How many children and young people with life-limiting conditions are clinically unstable? A national data linkage study

Objective: To determine the clinical stage (stable, unstable, deteriorating or dying) for children and young people (CYP) aged 0-25 years in Scotland with lifelimiting conditions (LLCs). Design: National cohort of CYP with LLCs using linked routinely collected healthcare data. Setting: Scotland. Patients: 20 436 CYP identified as having LLCs and resident in Scotland between 1 April 2009 and 31 March 2014. Main outcome: Clinical stage based on emergency inpatient and intensive care unit admissions and date of death. Results: Over 2200 CYP with LLCs in Scotland were unstable, deteriorating or dying in each year. Compared with 1-year-olds to 5-year-olds, children under 1 year of age had the highest risk of instability (OR 6.4, 95% CI 5.7 to 7.1); all older age groups had lower risk. Girls were more likely to be unstable than boys (OR 1.15, 95% CI 1.06 to 1.24). CYP of South Asian (OR 1.61, 95% CI 1.28 to 2.01), Black (OR 1.58, 95% CI 1.04 to 2.41) and Other (OR 1.33, 95% CI 1.02 to 1.74) ethnicity were more likely to experience instability than White CYP. Deprivation was not a significant predictor of instability. Compared with congenital abnormalities, CYP with most other primary diagnoses had a higher risk of instability; only CYP with a primary perinatal diagnosis had significantly lower risk (OR 0.23, 95% CI 0.19 to 0.29). Conclusions: The large number of CYP with LLCs who are unstable, deteriorating or dying may benefit from input from specialist paediatric palliative care. The age group under 1 and CYP of South Asian, Black and Other ethnicities should be priority groups

Evolution and Impact of High Content Imaging

Abstract/outline: The field of high content imaging has steadily evolved and expanded substantially across many industry and academic research institutions since it was first described in the early 1990′s. High content imaging refers to the automated acquisition and analysis of microscopic images from a variety of biological sample types. Integration of high content imaging microscopes with multiwell plate handling robotics enables high content imaging to be performed at scale and support medium- to high-throughput screening of pharmacological, genetic and diverse environmental perturbations upon complex biological systems ranging from 2D cell cultures to 3D tissue organoids to small model organisms. In this perspective article the authors provide a collective view on the following key discussion points relevant to the evolution of high content imaging:• Evolution and impact of high content imaging: An academic perspective• Evolution and impact of high content imaging: An industry perspective• Evolution of high content image analysis• Evolution of high content data analysis pipelines towards multiparametric and phenotypic profiling applications• The role of data integration and multiomics• The role and evolution of image data repositories and sharing standards• Future perspective of high content imaging hardware and softwar

Numerical simulation of a patent technology for sealing of deep-sea oil wells using nonlinear finite element method

For over 50 years bridge plugs and cement have been used for well abandonment, work over, and are still the material of choice. However, the failures of cement abandonments using bridge plugs has been reported on many occasions, some of which have resulted in fatal consequences. A new patented product is designed to address the shortcomings associated with using bridge plugs and cement. The new developed tools use an alloy based on bismuth that is melted in situ using Thermite reaction. The tool uses the expansion properties of bismuth to sea the well. Testing the new technology in real field under more than 2km deep sea water can be expensive. Virtual simulation of the new device under simulated thermal and mechanical environment can be achieved using nonlinear finite element method to validate the product and reduce cost. Experimental testing in the lab is performed to measure heat generated due to thermite reaction. Then, a sequential thermal mechanical explicit/implicit finite element solver is used to simulate the device under both testing lab and deep water conditions

Brain microenvironment-driven resistance to immune and targeted therapies in acral melanoma.

BACKGROUND: Combination treatments targeting the MEK-ERK pathway and checkpoint inhibitors have improved overall survival in melanoma. Resistance to treatment especially in the brain remains challenging, and rare disease subtypes such as acral melanoma are not typically included in trials. Here we present analyses from longitudinal sampling of a patient with metastatic acral melanoma that became resistant to successive immune and targeted therapies. METHODS: We performed whole-exome sequencing and RNA sequencing on an acral melanoma that progressed on successive immune (nivolumab) and targeted (dabrafenib) therapy in the brain to identify resistance mechanisms. In addition, we performed growth inhibition assays, reverse phase protein arrays and immunoblotting on patient-derived cell lines using dabrafenib in the presence or absence of cerebrospinal fluid (CSF) in vitro. Patient-derived xenografts were also developed to analyse response to dabrafenib. RESULTS: Immune escape following checkpoint blockade was not due to loss of tumour cell recognition by the immune system or low neoantigen burden, but was associated with distinct changes in the microenvironment. Similarly, resistance to targeted therapy was not associated with acquired mutations but upregulation of the AKT/phospho-inositide 3-kinase pathway in the presence of CSF. CONCLUSION: Heterogeneous tumour interactions within the brain microenvironment enable progression on immune and targeted therapies and should be targeted in salvage treatments

Convergent Bayesian global fits of 4D composite Higgs models

Models in which the Higgs boson is a composite pseudo-Nambu-Goldstone boson offer attractive solutions to the Higgs mass naturalness problem. We consider three such models based on the minimal SO(5) → SO(4) symmetry breaking pattern, and perform convergent global fits on the models under a Bayesian framework in order to find the regions of their parameter spaces that best fit a wide range of constraints, including recent Higgs measurements. We use a novel technique to analyse the fine-tuning of the models, quantifying the tuning as the Kullback-Leibler divergence from the prior to the posterior probability on the parameter space. Each model is found to be able to satisfy all constraints at the 3σ level simultaneously. As a by-product of the fits, we analyse the collider phenomenology of our models in these viable regions. In two of the three models, we find that the gg → H → γγ cross section is less than ∼90% that predicted by the SM, which is already in slight tension with experiment and could potentially be ruled out in the future high-luminosity run of the LHC. In addition, the lightest fermions F arising from the new strong dynamics in these models are seen in general to lie above ∼1.1 TeV, with the F → tW+ and F → b¯¯W+ decays offering particularly promising channels for probing these models in future collider searches.Ethan Carragher, Will Handley, Daniel Murnane, Peter Stangl, Wei Su, Martin White, Anthony G. William

Heterogeneity after harmonisation: a retrospective cohort study of bleeding and stroke risk after the introduction of direct oral anticoagulants in four Western European countries

Purpose: Database heterogeneity can impact effect estimates. Harmonisation provided by common protocols and common data models (CDMs) can increase the validity of pharmacoepidemiologic research. In a case study measuring the changes in the safety and effectiveness of stroke prevention therapy after the introduction of direct oral anticoagulants (DOACs), we performed an international comparison. Methods: Using data from Stockholm, Denmark, Scotland and Norway, harmonised with a common protocol and CDM, two calendar-based cohorts were created: 2012 and 2017. Patients with a diagnosis code of atrial fibrillation 5 years preceding the 1-year cohort window were included. DOAC, vitamin K antagonist and aspirin treatment were assessed in the 6 months prior to the start of each year while strokes and bleeds were assessed during the year. A Poisson regression generated incidence rate ratios (IRRs) to compare outcomes from 2017 to 2012 adjusted for changes in individual-level baseline characteristics. Results: In 280 359 patients in the 2012 cohort and 356 779 in the 2017 cohort, treatment with OACs increased on average from 45% to 65%, while treatment with aspirin decreased from 30% to 10%. In all countries except Scotland, there were decreases in the risk of stroke and no changes in bleeding risk, after adjustment for changes in baseline characteristics. In Scotland, major bleeding (IRR 1.09, 95% confidence interval [CI] [1.00; 1.18]) and intracranial haemorrhage (IRR 1.31, 95% CI [1.13; 1.52]) increased from 2012 to 2017. Conclusions: Stroke prevention therapy improved from 2012 to 2017 with a corresponding reduction in stroke risk without increasing the risk of bleeding in all countries, except Scotland. The heterogeneity that remains after methodological harmonisation can be informative of the underlying population and database

Cycling position optimisation – a systematic review of the impact of positional changes on biomechanical and physiological factors in cycling

Bike positional configuration changes strongly affect cycling performance. While consensus has emerged on saddle height optimisation, there is none for the relationship between other bike positional variables and cycling performance. Accordingly, this systematic review examines the effect of all major positional variables on performance in cycling, assessing differences between cycling disciplines and sex where possible. The systematic review, conducted per PRISMA guidelines, searched databases including Embase, Web of Science, Medline, and CINAHL, screening 16,578 studies. Of these, 47 were fully analysed. Study quality assessment using the NIH tool revealed none rated “good”, 5 “fair” and 33 “poor”. The analysis involved 724 participants (90 female, 454 male, 180 sex unstated). Studies focused on trunk angle/upper body position, handlebar height, Q factor, foot position, saddle fore-aft/height, seat tube angle and crank length. Participant cycling disciplines were often unspecified and few papers address women cyclists specifically. Key findings were associated with changing saddle height, trunk angle and saddle fore-aft. For trunk angle, accounting for the biomechanical and physiological effects as well as aerodynamic changes is important. Saddle fore-aft affects the hip angle and trunk angle. There are no clear recommendations for crank length, handlebar height, Q factor or cleat position

Influenza nucleoprotein delivered with aluminium salts protects mice from an influenza virus that expresses an altered nucleoprotein sequence

Influenza virus poses a difficult challenge for protective immunity. This virus is adept at altering its surface proteins, the proteins that are the targets of neutralizing antibody. Consequently, each year a new vaccine must be developed to combat the current recirculating strains. A universal influenza vaccine that primes specific memory cells that recognise conserved parts of the virus could prove to be effective against both annual influenza variants and newly emergent potentially pandemic strains. Such a vaccine will have to contain a safe and effective adjuvant that can be used in individuals of all ages. We examine protection from viral challenge in mice vaccinated with the nucleoprotein from the PR8 strain of influenza A, a protein that is highly conserved across viral subtypes. Vaccination with nucleoprotein delivered with a universally used and safe adjuvant, composed of insoluble aluminium salts, provides protection against viruses that either express the same or an altered version of nucleoprotein. This protection correlated with the presence of nucleoprotein specific CD8 T cells in the lungs of infected animals at early time points after infection. In contrast, immunization with NP delivered with alum and the detoxified LPS adjuvant, monophosphoryl lipid A, provided some protection to the homologous viral strain but no protection against infection by influenza expressing a variant nucleoprotein. Together, these data point towards a vaccine solution for all influenza A subtypes