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subspecies ( ) is an emerging environmental pathogen highly adapted to a wide range of niches, from treated water systems to mammalian tissues. On solid media, forms two distinct colony morphologies, smooth transparent (SmT) and smooth opaque (SmO). These colony morphologies are representative of broader differential phenotypic states in which SmT cells are virulent and have high resistance to antibiotics while SmO cells are avirulent, antibiotic-sensitive and grow faster than SmT cells in culture. Importantly, interconverts between these two morphotypes but the mechanism of SmT-SmO switching is unknown. Here we show that SmT-SmO switching is governed by a reversible transposition event that regulates expression of a periplasmic lipoprotein, Erp (extracellular repetitive protein). We found that transposition of IS , an endogenous insertion sequence, into the gene correlated with the SmT-SmO transition, and its precise removal coincided with the switch back to SmT. Genetic analyses showed that is required for maintenance of the SmT state and sufficient to drive the switch from SmO to SmT. We also identified a mutation in a periplasmic protease, MarP, that locks in the SmO state and blocks -mediated switching to SmT. Our results indicate that Erp and MarP function in a signal transduction pathway that regulates a broad transcriptional response to periplasmic stress. Moreover, identification of components that control colony morphology switching has revealed a potential new strategy for combating the inherent antibiotic resistance of infections.

Aggregates of medin amyloid (a fragment of the protein MFG-E8, also known as lactadherin) are found in the vasculature of almost all humans over 50 years of age 1 , 2 , making it the most common amyloid currently known. We recently reported that medin also aggregates in blood vessels of ageing wild-type mice, causing cerebrovascular dysfunction 3 . Here we demonstrate in amyloid-β precursor protein (APP) transgenic mice and in patients with Alzheimer’s disease that medin co-localizes with vascular amyloid-β deposits, and that in mice, medin deficiency reduces vascular amyloid-β deposition by half. Moreover, in both the mouse and human brain, MFG-E8 is highly enriched in the vasculature and both MFG-E8 and medin levels increase with the severity of vascular amyloid-β burden. Additionally, analysing data from 566 individuals in the ROSMAP cohort, we find that patients with Alzheimer’s disease have higher MFGE8 expression levels, which are attributable to vascular cells and are associated with increased measures of cognitive decline, independent of plaque and tau pathology. Mechanistically, we demonstrate that medin interacts directly with amyloid-β to promote its aggregation, as medin forms heterologous fibrils with amyloid-β, affects amyloid-β fibril structure, and cross-seeds amyloid-β aggregation both in vitro and in vivo. Thus, medin could be a therapeutic target for prevention of vascular damage and cognitive decline resulting from amyloid-β deposition in the blood vessels of the brain. Medin promotes the formation of vascular aggregates with amyloid-β in mouse models and in human patients with Alzheimer’s disease, and is associated with vascular defects and cognitive decline.

The hemizygous 22q11.2 microdeletion is a common copy number variant in humans. The deletion confers high risk for neurodevelopmental disorders, including autism and schizophrenia. Up to 41% of deletion carriers experience psychotic symptoms. We present a new mouse model (Df(h22q11)/+) of the deletion syndrome (22q11.2DS) and report on, to our knowledge, the most comprehensive study undertaken to date in 22q11.2DS models. The study was conducted in male mice. We found elevated postpubertal N-methyl-d-aspartate (NMDA) receptor antagonist–induced hyperlocomotion, age-independent prepulse inhibition (PPI) deficits and increased acoustic startle response (ASR). The PPI deficit and increased ASR were resistant to antipsychotic treatment. The PPI deficit was not a consequence of impaired hearing measured by auditory brain stem responses. The Df(h22q11)/+ mice also displayed increased amplitude of loudness-dependent auditory evoked potentials. Prefrontal cortex and dorsal striatal elevations of the dopamine metabolite DOPAC and increased dorsal striatal expression of the AMPA receptor subunit GluR1 was found. The Df(h22q11)/+ mice did not deviate from wild-type mice in a wide range of other behavioural and biochemical assays. The 22q11.2 microdeletion has incomplete penetrance in humans, and the severity of disease depends on the complete genetic makeup in concert with environmental factors. In order to obtain more marked phenotypes reflecting the severe conditions related to 22q11.2DS it is suggested to expose the Df(h22q11)/+ mice to environmental stressors that may unmask latent psychopathology. The Df(h22q11)/+ model will be a valuable tool for increasing our understanding of the etiology of schizophrenia and other psychiatric disorders associated with the 22q11DS.

Salmonella Typhimurium causes a self-limiting gastroenteritis that may lead to systemic disease. Bacteria invade the small intestine, crossing the intestinal epithelium from where they are transported to the mesenteric lymph nodes (MLNs) within migrating immune cells. MLNs are an important site at which the innate and adaptive immune responses converge but their architecture and function is severely disrupted during S . Typhimurium infection. To further understand host-pathogen interactions at this site, we used mass spectrometry imaging (MSI) to analyse MLN tissue from a murine model of S . Typhimurium infection. A molecule, identified as palmitoylcarnitine (PalC), was of particular interest due to its high abundance at loci of S . Typhimurium infection and MLN disruption. High levels of PalC localised to sites within the MLNs where B and T cells were absent and where the perimeter of CD169 + sub capsular sinus macrophages was disrupted. MLN cells cultured ex vivo and treated with PalC had reduced CD4 + CD25 + T cells and an increased number of B220 + CD19 + B cells. The reduction in CD4 + CD25 + T cells was likely due to apoptosis driven by increased caspase-3/7 activity. These data indicate that PalC significantly alters the host response in the MLNs, acting as a decisive factor in infection outcome.

Objective To estimate risks for all‐cause mortality and for severe COVID‐19 in multiple sclerosis patients and across relapsing–remitting multiple sclerosis patients exposed to disease‐modifying therapies. Methods We conducted a Swedish nationwide population‐based multi‐register linkage cohort study and followed all multiple sclerosis patients (n = 17,692 in March 2020), individually age‐, sex‐, and region‐matched to five population‐based controls (n = 86,176 in March 2020) during March 2020–June 2021. We compared annual all‐cause mortality within and across cohorts, and assessed incidence rates and relative risks for hospitalization, intensive care admission, and death due to COVID‐19 in relation to disease‐modifying therapy use, using Cox regression. Results Absolute all‐cause mortality among multiple sclerosis patients was higher from March to December 2020 than in previous years, but relative risks versus the population‐based controls were similar to preceding years. Incidence rates of hospitalization, intensive care admission, and death due to COVID‐19 remained in line with those for all‐cause hospitalization, intensive care admission, and mortality. Among relapsing–remitting patients on rituximab, trends for differences in risk of hospitalization due to COVID‐19 remained in the demographics‐, socioeconomic status‐, comorbidity‐, and multiple sclerosis severity‐adjusted model. Interpretation Risks of severe COVID‐19‐related outcomes were increased among multiple sclerosis patients as a whole compared to population controls, but risk increases were also seen for non‐COVID‐19 hospitalization, intensive care admission, and mortality, and did not significantly differ during the pandemic compared to pre‐pandemic years. The risk conveyed by disease‐modifying therapies was smaller than previously assumed, likely as a consequence of the possibility to better control for confounders.

Purpose To describe the prevalence of, risk factors for, and prognostic importance of gastrointestinal (GI) bleeding and use of acid suppressants in acutely ill adult intensive care patients. Methods We included adults without GI bleeding who were acutely admitted to the intensive care unit (ICU) during a 7-day period. The primary outcome was clinically important GI bleeding in ICU, and the analyses included estimations of baseline risk factors and potential associations with 90-day mortality. Results A total of 1,034 patients in 97 ICUs in 11 countries were included. Clinically important GI bleeding occurred in 2.6 % (95 % confidence interval 1.6–3.6 %) of patients. The following variables at ICU admission were independently associated with clinically important GI bleeding: three or more co-existing diseases (odds ratio 8.9, 2.7–28.8), co-existing liver disease (7.6, 3.3–17.6), use of renal replacement therapy (6.9, 2.7–17.5), co-existing coagulopathy (5.2, 2.3–11.8), acute coagulopathy (4.2, 1.7–10.2), use of acid suppressants (3.6, 1.3–10.2) and higher organ failure score (1.4, 1.2–1.5). In ICU, 73 % (71–76 %) of patients received acid suppressants; most received proton pump inhibitors. In patients with clinically important GI bleeding, crude and adjusted odds for mortality were 3.7 (1.7–8.0) and 1.7 (0.7–4.3), respectively. Conclusions In ICU patients clinically important GI bleeding is rare, and acid suppressants are frequently used. Co-existing diseases, liver failure, coagulopathy and organ failures are the main risk factors for GI bleeding. Clinically important GI bleeding was not associated with increased adjusted 90-day mortality, which largely can be explained by severity of comorbidity, other organ failures and age.

Objectives Osteoarthritis (OA) is the most prevalent form of arthritis and accounts for substantial morbidity and disability, particularly in older people. It is characterised by changes in joint structure, including degeneration of the articular cartilage, and its aetiology is multifactorial with a strong postulated genetic component. Methods A meta-analysis was performed of four genome-wide association (GWA) studies of 2371 cases of knee OA and 35 909 controls in Caucasian populations. Replication of the top hits was attempted with data from 10 additional replication datasets. Results With a cumulative sample size of 6709 cases and 44 439 controls, one genome-wide significant locus was identified on chromosome 7q22 for knee OA (rs4730250, p=9.2×10−9), thereby confirming its role as a susceptibility locus for OA. Conclusion The associated signal is located within a large (500 kb) linkage disequilibrium block that contains six genes: PRKAR2B (protein kinase, cAMP-dependent, regulatory, type II, β), HPB1 (HMG-box transcription factor 1), COG5 (component of oligomeric golgi complex 5), GPR22 (G protein-coupled receptor 22), DUS4L (dihydrouridine synthase 4-like) and BCAP29 (B cell receptor-associated protein 29). Gene expression analyses of the (six) genes in primary cells derived from different joint tissues confirmed expression of all the genes in the joint environment.

Immunogens and vaccination regimens can influence patterns of immune-epitope recognition, steering them towards or away from epitopes of potential viral vulnerability. HIV-1 envelope (Env)-specific antibodies targeting variable region 2 (V2) or 3 (V3) correlated with protection during the RV144 trial, however, it was suggested that the immunodominant V3 region might divert antibody responses away from other relevant sites. We mapped IgG responses against linear Env epitopes in five clinical HIV vaccine trials, revealing a specific pattern of Env targeting for each regimen. Notable V2 responses were only induced in trials administering CRF01_AE based immunogens, but targeting of V3 was seen in all trials, with the soluble, trimeric CN54gp140 protein eliciting robust V3 recognition. Strong V3 targeting was linked to greater overall response, increased number of total recognised antigenic regions, and where present, stronger V2 recognition. Hence, strong induction of V3-specific antibodies did not negatively impact the targeting of other linear epitopes in this study, suggesting that the induction of antibodies against V3 and other regions of potential viral vulnerability need not be necessarily mutually exclusive.

Planktonic foraminifera are widely used in biostratigraphic, palaeoceanographic and evolutionary studies, but the strength of many study conclusions could be weakened if taxonomic identifications are not reproducible by different workers. In this study, to assess the relative importance of a range of possible reasons for among-worker disagreement in identification, 100 specimens of 26 species of macroperforate planktonic foraminifera were selected from a core-top site in the subtropical Pacific Ocean. Twenty-three scientists at different career stages – including some with only a few days experience of planktonic foraminifera – were asked to identify each specimen to species level, and to indicate their confidence in each identification. The participants were provided with a species list and had access to additional reference materials. We use generalised linear mixed-effects models to test the relevance of three sets of factors in identification accuracy: participant-level characteristics (including experience), species-level characteristics (including a participant's knowledge of the species) and specimen-level characteristics (size, confidence in identification). The 19 less experienced scientists achieve a median accuracy of 57 %, which rises to 75 % for specimens they are confident in. For the 4 most experienced participants, overall accuracy is 79 %, rising to 93 % when they are confident. To obtain maximum comparability and ease of analysis, everyone used a standard microscope with only 35× magnification, and each specimen was studied in isolation. Consequently, these data provide a lower limit for an estimate of consistency. Importantly, participants could largely predict whether their identifications were correct or incorrect: their own assessments of specimen-level confidence and of their previous knowledge of species concepts were the strongest predictors of accuracy.

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, Barge Hognestad, HÃ¥kon 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 Bjarn 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 Tansager, 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 RognÃ¥s 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 prehospital management of traumatic brain injury (the PreTBI study protocol) Sophie-Charlott Seidenfaden, Ingunn S. Riddervold, Hans Kirkegaard, Niels Juul, Morten T. Batker 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