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ObjectiveTrauma-induced steroid changes have been studied post-hospital admission, resulting in a lack of understanding of the speed and extent of the immediate endocrine response to injury. The Golden Hour study was designed to capture the ultra-acute response to traumatic injury.DesignWe conducted an observational cohort study including adult male trauma patients MethodsWe recruited 31 adult male trauma patients (mean age 28 [range 19-59] years) with a mean injury severity score (ISS) of 16 (IQR 10-21). The median time to first sample was 35 (range 14-56) min, with follow-up samples collected 4-12 and 48-72 h post-injury. Serum steroids in patients and age- and sex-matched healthy controls (HCs) (n = 34) were analysed by tandem mass spectrometry.ResultsWithin 1 h of injury, we observed an increase in glucocorticoid and adrenal androgen biosynthesis. Cortisol and 11-hydroxyandrostendione increased rapidly, whilst cortisone and 11-ketoandrostenedione decreased, reflective of increased cortisol and 11-oxygenated androgen precursor biosynthesis by 11β-hydroxylase and increased cortisol activation by 11β-hydroxysteroid dehydrogenase type 1. Active classic gonadal androgens testosterone and 5α-dihydrotestosterone decreased, whilst the active 11-oxygenated androgen 11-ketotestosterone maintained pre-injury levels.ConclusionsChanges in steroid biosynthesis and metabolism occur within minutes of traumatic injury. Studies that address whether ultra-early changes in steroid metabolism are associated with patient outcomes are now required.

IntroductionTriage is a key principle in the effective management of major incidents. There is currently a paucity of evidence to guide the triage of children. The aim of this study was to perform a comparative analysis of nine adult and paediatric triage tools, including the novel ‘Sheffield Paediatric Triage Tool’ (SPTT), assessing their ability in identifying patients needing life-saving interventions (LSIs).MethodsA 10-year (2008–2017) retrospective database review of the Trauma Audit Research Network (TARN) Database for paediatric patients (15. Primary analysis was conducted on patients with complete prehospital physiological data with planned secondary analyses using first recorded data. Performance characteristics were evaluated using sensitivity, specificity, undertriage and overtriage.Results15 133 patients met TARN inclusion criteria. 4962 (32.8%) had complete prehospital physiological data and 8255 (54.5%) had complete first recorded physiological data. The majority of patients were male (69.5%), with a median age of 11.9 years. The overwhelming majority of patients (95.4%) sustained blunt trauma, yielding a median ISS of 9 and overall, 875 patients (17.6%) received at least one LSI. The SPTT demonstrated the greatest sensitivity of all triage tools at identifying need for LSI (92.2%) but was associated with the highest rate of overtriage (75.0%). Both the Paediatric Triage Tape (sensitivity 34.1%) and JumpSTART (sensitivity 45.0%) performed less well at identifying LSI. By contrast, the adult Modified Physiological Triage Tool-24 (MPTT-24) triage tool had the second highest sensitivity (80.8%) with tolerable rates of overtriage (70.2%).ConclusionThe SPTT and MPTT-24 outperform existing paediatric triage tools at identifying those patients requiring LSIs. This may necessitate a change in recommended practice. Further work is needed to determine the optimum method of paediatric major incident triage, but consideration should be given to simplifying major incident triage by the use of one generic tool (the MPTT-24) for adults and children.

IntroductionIndividuals with COVID-19 frequently experience symptoms and impaired quality of life beyond 4–12 weeks, commonly referred to as Long COVID. Whether Long COVID is one or several distinct syndromes is unknown. Establishing the evidence base for appropriate therapies is needed. We aim to evaluate the symptom burden and underlying pathophysiology of Long COVID syndromes in non-hospitalised individuals and evaluate potential therapies.Methods and analysisA cohort of 4000 non-hospitalised individuals with a past COVID-19 diagnosis and 1000 matched controls will be selected from anonymised primary care records from the Clinical Practice Research Datalink, and invited by their general practitioners to participate on a digital platform (Atom5). Individuals will report symptoms, quality of life, work capability and patient-reported outcome measures. Data will be collected monthly for 1 year.Statistical clustering methods will be used to identify distinct Long COVID-19 symptom clusters. Individuals from the four most prevalent clusters and two control groups will be invited to participate in the BioWear substudy which will further phenotype Long COVID symptom clusters by measurement of immunological parameters and actigraphy.We will review existing evidence on interventions for postviral syndromes and Long COVID to map and prioritise interventions for each newly characterised Long COVID syndrome. Recommendations will be made using the cumulative evidence in an expert consensus workshop. A virtual supportive intervention will be coproduced with patients and health service providers for future evaluation.Individuals with lived experience of Long COVID will be involved throughout this programme through a patient and public involvement group.Ethics and disseminationEthical approval was obtained from the Solihull Research Ethics Committee, West Midlands (21/WM/0203). Research findings will be presented at international conferences, in peer-reviewed journals, to Long COVID patient support groups and to policymakers.Trial registration number1567490.

ObjectiveUse of National Early Warning Score 2 (NEWS2) has been mandated in adults admitted to acute hospitals in England. Urgent clinical review is recommended at NEWS2 ≥5. This policy is recognised as requiring ongoing evaluation. We assessed NEWS2 acquisition, alerting at key thresholds and patient outcomes, to understand how response recommendations would affect clinical resource allocation.SettingAdult acute hospital in England.DesignRetrospective observational cohort study.Participants100 362 consecutive admissions between November 2018 and July 2019.OutcomeDeath or admission to intensive care unit within 24 hours of a score.MethodsNEWS2 were assembled as single scores from consecutive 24-hour time frames, (the first NEWS2 termed ‘Index-NEWS2’), or as all scores from the admission (termed All-NEWS2). Scores were excluded when a patient was in intensive care, in the presence of a decision not to attempt cardiopulmonary resuscitation, or on day 1 of elective admission.ResultsA mean of 4.5 NEWS2 were acquired per patient per day. The outcome rate following an Index-NEWS2 was 0.22/100 patient-days. The sensitivity of outcome prediction at Index-NEWS2 ≥5=0.46, and number needed to evaluate (NNE)=52. At this threshold, a mean of 37.6 alerts/100 patient-days would be generated, occurring in 12.3% of patients on any single day. Threshold changes to increase sensitivity by 0.1, would result in a twofold increase in alert rate and 1.5-fold increase in NNE. Overall, NEWS2 classification performance was significantly worse on Index-scores than All-scores (c-statistic=0.78 vs 0.85; pConclusionsThe combination of low event-rate, high alert-rate and low sensitivity, in patients for cardiopulmonary resuscitation, means that at current NEWS2 thresholds, resource demand would be sufficient to meaningfully compete with other pathways to clinical evaluation. In analyses that epitomise in-patient screening, NEWS2 performance suggests a need for re-evaluation of current response recommendations in this population.

Objectives The epidemiology of Behçet’s disease (BD) has not been well characterized in the UK. Evidence on the risk of cardiovascular disease, thromboembolic disease and mortality in patients with BD compared with the general population is scarce. Methods We used a large UK primary care database to investigate the epidemiology of BD. A retrospective matched cohort study was used to assess the following outcomes: risk of cardiovascular, thromboembolic disease and mortality. Controls were selected at a 1:4 ratio (age and gender matched). Cox proportional hazard models were used to derive adjusted hazard ratios (aHR). Results The prevalence of BD was 14.61 (95% CI 13.35–15.88) per 100 000 population in 2017. A total of 1281 patients with BD were compared with 5124 age- and gender-matched controls. There was significantly increased risk of ischaemic heart disease [aHR 3.09 (1.28–7.44)], venous thrombosis [aHR 4.80 (2.42–9.54)] and mortality [aHR 1.40 (1.07–1.84)] in patients with BD compared with corresponding controls. Patients with BD were at higher risk of pulmonary embolism compared with corresponding controls at baseline [adjusted odds ratio 4.64 (2.66–8.09), P < 0.0001]. The majority of patients with pulmonary embolism and a diagnosis of BD had pulmonary embolism preceding the diagnosis of BD, not after (87.5%; n = 28/32). Conclusion BD has a higher prevalence than previously thought. Physicians should be aware of the increased risk of developing ischaemic heart disease, stroke/transient ischaemic attack and deep venous thrombosis in patients with BD at an earlier age compared with the general population. Risk of embolism in patients with BD might vary across the disease course.

IntroductionTriage is a key principle in the effective management of major incidents. There is currently a paucity of evidence to guide the triage of children. The aim of this study was to perform a comparative analysis of nine adult and paediatric triage tools, including the novel ‘Sheffield Paediatric Triage Tool’ (SPTT), assessing their ability in identifying patients needing life-saving interventions (LSI).MethodsA ten-year retrospective database review of TARN data for paediatric patients (15. Primary analysis was conducted on patients with complete pre-hospital physiological data with planned secondary analyses using first recorded data. Performance characteristics were evaluated using sensitivity, specificity, under and over-triage.Results15133 patients met TARN inclusion criteria. 4962 (32.8%) had complete pre-hospital physiological data and 8255 (54.5%) had complete first recorded physiological data. Male patients predominated (69.5%), sustaining blunt trauma (95.4%) with a median ISS of 9. 875 patients (17.6%) received at least one LSI.The SPTT demonstrated the greatest sensitivity of all triage tools at identifying need for LSI (92.2%) but was associated with the highest rate of over-triage (75.0%). Both the PTT (sensitivity 34.1%) and JumpSTART (sensitivity 45.0%) performed less well at identifying LSI. By contrast, the adult MPTT-24 triage tool had the second highest sensitivity (80.8%) with tolerable rates of over-triage (70.2%).ConclusionThe SPTT and MPTT-24 outperform existing paediatric triage tools at identifying those patients requiring LSIs. This may necessitate a change in recommended practice. Further work is needed to determine the optimum method of paediatric major incident triage, but consideration should be given to simplifying major incident triage by the use of one generic tool (the MPTT-24) for adults and children.What this paper adds?Section 1: What is already known on this subject?Triage is a key principle in the effective management of major incidents. There is currently a paucity of evidence surrounding the use of existing paediatric major incident tools.In the UK, two methods of paediatric major incident triage exist, the Paediatric Triage Tape and the JumpSTART method. In previous studies they have demonstrated less than 50% sensitivity at identifying children in need of life-saving interventions.This study performed a comparative analysis on a UK paediatric trauma registry population and included a newly derived triage tool, the SPTT.Section 2: What this study addsThe PTT and JumpSTART perform poorly (The SPTT and the existing adult triage tool the MPTT-24 outperform all methods. Consideration should be given to simplifying major incident triage by the use of a single generic tool for both adults and children.

Context The incidence of differentiated thyroid cancer (DTC) is increasing, yet the prognosis is favourable and long-term survival is expected. Exogenous TSH suppression has been used for many years to prevent DTC recurrence and may be associated with increased risks of circulatory diseases. Design Risks of circulatory disease in patients treated for DTC were compared to randomly matched patients without DTC (controls) up to a 1:5 ratio using age, sex, body mass index (BMI) and smoking as the matching parameters in a population-based, open cohort study using The Health Improvement Network. Patients A total of 3009 patients treated for DTC with no pre-existing cardiovascular disease were identified and matched to 11 303 controls, followed up to median of 5 years. Results A total of 1259 incident circulatory events were recorded during the observation period. No difference in the risk of ischaemic heart disease (IHD) (adjusted hazards ratio [aHR]: 1.04, 95% CI: 0.80-1.36) or heart failure (HF) (aHR: 1.27, 95% CI: 0.89-1.81) was detected. The risk of atrial fibrillation (AF) and stroke was significantly higher in patients with DTC (aHR: 1.71, 95% CI: 1.36-2.15 and aHR: 1.34, 95% CI: 1.05-1.72, respectively). In a sensitivity analysis limited to newly diagnosed patients with DTC, only the risk of AF was consistently elevated (aHR: 1.86, 95% CI: 1.33-2.60). Conclusions The increased risk of AF in patients who have undergone treatment for DTC but without pre-existing CVD may warrant periodic screening for this arrhythmia. Whereas no evidence of increased risk of IHD or HF was observed, the increased risk of stroke/TIA warrants further investigation.

Aims/Objectives/BackgroundTriage is a key principle in the effective management of major incidents. There is currently a paucity of evidence to guide the triage of children. The aim of this study was to perform a comparative analysis of nine adult and paediatric triage tools, including the novel ‘Sheffield Paediatric Triage Tool’ (SPTT), assessing their ability in identifying patients needing life-saving interventions (LSI).Methods/DesignA ten-year retrospective database review of TARN data for paediatric patients (15. Primary analysis was conducted on patients with complete pre-hospital physiological data with planned secondary analyses using first recorded physiological data. Performance characteristics were evaluated using sensitivity, specificity, under and over-triage.Results15133 patients met TARN inclusion criteria. 4962 (32.8%) had complete pre-hospital physiological data and 8255 (54.5%) had complete first recorded data. Male patients predominated (69.5%), sustaining blunt trauma (95.4%) with a median ISS of 9. 875 patients (17.6%) received at least one LSI.The SPTT demonstrated the greatest sensitivity of all triage tools at identifying need for LSI (92.2%) but was associated with the highest rate of over-triage (75.0%). Both the PTT (sensitivity 34.1%) and JumpSTART (sensitivity 45.0%) performed less well at identifying LSI. By contrast, the adult MPTT-24 triage tool had the second highest sensitivity (80.8%) with tolerable rates of over-triage (70.2%).ConclusionThe SPTT and MPTT-24 outperform existing paediatric triage tools at identifying those patients requiring LSIs. This may necessitate a change in recommended practice. Further work is needed to determine the optimum method of paediatric major incident triage, but consideration should be given to simplifying major incident triage by the use of one generic tool (the MPTT-24) for adults and children.

Background The incidence of knife-related injuries is rising across the UK. This study aimed to determine the spectrum of knife-related injuries in a major UK city, with regards to patient and injury characteristics. A secondary aim was to quantify their impact on secondary care resources. Methods Observational study of patients aged 16+ years admitted to a major trauma centre following knife-related injuries resulting from interpersonal violence (May 2015 to April 2018). Patients were identified using Emergency Department and discharge coding, blood bank and UK national Trauma Audit and Research prospective registries. Patient and injury characteristics, outcome and resource utilisation were collected from ambulance and hospital records. Findings 532 patients were identified; 93% male, median age 26 years (IQR 20–35). Median injury severity score was 9 (IQR 3–13). 346 (65%) underwent surgery; 133 (25%) required intensive care; 95 (17·9%) received blood transfusion. Median length of stay was 3·3 days (IQR 1·7–6·0). In-hospital mortality was 10/532 (1·9%). 98 patients (18·5%) had previous attendance with violence-related injuries. 24/37 females (64·9%) were injured in a domestic setting. Intoxication with alcohol (19·2%) and illicit drugs (17·6%) was common. Causative weapon was household knife in 9%, knife (other/unspecified) in 38·0%, machete in 13·9%, small folding blade (2·8%) and, unrecorded in 36·3%. Interpretation Knife injuries constitute 12·9% of trauma team workload. Violence recidivism and intoxication are common, and females are predominantly injured in a domestic setting, presenting opportunities for targeted violence reduction interventions. 13·9% of injuries involved machetes, with implications for law enforcement strategies.

Background The 100,000 Genomes Project offers an unprecedented opportunity to leverage whole genome sequencing data to characterise the hereditary basis of Familial Thoracic Aortic Aneurysm Disease (FTAAD). FTAAD is a heterogeneous group of syndromic and isolated aortopathies. The genetic basis of this presentation often remains undiscovered. Purpose To define the FTAAD cohorts available in the 100,000 Genomes Project and assess the current diagnostic yield and space for future discovery. Materials and methods As of February 2019, 536 probands with FTAAD and HPO terms for thoracic aortic disease have been recruited to the 100,000 Genomes Project. Inclusion criteria included: Thoracic aortopathy Marfan syndrome with no identified FBN1 mutation or Loeys-Dietz syndrome or related condition, and Negative initial genetic screening to include FBN1, TGFBR1&2, ACTA2 where appropriate. Whole genome sequencing, quality control and filtering was carried out by Genomics England as previously described. Aortopathy genes are defined in PanelApp, an expert-curated gene list with validated associations with FTAAD. Genes curated for only skeletal phenotypes (eg FBN2, FLCN) with no evidence for aortic involvement were excluded. Tier 1 variants are rare and protein-truncating; tier 2 variants are rare and protein-altering. Tiered variants were excluded if Clinvar status was benign, or if they were not fully penetrant. Results The cohort has a mean age of 44 years (range 0–79). 110 probands were Only 8 Tier 1 variants in validated aortopathy genes were reported in this cohort. These were in BGN, FBN1, LOX, MYH11, MYLK, TGFB2 and TGFBR1 (see table1). This defines a diagnostic yield of just 8/536 (6%) in this patient group, using known aortopathy gene panels. Surprisingly, none of these variants were found in probands under 30 at disease onset. There were 68 classic trios in this cohort (proband + mother and father). However, just one of these has a clearly pathogenic de novo variant identified (in MYH11). There were just 2 Tier 2 variants of uncertain significance (VUS) in aortopathy genes in other trios. 10 larger family structures have yielded no clear pathogenic candidates to date. The majority of the cohort are recruited as singletons. 75 Tier 2 variants have been identified to date in 19 aortopathy genes (see figure 1). Just 1 of these (in LOX) can be classified as likely pathogenic. The remainder are VUSs. Conclusion In this genetically pre-screened cohort with FTAAD, genetic diagnosis remains elusive. The variety of genes in which protein-altering variants are found highlights the genetic heterogeneity of this condition. We plan further systematic studies of the family structures available in the 100,000 Genomes Project and case:control studies to further elucidate the genetic architecture of FTAAD. The negative findings to date, particularly in probands with young-onset aortopathy, make it likely that responsible genes are yet to be discovered in many cases. This research was made possible through access to the data and findings generated by the 100,000 Genomes Project. Conflict of Interest None

Imagine if we could compute across phenotype data as easily as genomic data; this article calls for efforts to realize this vision and discusses the potential benefits., Despite a large and multifaceted effort to understand the vast landscape of phenotypic data, their current form inhibits productive data analysis. The lack of a community-wide, consensus-based, human- and machine-interpretable language for describing phenotypes and their genomic and environmental contexts is perhaps the most pressing scientific bottleneck to integration across many key fields in biology, including genomics, systems biology, development, medicine, evolution, ecology, and systematics. Here we survey the current phenomics landscape, including data resources and handling, and the progress that has been made to accurately capture relevant data descriptions for phenotypes. We present an example of the kind of integration across domains that computable phenotypes would enable, and we call upon the broader biology community, publishers, and relevant funding agencies to support efforts to surmount today's data barriers and facilitate analytical reproducibility.

Ontologies are becoming increasingly important for the efficient storage, retrieval and mining of biological data. The description of phenotypes using ontologies is a particularly complex problem. We outline a schema that can be used to describe phenotypes by combining orthologous axiomatic ontologies. We also describe tools for storing, browsing and searching such complex ontologies. Central to this approach is that assays (protocols for measuring phenotypic characters) describe what has been measured as well as how this was done, allowing assays to link individual organisms to ontologies describing phenotypes. We have evaluated this approach by automatically annotating data on 600 000 mutant mice phenotypes using the SHIRPA protocol. We believe this approach will enable the flexible, extensible and detailed description of phenotypes from any organism.

Background The practice and research of medicine generates considerable quantities of data and model resources (DMRs). Although in principle biomedical resources are re-usable, in practice few can currently be shared. In particular, the clinical communities in physiology and pharmacology research, as well as medical education, (i.e. PPME communities) are facing considerable operational and technical obstacles in sharing data and models. Findings We outline the efforts of the PPME communities to achieve automated semantic interoperability for clinical resource documentation in collaboration with the RICORDO project. Current community practices in resource documentation and knowledge management are overviewed. Furthermore, requirements and improvements sought by the PPME communities to current documentation practices are discussed. The RICORDO plan and effort in creating a representational framework and associated open software toolkit for the automated management of PPME metadata resources is also described. Conclusions RICORDO is providing the PPME community with tools to effect, share and reason over clinical resource annotations. This work is contributing to the semantic interoperability of DMRs through ontology-based annotation by (i) supporting more effective navigation and re-use of clinical DMRs, as well as (ii) sustaining interoperability operations based on the criterion of biological similarity. Operations facilitated by RICORDO will range from automated dataset matching to model merging and managing complex simulation workflows. In effect, RICORDO is contributing to community standards for resource sharing and interoperability.