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Although the primary protein sequence of ubiquitin (Ub) is extremely stable over evolutionary time, it is highly tolerant to mutation during selection experiments performed in the laboratory. We have proposed that this discrepancy results from the difference between fitness under laboratory culture conditions and the selective pressures in changing environments over evolutionary timescales. Building on our previous work (Mavor et al., 2016), we used deep mutational scanning to determine how twelve new chemicals (3-Amino-1,2,4-triazole, 5-fluorocytosine, Amphotericin B, CaCl2, Cerulenin, Cobalt Acetate, Menadione, Nickel Chloride, p-Fluorophenylalanine, Rapamycin, Tamoxifen, and Tunicamycin) reveal novel mutational sensitivities of ubiquitin residues. Collectively, our experiments have identified eight new sensitizing conditions for Lys63 and uncovered a sensitizing condition for every position in Ub except Ser57 and Gln62. By determining the ubiquitin fitness landscape under different chemical constraints, our work helps to resolve the inconsistencies between deep mutational scanning experiments and sequence conservation over evolutionary timescales.

Although the primary protein sequence of ubiquitin (Ub) is extremely stable over evolutionary time, it is highly tolerant to mutation during selection experiments performed in the laboratory. We have proposed that this discrepancy results from the difference between fitness under laboratory culture conditions and the selective pressures in changing environments over evolutionary time scales. Building on our previous work (Mavor et al. 2016), we used deep mutational scanning to determine how twelve new chemicals reveal novel mutational sensitivities of ubiquitin residues. We found sensitization of Lys63 in eight new conditions. In total, our experiments have uncovered a highly sensitizing condition for every position in Ub except Ser57 and Gln62. By determining the Ubiquitin fitness landscape under different chemical constraints, our work helps to resolve the inconsistencies between deep mutational scanning experiments and sequence conservation over evolutionary timescales.

There is no single generally accepted clinical definition of frailty. Previously developed tools to assess frailty that have been shown to be predictive of death or need for entry into an institutional facility have not gained acceptance among practising clinicians. We aimed to develop a tool that would be both predictive and easy to use. We developed the 7-point Clinical Frailty Scale and applied it and other established tools that measure frailty to 2305 elderly patients who participated in the second stage of the Canadian Study of Health and Aging (CSHA). We followed this cohort prospectively; after 5 years, we determined the ability of the Clinical Frailty Scale to predict death or need for institutional care, and correlated the results with those obtained from other established tools. The CSHA Clinical Frailty Scale was highly correlated (r = 0.80) with the Frailty Index. Each 1-category increment of our scale significantly increased the medium-term risks of death (21.2% within about 70 mo, 95% confidence interval [CI] 12.5%-30.6%) and entry into an institution (23.9%, 95% CI 8.8%-41.2%) in multivariable models that adjusted for age, sex and education. Analyses of receiver operating characteristic curves showed that our Clinical Frailty Scale performed better than measures of cognition, function or comorbidity in assessing risk for death (area under the curve 0.77 for 18-month and 0.70 for 70-month mortality). Frailty is a valid and clinically important construct that is recognizable by physicians. Clinical judgments about frailty can yield useful predictive information.

The workshops that supported the writing of this manuscript were funded by the Swedish Foundation for Strategic Environmental Research “Mistra”. LNV was funded by Award Number K22ES025811 from the National Institute of Environmental Health Sciences of the National Institutes of Health. TJW was funded by The Clarence Heller Foundation (A123547), the Passport Foundation, the Forsythia Foundation, the National Institute of Environmental Health Sciences (grants ES018135 and ESO22841), and U.S. EPA STAR grants (RD83467801 and RD83543301). JT was funded by the Academy of Finland and Sigrid Juselius. UH was funded by the Danish EPA. KAK was funded by the Canada Research Chairs program grant number 950–230607.

Intratumor heterogeneity is an important mediator of poor outcomes in many cancers, including breast cancer. Genetic subclones frequently contribute to this heterogeneity; however, their growth dynamics and interactions remain poorly understood. PIK3CA and HER2 alterations are known to coexist in breast and other cancers. Herein, we present data that describe the ability of oncogenic PIK3CA mutant cells to induce the proliferation of quiescent HER2 mutant cells through a cell contact-mediated mechanism. Interestingly, the HER2 cells proliferated to become the major subclone over PIK3CA counterparts both in vitro and in vivo. Furthermore, this phenotype was observed in both hormone receptor-positive and -negative cell lines, and was dependent on the expression of fibronectin from mutant PIK3CA cells. Analysis of human tumors demonstrated similar HER2:PIK3CA clonal dynamics and fibronectin expression. Our study provides insight into nonrandom subclonal architecture of heterogenous tumors, which may aid the understanding of tumor evolution and inform future strategies for personalized medicine.

A suite of analyses was performed on sediments accumulated during the last 10 700 years in Lake Spaime, a small, hydrologically open water body in the modem alpine tundra zone of the Scandes Mountains, west-central Sweden. The study aimed to evaluate (1) the nature of climate changes that forced the late-Holocene lowering of altitudinal tree limit in the region, the timing of which is known from prior studies based on radiocarbon dating of subfossil wood, and (2) the impact of these vegetational changes on an aquatic ecosystem. Arboreal pollen and plant macrofossil data confirm the persistence of trees in the lake catchment at least from c. 9700 cal. BP until c. 3700 cal. BP. Although growing-season temperature is commonly believed to be the dominant factor driving boreal forest tree-limit variations in the region, a chironomid-based reconstruction of mean July air temperature suggests that local deforestation during the late Holocene was not accompanied by a significant cooling. The tree-limit retreat was more likely caused by increasing effective moisture and declining length of the growing season. The ecohydrological response of Lake Spaime to this combination of climate and vegetational changes included a decline in primary productivity, as indicated by an abrupt decrease in sediment organic matter content, while associated increases in organic 613C, 615N and C/N point to diminished fluxes and altered balance of catchment derived nutrients following deforestation. The decline in aquatic productivity is also marked by a distinct change in the mineral magnetic properties, from a high magnetic concentration assemblage dominated by fine-grained magnetite of biogenic origin to one dominated by background levels of coarse-grained detrital magnetite.

Table of contents I1: Trauma, Pre-hospital and Cardiac Arrest Care 2015 Pascale Avery, Leopold Salm, Flora Bird A1: Retrospective evaluation of HEMS ‘Direct to CT’ protocol Anja Hutchinson, Ashley Matthies, Anthony Hudson, Heather Jarman A2 Rush hour – Crush hour: temporal relationship of cyclist vs. HGV trauma admissions. A single site observational study Maria Bergman Nilsson, Tom Konig, Nigel Tai A3 Semiprone position endotracheal intubation during continuous cardiopulmonary resuscitation in drowned children with regurgitation: a case report and experimental manikin study Espen Fevang, Børge Hognestad, Håkon B. Abrahamsen A4 An audit of CO2 A-a gradient in non-trauma patients receiving pre-hospital anaesthesia Olivia V Cheetham, Matthew JC Thomas, Kieron D Rooney A5 Can the use of c-spine immobilisation collars be avoided in non-trauma patients presenting to the Emergency Department? Josephine Murray, Malcolm Tunnicliff A6 Curriculum mapping in ED point of care simulation Joseph W Collinson, Thomas Brown, Christopher Pritchett A7 Point of care multidisciplinary trauma team simulation & participant satisfaction in a geographically remote trauma unit in Cornwall Christopher SA Pritchett, Mark Jadav, Gareth Meredith, Jamie Plumb, Steve Harris, Roger Langford A8 Conservative management of head injury inpatients - the challenge of simplifying injury management in a non-neurosurgical hospital JG Hunter, A Sage, R Madden, O Flamank, B Broadbent, S Marsh, H Lewis, E Daniels, N Roberts A9 Improving the care of traumatic brain injury at non-neurosurgical hospitals: Introducing a head injury pathway and single place of care is associated with significant improvements in neurological observation JG Hunter, A Sage, R Madden, O Flamank, B Broadbent, S Marsh, H Lewis, E Daniels, N Lin, N Roberts A10 The experience of inter-disciplinary students undertaking cardiac arrest moulage training Samuel Bulford, Silas Houghton-Budd, Sam Pearson, Megan Clear-Hill A11 Impact brain apnoea – nine cases David J Menzies, James P Leonard, Conor Keogh, Ray Quinn, John D Hinds A12 Time well spent? Improving the performance improvement programme in a busy Trauma Unit N Roberts, D Ashton-Cleary, M Jadav A14 Clinical significant and outcome of pulmonary contusions in patients with blunt chest trauma Ismail Mahmood, Ayman El-Menyar, Basil Younis, Ahmed Khalid, Syed Nabir, Mohamed Nadeem Ahmed, Omer Al-Yahri, Hassan Al-Thani A15 Plastics operative workload in major trauma centres: a national prospective survey Katie Young, Susan A. Hendrickson, Georgina Phillips, Matthew D. Gardiner, Shehan Hettiaratchy A16 A survey to assess the accuracy of estimating height by pre-hospital clinicians: can we reliably predict those most at risk of serious injury? Alexandra Alice Crossland, Anthony Hudson A17 An audit of the cause, outcome and adherence to treatment Standard Operating Procedure (SOP) for all traumatic cardiac arrests at a Helicopter Emergency Medical Service over a 12-month period Nicholas C Brassington, Anthony Hudson, Emily McWhirter A18 Should we “stay-and-play? A study of patient physiology in Norwegian Helicopter Emergency Services Bjørn O Reid, Marius Rehn, Oddvar Uleberg, Andreas J Krüger A19 Training in resuscitative thoracotomy: have we cracked it? A survey of higher Emergency Medicine trainees in London Cara Jennings, Yasmin Kapadia, Duncan Bew A20 London’s Air Ambulance (LAA): 25-years of drownings in an urban environment Jenny Townsend, Tom P Hurst, Elizabeth A Foster A21 Live patients in trauma simulation – more than just simulation on a shoestring? Thomas B Brown, Joseph Collinson, Christopher Pritchett, Toby Slade A22 Collecting core data in pre-hospital critical care using a consensus based template Kristin Tønsager, Marius Rehn, Kjetil G.Ringdal, Andreas J.Krüger A23 Prehospital interventions before and after implementation of a physician staffed helicopter Rasmus Hesselfeldt, Sandra Wulffeld, Asger Sonne, Lars S. Rasmussen, Jacob Steinmetz A24 Duration of ventilation following prehospital drug assisted intubation; a retrospective review Thomas J Renninson, Nadine Thomson, Harvey Pynn, Timothy J Hooper A25 Non-haemorrhagic shock in trauma: a novel guideline for management in ED Anthony Hudson, Jacinta Dawson, Ashley Matthies A26 Patient-tailored triage decisions by anaesthetist-staffed pre-hospital critical care teams Morten Langfeldt Friberg, Leif Rognås A27 Anatomical accuracy and appropriate sizing of pre-hospital thoracostomies Jessica FG Wills, Anthony Hudson A28 Pre-hospital management of mass casualty civilian shootings Conor DA Turner, Marius Rehn A30 The prevalence of alcohol-related trauma recidivism: a systematic review James Nunn, Mete Erdogan, Robert S. Green A31 Development of a hospital-wide program for simulation-based training in trauma care and management Samuel Minor, Mete Erdogan, Kathy Hartlen, Robert S. Green A32 Out of Hospital Cardiac Arrests (OOHCA); lessons from Hollywood Ruth Bird, Rachael L. Grupping A33 Mechanism of injury as a predictor of severity of injury in road traffic collisions: a literature review Amelia M. Stacey, Marius Rehn, David J. Lockey A34 Lessons to be learned from prehospital airway intervention documentation? Are airway intervention documentation templates as successful in-hospital as prehospitally? S. Abiks, L. Cutler, K. Monaghan, A. Al-Rais, C. Hymers, R. Bloomer, Y. Kapadia A35 Novel biomarkers in pre hospital management of t raumatic b rain i njury (the PreTBI study protocol) Sophie-Charlott Seidenfaden, Ingunn S. Riddervold, Hans Kirkegaard, Niels Juul, Morten T. Bøtker A36 Hospital outcomes of traumatic railway incidents: a seven-year observational retrospective study of a major trauma centre Alice Gao, Zane Perkins; Gareth Grier, Alex Tzannes A37 Does taking a third crew member affect the on-scene time of HEMS jobs? Nathan Hudson-Peacock, Quentin Otto, Laurie Phillipson, Rik Thomas, Ainsley Heyworth A38 Does pre-hospital rapid sequence induction affect on-scene time of HEMS jobs? Quentin Otto, Nathan Hudson-Peacock, Laurie Phillipson, Ainsley Heyworth, Erica Ley A39 Code red: shock index as a prehospital indicator of massive haemorrhage Daniel Banner, Ainsley Heyworth, Erica Ley A40 Air ambulance tasking: how accurate are our current methods? Madeleine Benson, Nathan Hudson-Peacock, Tony Stone, Erica Ley, Louise Rousson, Ainsley Heyworth A41 Modern trauma burden in a district general hospital Beth A Lineham, Matthew J Lee, Martin Gough A42 Establishing a legal service for major trauma patients in two UK major trauma centres William H Seligman, Hannah E Thould, Andrew Dinsmore, Charlotte Tan, Julian Thompson, C Andy Eynon, David J Lockey A43 Prehospital assessment and care of patients – a study of the use of guidelines when assessing head trauma Rebecka M Rubenson Wahlin, Veronica Lindström, Sari Ponzer, Veronica Vicente A44 An audit of pre-hospital blood pressure management resulting from head injury Pamela Eligio, Anthony Hudson A45 The surgical contribution of surface shading volumetric rendering techniques in rib fracture management Robert Young, Dimitri Amiras, Ian Sinha

Carrier lifetime measurements and wafer mappings have been done on several different 4H SiC epiwafers to compare two different measurement techniques, time-resolved photoluminescence and microwave induced photoconductivity decay. The absolute values of the decay time differ by a factor of two, as expected from recombination and measurement theory. Variations within each wafer are comparable with the two techniques. Both techniques are shown to be sensitive to substrate quality and distribution of extended defects.

Personalized genome sequencing has revealed millions of genetic differences between individuals, but our understanding of their clinical relevance remains largely incomplete. To systematically decipher the effects of human genetic variants, we obtained whole genome sequencing data for 809 individuals from 233 primate species, and identified 4.3 million common protein-altering variants with orthologs in human. We show that these variants can be inferred to have non-deleterious effects in human based on their presence at high allele frequencies in other primate populations. We use this resource to classify 6% of all possible human protein-altering variants as likely benign and impute the pathogenicity of the remaining 94% of variants with deep learning, achieving state-of-the-art accuracy for diagnosing pathogenic variants in patients with genetic diseases. Deep learning classifier trained on 4.3 million common primate missense variants predicts variant pathogenicity in humans.