Implementing evidence-based recommended practices for the management of patients with mild traumatic brain injuries in Australian emergency care departments: study protocol for a cluster randomised controlled trial

Background: Mild head injuries commonly present to emergency departments. The challenges facing clinicians in emergency departments include identifying which patients have traumatic brain injury, and which patients can safely be sent home. Traumatic brain injuries may exist with subtle symptoms or signs, but can still lead to adverse outcomes. Despite the existence of several high quality clinical practice guidelines, internationally and in Australia, research shows inconsistent implementation of these recommendations. The aim of this trial is to test the effectiveness of a targeted, theory- and evidence-informed implementation intervention to increase the uptake of three key clinical recommendations regarding the emergency department management of adult patients (18 years of age or older) who present following mild head injuries (concussion), compared with passive dissemination of these recommendations. The primary objective is to establish whether the intervention is effective in increasing the percentage of patients for which appropriate post-traumatic amnesia screening is performed. Methods/design: The design of this study is a cluster randomised trial. We aim to include 34 Australian 24-hour emergency departments, which will be randomised to an intervention or control group. Control group departments will receive a copy of the most recent Australian evidence-based clinical practice guideline on the acute management of patients with mild head injuries. The intervention group will receive an implementation intervention based on an analysis of influencing factors, which include local stakeholder meetings, identification of nursing and medical opinion leaders in each site, a train-the-trainer day and standardised education and interactive workshops delivered by the opinion leaders during a 3 month period of time. Clinical practice outcomes will be collected retrospectively from medical records by independent chart auditors over the 2 month period following intervention delivery (patient level outcomes). In consenting hospitals, eligible patients will be recruited for a follow-up telephone interview conducted by trained researchers. A cost-effectiveness analysis and process evaluation using mixed-methods will be conducted. Sample size calculations are based on including 30 patients on average per department. Outcome assessors will be blinded to group allocation

A Peptidomimetic Ligand Targeting the Chromodomain of MPP8 Reveals HRP2's Association with the HUSH Complex

The interpretation of histone post-translational modifications (PTMs), specifically lysine methylation, by specific classes of "reader"proteins marks an important aspect of epigenetic control of gene expression. Methyl-lysine (Kme) readers often regulate gene expression patterns through the recognition of a specific Kme PTM while participating in or recruiting large protein complexes that contain enzymatic or chromatin remodeling activity. Understanding the composition of these Kme-reader-containing protein complexes can serve to further our understanding of the biological roles of Kme readers, while small molecule chemical tools can be valuable reagents in interrogating novel protein-protein interactions. Here, we describe our efforts to target the chromodomain of M-phase phosphoprotein 8 (MPP8), a member of the human silencing hub (HUSH) complex and a histone 3 lysine 9 trimethyl (H3K9me3) reader that is vital for heterochromatin formation and has specific roles in cancer metastasis. Utilizing a one-bead, one-compound (OBOC) combinatorial screening approach, we identified UNC5246, a peptidomimetic ligand capable of interacting with the MPP8 chromodomain in the context of the HUSH complex. Additionally, a biotinylated derivative of UNC5246 facilitated chemoproteomics studies which revealed hepatoma-derived growth factor-related protein 2 (HRP2) as a novel protein associated with MPP8. HRP2 was further shown to colocalize with MPP8 at the E-cadherin gene locus, suggesting a possible role in cancer cell plasticity

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes

Seasonality and spatial heterogeneity of the surface ocean carbonate system in the northwest European continental shelf

In 2014–5 the UK NERC sponsored an 18 month long Shelf Sea Biogeochemistry research programme which collected over 1500 nutrient and carbonate system samples across the NW European Continental shelf, one of the largest continental shelves on the planet. This involved the cooperation of 10 different Institutes and Universities, using 6 different vessels. Additional carbon dioxide (CO2) data were obtained from the underway systems on three of the research vessels. Here, we present and discuss these data across 9 ecohydrodynamic regions, adapted from those used by the EU Marine Strategy Framework Directive (MSFD). We observed strong seasonal and regional variability in carbonate chemistry around the shelf in relation to nutrient biogeochemistry. Whilst salinity increased (and alkalinity decreased) out from the near-shore coastal waters offshore throughout the year nutrient concentrations varied with season. Spatial and seasonal variations in the ratio of DIC to nitrate concentration were seen that could impact carbon cycling. A decrease in nutrient concentrations and a pronounced under-saturation of surface pCO2 was evident in the spring in most regions, especially in the Celtic Sea. This decrease was less pronounced in Liverpool Bay and to the North of Scotland, where nutrient concentrations remained measurable throughout the year. The near-shore and relatively shallow ecosystems such as the eastern English Channel and southern North Sea were associated with a thermally driven increase in pCO2 to above atmospheric levels in summer and an associated decrease in pH. Non-thermal processes (such as mixing and the remineralisation of organic material) dominated in winter in most regions but especially in the northwest of Scotland and in Liverpool Bay. The large database collected will improve understanding of carbonate chemistry over the North-Western European Shelf in relation to nutrient biogeochemistry, particularly in the context of climate change and ocean acidification

Is local alcohol outlet density related to alcohol-related morbidity and mortality in Scottish cities?

Alcohol consumption may be influenced by the local alcohol retailing environment. This study is the first to examine neighbourhood alcohol outlet availability (on- and off-sales outlets) and alcohol-related health outcomes in Scotland. Alcohol-related hospitalisations and deaths were significantly higher in neighbourhoods with higher outlet densities, and off-sales outlets were more important than on-sales outlets. The relationships held for most age groups, including those under the legal minimum drinking age, although were not significant for the youngest legal drinkers (18–25 years). Alcohol-related deaths and hospitalisations were higher in more income-deprived neighbourhoods, and the gradient in deaths (but not hospitalisations) was marginally larger in neighbourhoods with higher off-sales outlet densities. Efforts to reduce alcohol-related harm should consider the potentially important role of the alcohol retail environment

Comparison of the impacts of elevated CO₂ soil gas concentrations on selected European terrestrial environments

Selected European studies have illustrated the impacts of elevated CO₂ concentrations in shallow soils on pasture. For the first time, general unified conclusions can be made, providing CO₂ thresholds where effects on plants and soil microbiology are observed and making recommendations on how this information can be used when planning projects for CO₂ storage. The sites include those where CO₂ is being naturally released to the atmosphere from deep geological formations; and a non-adapted site, with no previous history of CO₂ seepage, where CO₂ has been injected into the unsaturated soil horizon. Whilst soil gas concentrations will be influenced by flux rates and other factors, the results suggest that a concentration of between 10% and 15% CO₂ soil gas at 20 cm depth, which is within the root zone, is an important threshold level for observing changes in plant coverage. Site-specific plant ‘indicators’ are also observed for CO₂ concentrations at ≥35%. Microbiological changes are seen where CO₂ soil gas concentrations are between 15% and 40%. As part of site characterisation, an evaluation of the risks of leakage and their potential environmental impacts should be undertaken

The SPECTRUM Consortium: a new UK Prevention Research Partnership consortium focussed on the commercial determinants of health, the prevention of non-communicable diseases, and the reduction of health inequalities

The main causes of non-communicable diseases (NCDs), health inequalities and health inequity include consumption of unhealthy commodities such as tobacco, alcohol and/or foods high in fat, salt and/or sugar. These exposures are preventable, but the commodities involved are highly profitable. The economic interests of ‘Unhealthy Commodity Producers’ (UCPs) often conflict with health goals but their role in determining health has received insufficient attention. In order to address this gap, a new research consortium has been established. This open letter introduces the SPECTRUM (Shaping Public hEalth poliCies To Reduce ineqUalities and harM) Consortium: a multi-disciplinary group comprising researchers from 10 United Kingdom (UK) universities and overseas, and partner organisations including three national public health agencies in Great Britain (GB), five multi-agency alliances and two companies providing data and analytic support. Through eight integrated work packages, the Consortium seeks to provide an understanding of the nature of the complex systems underlying the consumption of unhealthy commodities, the role of UCPs in shaping these systems and influencing health and policy, the role of systems-level interventions, and the effectiveness of existing and emerging policies. Co-production is central to the Consortium’s approach to advance research and achieve meaningful impact and we will involve the public in the design and delivery of our research. We will also establish and sustain mutually beneficial relationships with policy makers, alongside our partners, to increase the visibility, credibility and impact of our evidence. The Consortium’s ultimate aim is to achieve meaningful health benefits for the UK population by reducing harm and inequalities from the consumption of unhealthy commodities over the next five years and beyond

Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: A systematic analysis for the Global Burden of Disease Study 2015

Background: The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. Methods: We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors—the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). Findings: Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6–58·8) of global deaths and 41·2% (39·8–42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to 163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI (120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to 123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high total cholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7 million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high in sodium (83·0 million [49·3 million to 127·5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. Interpretation: Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. Funding: Bill & Melinda Gates Foundation