polymorphisms (SNP), and by six individual SNPs considered separately. Multivariable, mixed-effects models with product terms for the gene-environment interactions were estimated.ResultsAfter accounting for likely confounding, the association between proximity to takeaway/fast-food outlets and BMI was stronger among those at increased genetic risk of obesity, with evidence of an interaction with polygenic risk scores (p=0.018 and p=0.028 for 69-SNP and 91-SNP scores, respectively) and in particular with a SNP linked to MC4R (p=0.009), a gene known to regulate food intake. We found very little evidence of gene-environment interaction for the availability of physical activity facilities.ConclusionsIndividuals at an increased genetic risk of obesity may be more sensitive to exposure to the local fast-food environment. Ensuring that neighbourhood residential environments are designed to promote a healthy weight may be particularly important for those with greater genetic susceptibility to obesity

Do neighbourhood characteristics act together to influence BMI? A cross-sectional study of urban parks and takeaway/fast-food stores as modifiers of the effect of physical activity facilities

Studies exploring associations between neighbourhood environment and obesity often overlook the fact that neighbourhoods are multi-dimensional and that the effects of one environmental exposure may be modified by another. We examine whether associations between neighbourhood density of formal physical activity (PA) facilities and body mass index (BMI) are modified by the density of neighbourhood green spaces and takeaway stores. We used cross-sectional data from the UK Biobank cohort and linked UK Biobank Urban Morphometric Platform (UKBUMP) for 345,269 urban-dwelling adults aged 40-69. We examined associations between objectively measured BMI and the number of formal PA facilities (gyms, pools, etc.) within 1 km of each individual's home, testing separately for interactions with the number of local public green spaces, and number of takeaway stores, within the same 1 km buffers. We estimated modifier-stratified associations using multivariable, multilevel models to account for a clustered sampling design and potential confounding. Likelihood ratio tests were used to assess statistical interaction. We found that the association between a greater number of local PA facilities and lower BMI was stronger among people with fewer urban green spaces in their neighbourhood than among those with more green spaces (Pinteraction = 0.021). The same relationship between PA facilities and BMI was also noticeably attenuated among those with more takeaway stores near home, compared with people with none (Pinteraction = 0.014). We conclude that formal PA facilities may buffer against a lack of informal, green resources for PA in areas where the latter are scarce. However, the potential benefits of formal PA facilities in terms of obesity risk may be undermined by an unhealthy food environment close to home. Locating formal PA facilities in places with fewer public green resources and reducing the prevalence of takeaway stores in areas with formal PA resources may maximise the health benefits to be derived from these neighbourhood resources

Comprehensive Analysis of mRNA Methylation Reveals Enrichment in 3′ UTRs and near Stop Codons

SummaryMethylation of the N6 position of adenosine (m6A) is a posttranscriptional modification of RNA with poorly understood prevalence and physiological relevance. The recent discovery that FTO, an obesity risk gene, encodes an m6A demethylase implicates m6A as an important regulator of physiological processes. Here, we present a method for transcriptome-wide m6A localization, which combines m6A-specific methylated RNA immunoprecipitation with next-generation sequencing (MeRIP-Seq). We use this method to identify mRNAs of 7,676 mammalian genes that contain m6A, indicating that m6A is a common base modification of mRNA. The m6A modification exhibits tissue-specific regulation and is markedly increased throughout brain development. We find that m6A sites are enriched near stop codons and in 3′ UTRs, and we uncover an association between m6A residues and microRNA-binding sites within 3′ UTRs. These findings provide a resource for identifying transcripts that are substrates for adenosine methylation and reveal insights into the epigenetic regulation of the mammalian transcriptome

Dynamic Near-Infrared Optical Imaging of 2-Deoxyglucose Uptake by Intracranial Glioma of Athymic Mice

BACKGROUND: It is recognized that cancer cells exhibit highly elevated glucose metabolism compared to non-tumor cells. We have applied in vivo optical imaging to study dynamic uptake of a near-infrared dye-labeled glucose analogue, 2-deoxyglucose (2-DG) by orthotopic glioma in a mouse model. METHODOLOGY AND PRINCIPAL FINDINGS: The orthotopic glioma model was established by surgically implanting U87-luc glioma cells into the right caudal nuclear area of nude mice. Intracranial tumor growth was monitored longitudinally by bioluminescence imaging and MRI. When tumor size reached >4 mm diameter, dynamic fluorescence imaging was performed after an injection of the NIR labeled 2-DG, IRDye800CW 2-DG. Real-time whole body images acquired immediately after i.v. infusion clearly visualized the near-infrared dye circulating into various internal organs sequentially. Dynamic fluorescence imaging revealed significantly higher signal intensity in the tumor side of the brain than the contralateral normal brain 24 h after injection (tumor/normal ratio, TNR = 2.8+/-0.7). Even stronger contrast was achieved by removing the scalp (TNR = 3.7+/-1.1) and skull (TNR = 4.2+/-1.1) of the mice. In contrast, a control dye, IRDye800CW carboxylate, showed little difference (1.1+/-0.2). Ex vivo fluorescence imaging performed on ultrathin cryosections (20 microm) of tumor bearing whole brain revealed distinct tumor margins. Microscopic imaging identified cytoplasmic locations of the 2-DG dye in tumor cells. CONCLUSION AND SIGNIFICANCE: Our results suggest that the near-infrared dye labeled 2-DG may serve as a useful fluorescence imaging probe to noninvasively assess intracranial tumor burden in preclinical animal models

Environmental and microbial controls on microbial necromass recycling, an important precursor for soil carbon stabilization

There is an emerging consensus that microbial necromass carbon is the primary constituent of stable soil carbon, yet the controls on the stabilization process are unknown. Prior to stabilization, microbial necromass may be recycled by the microbial community. We propose that the efficiency of this recycling is a critical determinant of soil carbon stabilization rates. Here we explore the controls on necromass recycling efficiency in 27 UK grassland soils using stable isotope tracing and indicator species analysis. We found that recycling efficiency was unaffected by land management. Instead, recycling efficiency increased with microbial growth rate on necromass, and was highest in soils with low historical precipitation. We identified bacterial and fungal indicators of necromass recycling efficiency, which could be used to clarify soil carbon stabilization mechanisms. We conclude that environmental and microbial controls have a strong influence on necromass recycling, and suggest that this, in turn, influences soil carbon stabilization

Age-Adjusted Associations Between Comorbidity and Outcomes of COVID-19: A Review of the Evidence From the Early Stages of the Pandemic

Objectives: Early in the COVID-19 pandemic, people with underlying comorbidities were overrepresented in hospitalised cases of COVID-19, but the relationship between comorbidity and COVID-19 outcomes was complicated by potential confounding by age. This review therefore sought to characterise the international evidence base available in the early stages of the pandemic on the association between comorbidities and progression to severe disease, critical care, or death, after accounting for age, among hospitalised patients with COVID-19.Methods: We conducted a rapid, comprehensive review of the literature (to 14 May 2020), to assess the international evidence on the age-adjusted association between comorbidities and severe COVID-19 progression or death, among hospitalised COVID-19 patients – the only population for whom studies were available at that time.Results: After screening 1,100 studies, we identified 14 eligible for inclusion. Overall, evidence for obesity and cancer increasing risk of severe disease or death was most consistent. Most studies found that having at least one of obesity, diabetes mellitus, hypertension, heart disease, cancer, or chronic lung disease was significantly associated with worse outcomes following hospitalisation. Associations were more consistent for mortality than other outcomes. Increasing numbers of comorbidities and obesity both showed a dose-response relationship. Quality and reporting were suboptimal in these rapidly conducted studies, and there was a clear need for additional studies using population-based samples.Conclusions: This review summarises the most robust evidence on this topic that was available in the first few months of the pandemic. It was clear at this early stage that COVID-19 would go on to exacerbate existing health inequalities unless actions were taken to reduce pre-existing vulnerabilities and target control measures to protect groups with chronic health conditions.</jats:p

Supporting healthcare professionals to address child weight with parents: A qualitative study

Background: Primary care and community healthcare professionals (HCP) are well placed to discuss child excess weight with parents and support them to make changes. However, HCPs have concerns about doing this. There is a need to understand the factors that influence HCPs in undertaking these activities to inform strategies to support them. Aim: To explore with HCPs working in primary care and community settings their experiences of having conversations about child weight with parents, and the factors that create barriers or facilitate them to have these conversations. Design and setting: A qualitative study with General Practitioners (GP), Primary Care Nurses (PN), and School Nurses (SN) in England. Method: GPs and PNs were recruited to participate in semi-structured interviews. SNs from a community healthcare NHS trust were recruited to participate in focus groups. Vignettes were used to stimulate discussion. Data were analysed guided by the Framework approach. Results: 13 GPs, 7 PNs, and 20 SNs participated. Identified barriers included structural, HCP-related and parent/family-related factors. Facilitating factors for having conversations with parents about child excess weight included structural changes (e.g. dedicated appointments, access to weight assessment data, joined up working across agencies), specific approaches adopted by HCPs, and enhancing HCPs’ skills (general and weight management-related) and knowledge of child weight management services. Conclusion: A range of barriers exist to HCPs addressing child excess weight with parents in primary care and community settings. Actions to effect structural changes and support HCPs in developing relevant knowledge and skills are required to overcome these

Maternal psychological distress in primary care and association with child behavioural outcomes at age three

Observational studies indicate children whose mothers have poor mental health are at increased risk of socio-emotional behavioural difficulties, but it is unknown whether these outcomes vary by the mothers’ mental health recognition and treatment status. To examine this question, we analysed linked longitudinal primary care and research data from 1078 women enrolled in the Born in Bradford cohort. A latent class analysis of treatment status and self-reported distress broadly categorised women as (a) not having a common mental disorder (CMD) that persisted through pregnancy and the first 2 years after delivery (N = 756, 70.1 %), (b) treated for CMD (N = 67, 6.2 %), or (c) untreated (N = 255, 23.7 %). Compared to children of mothers without CMD, 3-year-old children with mothers classified as having untreated CMD had higher standardised factor scores on the Strengths and Difficulties Questionnaire (d = 0.32), as did children with mothers classified as having treated CMD (d = 0.27). Results were only slightly attenuated in adjusted analyses. Children of mothers with CMD may be at risk for socio-emotional and behavioural difficulties. The development of effective treatments for CMD needs to be balanced by greater attempts to identify and treat women

Trends in inequalities in Children Looked After in England between 2004 and 2019: a local area ecological analysis.

OBJECTIVE:To assess trends in inequalities in Children Looked After (CLA) in England between 2004 and 2019, after controlling for unemployment, a marker of recession and risk factor for child maltreatment. DESIGN:Longitudinal local area ecological analysis. SETTING:150 English upper-tier local authorities. PARTICIPANTS:Children under the age of 18 years. PRIMARY OUTCOME MEASURE:The annual age-standardised rate of children starting to be looked after (CLA rate) across English local authorities, grouped into quintiles based on their level of income deprivation. Slope indices of inequality were estimated using longitudinal segmented mixed-effects models, controlling for unemployment. RESULTS:Since 2008, there has been a precipitous rise in CLA rates and a marked widening of inequalities. Unemployment was associated with rising CLA rates: for each percentage point increase in unemployment rate, an estimated additional 9 children per 100 000 per year (95% CI 6 to 11) became looked after the following year. However, inequalities increased independently of the effect of unemployment. Between 2007 and 2019, after controlling for unemployment, the gap between the most and least deprived areas increased by 15 children per 100 000 per year (95% CI 4 to 26) relative to the 2004-2006 trend. CONCLUSIONS:The dramatic increase in the rate of children starting to be looked after has been greater in poorer areas and in areas more deeply affected by recession. But trends in unemployment do not explain the decade-long rise in inequalities, suggesting that other socioeconomic factors, including rising child poverty and reduced spending on children's services, may be fuelling inequalities. Policies to safely reduce the CLA rate should urgently address the social determinants of child health and well-being