Healthy early years settings: a scoping study

This briefing paper considers the diversity in early years provision. It was produced for the Healthy Early Years study, which was funded by the Department of Health, to help inform decisions about extending the Healthy Schools Programme approach to early years settings. The paper focuses on childcare and early education provision for children aged from birth to five years: maintained and private nursery schools, Sure Start local programmes, children's centres, day nurseries, pre-school playgroups and childminders. An overview of the relevant issues and of the distinguishing features of each type of setting is provided

Cannabis and depression: A twin model approach to co-morbidity

Cannabis use disorder (CUD) co-occurs with major depressive disorder (MDD) more frequently than would be expected by chance. However, studies to date have not produced a clear understanding of the mechanisms underlying this co-morbidity. Genetically informative studies can add valuable insight to this problem, as they allow the evaluation of competing models of co-morbidity. This study uses data from the Australian Twin Registry to compare 13 co-morbidity twin models initially proposed by Neale and Kendler (Am J Hum Genet 57:935–953, 1995). The analysis sample comprised 2410 male and female monozygotic and dizygotic twins (average age 32) who were assessed on CUD and MDD using the SSAGA-OZ interview. Data were analyzed in OpenMx. Of the 13 different co-morbidity models, two fit equally well: CUD causes MDD and Random Multiformity of CUD. Both fit substantially better than the Correlated Liabilities model. Although the current study cannot differentiate between them statistically, these models, in combination, suggest that CUD risk factors may causally influence the risk to develop MDD, but only when risk for CUD is high

Overlap of heritable influences between Cannabis Use Disorder, frequency of use and opportunity to use cannabis: Trivariate twin modelling and implications for genetic design

Background: The genetic component of Cannabis Use Disorder may overlap with influences acting more generally on early stages of cannabis use. This paper aims to determine the extent to which genetic influences on the development of cannabis abuse/dependence are correlated with those acting on the opportunity to use cannabis and frequency of use. Methods: A cross-sectional study of 3303 Australian twins, measuring age of onset of cannabis use opportunity, lifetime frequency of cannabis use, and lifetime DSM-IV cannabis abuse/dependence. A trivariate Cholesky decomposition estimated additive genetic (A), shared environment (C) and unique environment (E) contributions to the opportunity to use cannabis, the frequency of cannabis use, cannabis abuse/dependence, and the extent of overlap between genetic and environmental factors associated with each phenotype. Results: Variance components estimates were A = 0.64 [95% confidence interval (CI) 0.58–0.70] and E = 0.36 (95% CI 0.29–0.42) for age of opportunity to use cannabis, A = 0.74 (95% CI 0.66–0.80) and E = 0.26 (95% CI 0.20–0.34) for cannabis use frequency, and A = 0.78 (95% CI 0.65–0.88) and E = 0.22 (95% CI 0.12–0.35) for cannabis abuse/dependence. Opportunity shares 45% of genetic influences with the frequency of use, and only 17% of additive genetic influences are unique to abuse/dependence from those acting on opportunity and frequency. Conclusions: There are significant genetic contributions to lifetime cannabis abuse/dependence, but a large proportion of this overlaps with influences acting on opportunity and frequency of use. Individuals without drug use opportunity are uninformative, and studies of drug use disorders must incorporate individual exposure to accurately identify aetiology

Scan-Negative Cauda Equina Syndrome A Prospective Cohort Study

Objective: To describe clinical features relevant to diagnosis, mechanism, and etiology in patients with “scan-negative” cauda equina syndrome (CES). Methods: We carried out a prospective study of consecutive patients presenting with the clinical features of CES to a regional neurosurgery center comprising semi-structured interview and questionnaires investigating presenting symptoms, neurologic examination, psychiatric and functional disorder comorbidity, bladder/bowel/sexual function, distress, and disability. Results: A total of 198 patients presented consecutively over 28 months. A total of 47 were diagnosed with scan-positive CES (mean age 48 years, 43% female). A total of 76 mixed category patients had nerve root compression/displacement without CES compression (mean age 46 years, 71% female) and 61 patients had scan-negative CES (mean age 40 years, 77% female). An alternative neurologic cause of CES emerged in 14/198 patients during admission and 4/151 patients with mean duration 25 months follow-up. Patients with scan-negative CES had more positive clinical signs of a functional neurologic disorder (11% scan-positive CES vs 34% mixed and 68% scan-negative, p < 0.0001), were more likely to describe their current back pain as worst ever (41% vs 46% and 70%, p = 0.005), and were more likely to have symptoms of a panic attack at onset (37% vs 57% and 70%, p = 0.001). Patients with scan-positive CES were more likely to have reduced/absent bilateral ankle jerks (78% vs 30% and 12%, p < 0.0001). There was no significant difference between groups in the frequency of reduced anal tone and urinary retention. Conclusion: The first well-phenotyped, prospective study of scan-negative CES supports a model in which acute pain, medication, and mechanisms overlapping with functional neurologic disorders may be relevant

Acetylation of H2A.Z is a key epigenetic modification associated with gene deregulation and epigenetic remodeling in cancer

Histone H2A.Z (H2A.Z) is an evolutionarily conserved H2A variant implicated in the regulation of gene expression; however, its role in transcriptional deregulation in cancer remains poorly understood. Using genome-wide studies, we investigated the role of promoter-associated H2A.Z and acetylated H2A.Z (acH2A.Z) in gene deregulation and its relationship with DNA methylation and H3K27me3 in prostate cancer. Our results reconcile the conflicting reports of positive and negative roles for histone H2A.Z and gene expression states. We find that H2A.Z is enriched in a bimodal distribution at nucleosomes, surrounding the transcription start sites (TSSs) of both active and poised gene promoters. In addition, H2A.Z spreads across the entire promoter of inactive genes in a deacetylated state. In contrast, acH2A.Z is only localized at the TSSs of active genes. Gene deregulation in cancer is also associated with a reorganization of acH2A.Z and H2A.Z nucleosome occupancy across the promoter region and TSS of genes. Notably, in cancer cells we find that a gain of acH2A.Z at the TSS occurs with an overall decrease of H2A.Z levels, in concert with oncogene activation. Furthermore, deacetylation of H2A.Z at TSSs is increased with silencing of tumor suppressor genes. We also demonstrate that acH2A.Z anti-correlates with promoter H3K27me3 and DNA methylation. We show for the first time, that acetylation of H2A.Z is a key modification associated with gene activity in normal cells and epigenetic gene deregulation in tumorigenesis

Genetic aetiology of self-harm ideation and behaviour

Family studies have identified a heritable component to self-harm that is partially independent from comorbid psychiatric disorders. However, the genetic aetiology of broad sense (non-suicidal and suicidal) self-harm has not been characterised on the molecular level. In addition, controversy exists about the degree to which suicidal and non-suicidal self-harm share a common genetic aetiology. In the present study, we conduct genome-wide association studies (GWAS) on lifetime self-harm ideation and self-harm behaviour (i.e. any lifetime self-harm act regardless of suicidal intent) using data from the UK Biobank (n > 156,000). We also perform genome wide gene-based tests and characterize the SNP heritability and genetic correlations between these traits. Finally, we test whether polygenic risk scores (PRS) for self-harm ideation and self-harm behaviour predict suicide attempt, suicide thoughts and non-suicidal self-harm (NSSH) in an independent target sample of 8,703 Australian adults. Our GWAS results identified one genome-wide significant locus associated with each of the two phenotypes. SNP heritability (h) estimates were ~10%, and both traits were highly genetically correlated (LDSC r > 0.8). Gene-based tests identified seven genes associated with self-harm ideation and four with self-harm behaviour. Furthermore, in the target sample, PRS for self-harm ideation were significantly associated with suicide thoughts and NSSH, and PRS for self-harm behaviour predicted suicide thoughts and suicide attempt. Follow up regressions identified a shared genetic aetiology between NSSH and suicide thoughts, and between suicide thoughts and suicide attempt. Evidence for shared genetic aetiology between NSSH and suicide attempt was not statistically significant

Presentation, management, and outcomes of cauda equina syndrome up to one year after surgery, using clinician and participant reporting: A multi-centre prospective cohort study.

BACKGROUND: Cauda equina syndrome (CES) results from nerve root compression in the lumbosacral spine, usually due to a prolapsed intervertebral disc. Evidence for management of CES is limited by its infrequent occurrence and lack of standardised clinical definitions and outcome measures. METHODS: This is a prospective multi-centre observational cohort study of adults with CES in the UK. We assessed presentation, investigation, management, and all Core Outcome Set domains up to one year post-operatively using clinician and participant reporting. Univariable and multivariable associations with the Oswestry Disability Index (ODI) and urinary outcomes were investigated. FINDINGS: In 621 participants with CES, catheterisation for urinary retention was required pre-operatively in 31% (191/615). At discharge, only 13% (78/616) required a catheter. Median time to surgery from symptom onset was 3 days (IQR:1-8) with 32% (175/545) undergoing surgery within 48 h. Earlier surgery was associated with catheterisation (OR:2.2, 95%CI:1.5-3.3) but not with admission ODI or radiological compression. In multivariable analyses catheter requirement at discharge was associated with pre-operative catheterisation (OR:10.6, 95%CI:5.8-20.4) and one-year ODI was associated with presentation ODI (r = 0.3, 95%CI:0.2-0.4), but neither outcome was associated with time to surgery or radiological compression. Additional healthcare services were required by 65% (320/490) during one year follow up. INTERPRETATION: Post-operative functional improvement occurred even in those presenting with urinary retention. There was no association between outcomes and time to surgery in this observational study. Significant healthcare needs remained post-operatively. FUNDING: DCN Endowment Fund funded study administration. Castor EDC provided database use. No other study funding was received

Evaluation of nationwide referral pathways, investigation and treatment of suspected cauda equina syndrome in the United Kingdom.

Purpose: Cauda equina syndrome (CES) is a spinal emergency with clinical symptoms and signs that have low diagnostic accuracy. National guidelines in the United Kingdom (UK) state that all patients should undergo an MRI prior to referral to specialist spinal units and surgery should be performed at the earliest opportunity. We aimed to evaluate the current practice of investigating and treating suspected CES in the UK. Materials and Methods: A retrospective, multicentre observational study of the investigation and management of patients with suspected CES was conducted across the UK, including all patients referred to a spinal unit over 6 months between 1st October 2016 and 31st March 2017. Results: A total of 28 UK spinal units submitted data on 4441 referrals. Over half of referrals were made without any previous imaging (n = 2572, 57.9%). Of all referrals, 695 underwent surgical decompression (15.6%). The majority of referrals were made out-of-hours (n = 2229/3517, 63.4%). Patient location and pre-referral imaging were not associated with time intervals from symptom onset or presentation to decompression. Patients investigated outside of the spinal unit experienced longer time intervals from referral to undergoing the MRI scan. Conclusions: This is the largest known study of the investigation and management of suspected CES. We found that the majority of referrals were made without adequate investigations. Most patients were referred out-of-hours and many were transferred for an MRI without subsequently requiring surgery. Adherence to guidelines would reduce the number of referrals to spinal services by 72% and reduce the number of patient transfers by 79%

Climatically sensitive transfer of iron to maritime Antarctic ecosystems by surface runoff

Iron supplied by glacial weathering results in pronounced hotspots of biological production in an otherwise iron-limited Southern Ocean Ecosystem. However, glacial iron inputs are thought to be dominated by icebergs. Here we show that surface runoff from three island groups of the maritime Antarctic exports more filterable (<0.45 μm) iron (6–81 kg km−2 a−1) than icebergs (0.0–1.2 kg km−2 a−1). Glacier-fed streams also export more acid-soluble iron (27.0–18,500 kg km−2 a−1) associated with suspended sediment than icebergs (0–241 kg km−2 a−1). Significant fluxes of filterable and sediment-derived iron (1–10 Gg a−1 and 100–1,000 Gg a−1, respectively) are therefore likely to be delivered by runoff from the Antarctic continent. Although estuarine removal processes will greatly reduce their availability to coastal ecosystems, our results clearly indicate that riverine iron fluxes need to be accounted for as the volume of Antarctic melt increases in response to 21st century climate change