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Background Free tumour cells in the peritoneal cavity of patients with pancreatic carcinoma carry a poor prognosis. Reactive or degenerative mesothelial cells can make cytological interpretation with conventional stains difficult. Detection of the tumour-associated antigens carcinoembryonic antigen (CEA) and CA19-9 may improve detection. Methods At staging laparoscopy, 22 patients with pancreatic or periampullary tumours had ascitic fluid aspirated or peritoneal lavage performed. Both conventional and immunocytologically stained preparations were examined. Antibodies to CEA and CA19-9 and the epithelial marker BerEP4 were used. Lavage fluid from ten patients having operative treatment for benign pancreatic or biliary conditions was also examined. Results No malignant cells on conventional cytological criteria were recovered. Thirteen of the 22 patients with pancreatic or periampullary carcinoma had peritoneal cells that were positive for CEA and/or CA19-9. None was positive for BerEP4. No patients with resectable disease had cells that were positive for CEA or CA19-9 compared with 13 of 18 (72%) who had unresectable disease. One patient (10%) with benign disease (chronic pancreatitis) had cells recovered that were weakly positive for CEA but negative for CA19-9 and BerEP4. Discussion Recovery of cells from the peritoneal cavity of patients with pancreatic or periampullary carcinoma that are expressing the tumour-associated antigens CEA or CA19-9 does not indicate the presence of free tumour cells but is associated with advanced disease. [ABSTRACT FROM AUTHOR]

Background: Textbook outcomes are composite outcome measures that reflect the ideal overall experience for patients. There are many of these in the elective surgery literature but no textbook outcomes have been proposed for patients following emergency laparotomy. The aim was to achieve international consensus amongst experts and patients for the best Textbook Outcomes for non-trauma and trauma emergency laparotomy., Methods: A modified Delphi exercise was undertaken with three planned rounds to achieve consensus regarding the best Textbook Outcomes based on the category, number and importance (Likert scale of 1-5) of individual outcome measures. There were separate questions for non-trauma and trauma. A patient engagement exercise was undertaken after round 2 to inform the final round., Results: A total of 337 participants from 53 countries participated in all three rounds of the exercise. The final Textbook Outcomes were divided into 'early' and 'longer-term'. For non-trauma patients the proposed early Textbook Outcome was 'Discharged from hospital without serious postoperative complications (Clavien-Dindo ≥ grade III; including intra-abdominal sepsis, organ failure, unplanned re-operation or death). For trauma patients it was 'Discharged from hospital without unexpected transfusion after haemostasis, and no serious postoperative complications (adapted Clavien-Dindo for trauma ≥ grade III; including intra-abdominal sepsis, organ failure, unplanned re-operation on or death)'. The longer-term Textbook Outcome for both non-trauma and trauma was 'Achieved the early Textbook Outcome, and restoration of baseline quality of life at 1 year'., Conclusion: Early and longer-term Textbook Outcomes have been agreed by an international consensus of experts for non-trauma and trauma emergency laparotomy. These now require clinical validation with patient data., (© The Author(s) 2024. Published by Oxford University Press on behalf of BJS Foundation Ltd.)

Background: Direct assessment of microcirculatory function remains a critical care research tool but approaches for analysis of microcirculatory videomicroscopy clips are shifting from manual to automated algorithms, with a view to clinical application in the intensive care unit. Automated analysis software associated with current sidestream darkfield videomicroscopy systems is demonstrably unreliable; therefore, semi-automated analysis of captured clips should be undertaken in older generations of software. We present a method for capture of microcirculatory clips using current version videomicroscope hardware and resizing of clips to allow compatibility with legacy analysis software. The interobserver reliability of this novel approach is examined, in addition to a comparison of this approach with the current generation of automated analysis software., Results: Resizing microcirculatory clips did not significantly change image quality. Assessment of bias between observers for manual analysis of resized clips; and between manually analysed clips and automated software analysis was undertaken by Bland-Altman analysis. Bias was demonstrated for all parameters for manual analysis of resized clips (total vessel density = 6.8, perfused vessel density = 6.3, proportion of perfused vessels = - 8.79, microvascular flow index = - 0.08). Marked bias between manual analysis and automated analysis was also evident (total vessel density = 16.6, perfused vessel density = 16.0, proportion of perfused vessels = 1.8). The difference between manual and automated analysis was linearly related to the magnitude of the measured parameter., Conclusions: Poor reliability of automated analysis is a significant hurdle for clinical translation of microcirculatory monitoring. The method presented here allows capture of microcirculatory clips using current hardware that are backwards compatible with older versions of manual analysis software. We conclude that this approach is appropriate for research applications in the intensive care unit, however the time delay to results limits utility for clinical translation., (© 2023. The Author(s).)

It is generally accepted that the human abdominal wall comprises skin, subcutaneous tissues, muscles and their aponeuroses, and the parietal peritoneum. Understanding these layers and their mechanical properties provides valuable information to those designing procedural skills trainers, supporting surgical procedures (hernia repair), and engineering-based work (in silico simulation). However, there is little literature available on the mechanical properties of the abdominal wall in layers or as a composite in the context of designing a procedural skills trainer. This work characterizes the tensile properties of the human abdominal wall by layer and as a partial composite. Tissues were collected from fresh-never-frozen and fresh-frozen cadavers and tested in uniaxial tension at a rate of 5 mm/min until failure. Stress-strain curves were created for each sample, and the values for elastic moduli, ultimate tensile strength, and strain at failure were obtained. The experimental outcomes from this study demonstrated variations in tensile properties within and between tissues. The data also suggest that the tensile properties of composite abdominal walls are not additive. Ultimately, this body of work contributes to a deeper comprehension of these mechanical properties and will serve to enhance patient care, refine surgical interventions, and assist with more sophisticated engineering solutions.

Objective: To examine the relationship between sublingual microcirculatory measures and frailty index in those attending a kidney transplant assessment clinic., Methods: Patients recruited had their sublingual microcirculation taken using sidestream dark field videomicroscopy (MicroScan, Micro Vision Medical, Amsterdam, the Netherlands) and their frailty index score using a validated short form via interview., Results: A total of 44 patients were recruited with two being excluded due to microcirculatory image quality scores exceeding 10. The frailty index score indicated significant correlations with total vessel density (p < .0001, r = -.56), microvascular flow index (p = .004, r = -.43), portion of perfused vessels (p = .0004, r = -.52), heterogeneity index (p = .015, r = .32), and perfused vessel density (p < .0001, r = -.66). No correlation was shown between the frailty index and age (p = .08, r = .27)., Conclusions: There is a relationship between the frailty index and microcirculatory health in those attending a kidney transplant assessment clinic, that is not confounded by age. These findings suggest that the impaired microcirculation may be an underlying cause of frailty., (© 2023 The Authors. Microcirculation published by John Wiley & Sons Ltd.)

Background: In our experience, the anterior carotid sheath forms an important plane of dissection when excising temporal bone region cancers. However, its anatomical composition, relationships, and radiological appearance remains unclear., Methods: Eight sides of cadaveric heads were dissected. Anatomical findings were correlated with a high-resolution baseline T1 MRI., Results: The anterior carotid sheath was formed by the tensor-vascular-styloid fascia, stylopharyngeal fascia, buccopharyngeal fascia (BPF), and longus capitis fascia (LCF), and appeared as a hypointense line on MRI. Not previously described, the glossopharyngeal nerve pierced the sheath 9.0 mm (SD 2.1 mm) below the skull base and traveled through its LCF and BPF layers to exit near the pharynx., Conclusion: Multiple fascial layers formed the anterior carotid sheath at the skull base, and this was radiologically identifiable. Further studies are required to validate findings and investigate the role this fascial plane has in forming an effective barrier to spread of malignancy., (© 2023 The Authors. Head & Neck published by Wiley Periodicals LLC.)

Background: Haemorrhage is the leading cause of death on the battlefield. Seventy percent of injuries are due to explosive mechanisms. Anecdotally, these patients have had poorer outcomes when compared to those with penetrating mechanisms of injury (MOI). We wished to test the hypothesis that outcomes following vascular reconstruction were worse in blast-injured than non blast-injured patients., Methods: Retrospective cohort study. British and American combat casualties with arterial injuries sustained in Iraq or Afghanistan (2003-2014) were identified from the UK Joint Theatre Trauma Registry (JTTR). Eligibility included explosive or penetrating MOI, with follow-up to UK hospital discharge, or death. Outcomes were mortality, amputation, graft thrombosis, haemorrhage, and infection. Statistical analysis was performed using Pearson Chi-Square test, t-tests, ANOVA or non-parametric equivalent, and survival analyses., Results: One hundred and fifteen patients were included, 80 injured by explosive and 35 by penetrating mechanisms. Evacuation time, ISS, number of arterial injuries, age and gender were comparable between groups. Seventy percent of arterial injuries resulted from an explosive MOI. The explosive injuries group received more blood products (p = 0.008) and suffered more regions injured (p < 0.0001). Early surgical interventions in both were ligation (n = 36, 31%), vein graft (n = 33, 29%) and shunting (n = 9, 8%). Mortality (n = 12, 10%) was similar between groups. Differences in limb salvage rates following explosive (n = 17, 53%) vs penetrating (n = 13, 76.47%) mechanisms approached statistical significance (p = 0.056). Nine (28%) vein grafted patients developed complications. No evidence of a difference in the incidence of vein graft thrombosis was found when comparing explosive with non-explosive cohorts (p = 0.154)., Conclusions: The recorded numbers of vein grafts following combat arterial trauma in are small in the JTTR. No statistically-significant differences in complications, including vein graft thrombosis, were found between cohorts injured by explosive and non-explosive mechanisms., (Crown Copyright © 2018. Published by Elsevier Ltd. All rights reserved.)

Background: Preclinical studies report that higher plasma viscosity improves microcirculatory flow after haemorrhagic shock and resuscitation, but no clinical study has tested this hypothesis., Objective: We investigated the relationship between plasma viscosity and sublingual microcirculatory flow in patients during resuscitation for traumatic haemorrhagic shock (THS)., Methods: Sublingual video-microscopy was performed for 20 trauma patients with THS as soon as feasible in hospital, and then at 24 h and 48 h. Values were obtained for total vessel density, perfused vessel density, proportion of perfused vessels, microcirculatory flow index (MFI), microcirculatory heterogeneity index (MHI), and Point of Care Microcirculation (POEM) scores. Plasma viscosity was measured using a Wells-Brookfield cone and plate micro-viscometer. Logistic regression analyses examined relationships between microcirculatory parameters and plasma viscosity, adjusting for covariates (systolic blood pressure, heart rate, haematocrit, rate and volume of fluids, and rate of noradrenaline)., Results: Higher plasma viscosity was not associated with improved microcirculatory parameters. Instead, there were weakly significant associations between higher plasma viscosity and lower (poorer) MFI (p = 0.040), higher (worse) MHI (p = 0.033), and lower (worse) POEM scores (p = 0.039)., Conclusions: The current study did not confirm the hypothesis that higher plasma viscosity improves microcirculatory flow dynamics in patients with THS. Further clinical investigations are warranted to determine whether viscosity is a physical parameter of importance during resuscitation of these patients.

Objectives: To describe the 'Resuscitation with Pre-HospItaL bLood products' trial (RePHILL) - a multi-centre randomised controlled trial of pre-hospital blood product (PHBP) administration vs standard care for traumatic haemorrhage., Background: PHBP are increasingly used for pre-hospital trauma resuscitation despite a lack of robust evidence demonstrating superiority over crystalloids. Provision of PHBP carries additional logistical and regulatory implications, and requires a sustainable supply of universal blood components., Methods: RePHILL is a multi-centre, two-arm, parallel group, open-label, phase III randomised controlled trial currently underway in the UK. Patients attended by a pre-hospital emergency medical team, with traumatic injury and hypotension (systolic blood pressure <90 mmHg or absent radial pulse) believed to be due to traumatic haemorrhage are eligible. Exclusion criteria include age <16 years, blood product receipt on scene prior to randomisation, Advanced Medical Directive forbidding blood product administration, pregnancy, isolated head injury and prisoners. A total of 490 patients will be recruited in a 1 : 1 ratio to receive either the intervention (up to two units of red blood cells and two units of lyophilised plasma) or the control (up to four boluses of 250 mL 0.9% saline). The primary outcome measure is a composite of failure to achieve lactate clearance of ≥20%/h over the first 2 hours after randomisation and all-cause mortality between recruitment and discharge from the primary receiving facility to non-acute care. Secondary outcomes include pre-hospital time, coagulation indices, in-hospital transfusion requirements and morbidity., Results: Pilot study recruitment began in December 2016. Approval to proceed to the main trial was received in June 2017. Recruitment is expected to continue until 2020., Conclusions: RePHILL will provide high-quality evidence regarding the efficacy and safety of PHBP resuscitation for trauma., (© 2017 British Blood Transfusion Society.)

Objectives: To assess the relationship between microcirculatory perfusion and multiple organ dysfunction syndrome in patients following traumatic hemorrhagic shock., Design: Multicenter prospective longitudinal observational study., Setting: Three U.K. major trauma centers., Patients: Fifty-eight intubated and ventilated patients with traumatic hemorrhagic shock., Interventions: Sublingual incident dark field microscopy was performed within 12 hours of ICU admission (D0) and repeated 24 and 48 hours later. Cardiac output was assessed using oesophageal Doppler. Multiple organ dysfunction syndrome was defined as Serial Organ Failure Assessment score greater than or equal to 6 at day 7 post injury., Measurements and Main Results: Data from 58 patients were analyzed. Patients had a mean age of 43 ± 19 years, Injury Severity Score of 29 ± 14, and initial lactate of 7.3 ± 6.1 mmol/L and received 6 U (interquartile range, 4-11 U) of packed RBCs during initial resuscitation. Compared with patients without multiple organ dysfunction syndrome at day 7, patients with multiple organ dysfunction syndrome had lower D0 perfused vessel density (11.2 ± 1.8 and 8.6 ± 1.8 mm/mm; p < 0.01) and microcirculatory flow index (2.8 [2.6-2.9] and 2.6 [2.2-2.8]; p < 0.01) but similar cardiac index (2.5 [± 0.6] and 2.1 [± 0.7] L/min//m; p = 0.11). Perfused vessel density demonstrated the best discrimination for predicting subsequent multiple organ dysfunction syndrome (area under curve 0.87 [0.76-0.99]) compared with highest recorded lactate (area under curve 0.69 [0.53-0.84]), cardiac index (area under curve 0.66 [0.49-0.83]) and lowest recorded systolic blood pressure (area under curve 0.54 [0.39-0.70])., Conclusions: Microcirculatory hypoperfusion immediately following traumatic hemorrhagic shock and resuscitation is associated with increased multiple organ dysfunction syndrome. Microcirculatory variables are better prognostic indicators for the development of multiple organ dysfunction syndrome than more traditional indices. Microcirculatory perfusion is a potential endpoint of resuscitation following traumatic hemorrhagic shock.

Introduction: The Trauma and Injury Severity Score (TRISS) methodology is used in both the UK and US Military trauma registries. The method relies on dividing casualties according to mechanism, penetrating or blunt, and uses different weighting coefficients accordingly. The UK Military Joint Theatre Trauma Registry uses the original coefficients devised in 1987, whereas the US military registry uses updated civilian coefficients, but it is not clear how either registry analyzes explosive casualties according to the TRISS methodology. This study aims to use the UK Military Joint Theatre Trauma Registry to calculate new TRISS coefficients for contemporary battlefield casualties injured by either gunshot or explosive mechanisms. The secondary aim of this study is to apply the revised TRISS coefficients to examine the survival trends of UK casualties from recent military conflicts., Materials and Methods: The Joint Theatre Trauma Registry was searched for all UK casualties injured or killed in Iraq and Afghanistan by explosive or gunshot mechanisms between January 1, 2003 and December 31, 2014. Details of these casualties including injuries and vital signs were reviewed. Logistic regression analysis was performed to devise new TRISS coefficients; these were then used to examine survival over the 12 yr of the study., Results: Comparing the predictions from the gunshot TRISS model to the observed outcomes, it demonstrates a sensitivity of 98.1% and a specificity of 96.8% and an overall accuracy of 97.8%. With respect to the explosive TRISS model, there is a sensitivity of 98.6%, a specificity of 97.4%, and an overall accuracy of 98.4%. When this updated and mechanism-specific TRISS methodology was used to measure changes in survival over the study period, survival following these injuries improved until 2012 when performance was maintained for the last 2 yr of the study., Conclusion: This study for the first time refines the TRISS methodology with coefficients appropriate for use within combat casualty care systems. This improved methodology reveals that UK combat casualty care performance appears to have improved until 2012 when this standard was maintained., (© Crown copyright 2018. This article contains public sector information licensed under the Open Government Licence v3.0 (http://www.nationalarchives.gov.uk/doc/open-government-licence/version/3/).)

Background: Haemorrhage is a major cause of mortality and morbidity following both military and civilian trauma. Haemostatic dressings may offer effective haemorrhage control as part of prehospital treatment., Aim: To conduct a systematic review of the clinical literature to assess the prehospital use of haemostatic dressings in controlling traumatic haemorrhage, and determine whether any haemostatic dressings are clinically superior., Methods: MEDLINE and EMBASE databases were searched using predetermined criteria. The reference lists of all returned review articles were screened for eligible studies. Two authors independently undertook the search, performed data extraction, and risk of bias and Grading of Recommendations, Assessment, Development and Evaluation quality assessments. Meta-analysis could not be undertaken due to study and clinical heterogeneity., Results: Our search yielded 470 studies, of which 17 met eligibility criteria, and included 809 patients (469 military and 340 civilian). There were 15 observational studies, 1 case report and 1 randomised controlled trial. Indications for prehospital haemostatic dressing use, wound location, mechanism of injury, and source of bleeding were variable. Seven different haemostatic dressings were reported with QuikClot Combat Gauze being the most frequently applied (420 applications). Cessation of bleeding ranged from 67% to 100%, with a median of 90.5%. Adverse events were only reported with QuikClot granules, resulting in burns. No adverse events were reported with QuikClot Combat Gauze use in three studies. Seven of the 17 studies did not report safety data. All studies were at risk of bias and assessed of 'very low' to 'moderate' quality., Conclusions: Haemostatic dressings offer effective prehospital treatment for traumatic haemorrhage. QuikClot Combat Gauze may be justified as the optimal agent due to the volume of clinical data and its safety profile, but there is a lack of high-quality clinical evidence, and randomised controlled trials are warranted., Level of Evidence: Systematic review, level IV., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Trauma patients are vulnerable to coagulopathy and inflammatory dysfunction associated with endotheliopathy of trauma (EoT). In vitro evidence has suggested that tranexamic acid (TXA) may ameliorate endotheliopathy. We aimed to investigate how soon after injury EoT occurs, its association with multiple organ dysfunction syndrome (MODS), and whether TXA ameliorates it., Methods: A prospective observational study included 91 trauma patients enrolled within 60 min of injury and 19 healthy controls. Blood was sampled on enrolment and again 4 to 12 h later. ELISAs measured serum concentrations of syndecan-1 and thrombomodulin as biomarkers of EoT. MODS was compared between groups according to biomarker dynamics: persistently abnormal; abnormal to normal; and persistently normal. Timing of EoT was estimated by plotting biomarker data against time, and then fitting generalized additive models. Biomarker dynamics were compared between those who did or did not receive prehospital TXA., Results: Median age was 38 (interquartile range [IQR] 24-55) years; 78 of 91 were male. Median injury severity score (ISS) was 22 (IQR 12-36). EoT was estimated to occur at 5 to 8 min after injury. There were no significant differences in ISS between those with or without prehospital EoT. Forty-two patients developed MODS; 31 of 42 with persistently abnormal; 8 of 42 with abnormal to normal; and 3 of 42 with persistently normal biomarkers; P < 0.05. There were no significant differences between TXA and non-TXA groups., Conclusions: EoT was present at the scene of injury. MODS was more likely when biomarkers of EoT were persistently raised. There were no significant differences between TXA and non-TXA groups. Prehospital interventions aimed at endothelial restoration may represent a clinically meaningful target for prehospital resuscitation.

Objectives: We investigated how often intravenous fluids have been delivered during physician-led prehospital treatment of patients with hypotensive trauma in the UK and which fluids were given. These data were used to estimate the potential national requirement for prehospital blood products (PHBP) if evidence from ongoing trials were to report clinical superiority., Setting: The Regional Exploration of Standard Care during Evacuation Resuscitation (RESCUER) retrospective observational study was a collaboration between 11 UK air ambulance services. Each was invited to provide up to 5 years of data and total number of taskings during the same period., Participants: Patients with hypotensive trauma (systolic blood pressure <90 mm Hg or absent radial pulse) attended by a doctor., Primary and Secondary Outcome Measures: The primary outcome was the number of patients with hypotensive trauma given prehospital fluids. Secondary outcomes were types and volumes of fluids. These data were combined with published data to estimate potential national eligibility for PHBP., Results: Of 29 037 taskings, 729 (2.5%) were for patients with hypotensive trauma attended by a physician. Half were aged 21-50 years; 73.4% were male. A total of 537 out of 729 (73.7%) were given fluids. Five hundred and ten patients were given a single type of fluid; 27 received >1 type. The most common fluid was 0.9% saline, given to 486/537 (90.5%) of patients who received fluids, at a median volume of 750 (IQR 300-1500) mL. Three per cent of patients received PHBP. Estimated projections for patients eligible for PHBP at these 11 services and in the whole UK were 313 and 794 patients per year, respectively., Conclusions: One in 40 air ambulance taskings were manned by physicians to retrievepatients with hypotensive trauma. The most common fluid delivered was 0.9% saline. If evidence justifies universal provision of PHBP, approximately 800 patients/year would be eligible in the UK, based on our data combined with others published. Prospective investigations are required to confirm or adjust these estimations., Competing Interests: Competing interests: DNN, JMH, IMS, NC, GP, HD and MJM are investigators in the RePHILL (Resuscitation with PreHospItaL bLood Products) study, a multicentre randomised controlled trial of prehospital blood product administration versus standard care for traumatic haemorrhage., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Endothelial cell damage and glycocalyx shedding after trauma can increase the risk of inflammation, coagulopathy, vascular permeability, and death. Bedside sublingual video-microscopy may detect worse flow and perfusion associated with this endotheliopathy. We compared markers of endotheliopathy with physical flow dynamics after traumatic hemorrhagic shock., Methods: Sublingual incident dark field video-microscopy was performed at three time points after injury (<10 hours, 10-30 hours, and 30-50 hours). Values for microcirculatory flow index (MFI), Point Of carE Microcirculation assessment (POEM) score, proportion of perfused vessels (PPV), microcirculatory heterogeneity index (MHI), perfused vessel density (PVD), and total vessel density (TVD) were obtained. ELISAs were performed to measure concentrations of thrombomodulin and syndecan-1 as biomarkers of endothelial cell damage and glycocalyx shedding respectively. Flow parameters were dichotomized to above and below average, and biomarkers compared between groups; below average MFI, POEM, PPV, PVD, and TVD, and above average MHI were considered poor microcirculatory flow dynamics., Results: A total of 155 sublingual video-microscopy clips corresponding to 39 time points from 17 trauma patients were analyzed. Median age was 35 (IQR 25-52); 16/17 were men. Within 10 hours of injury, syndecan-1 concentrations were significantly higher compared to 17 age- and sex-matched healthy controls (30 [IQR 20-44] ng/mL) for worse TVD (78 [IQR 63-417] ng/mL), PVD (156 [IQR 63-590] ng/mL), PPV (249 [IQR 64-578] ng/mL), MFI (249 [IQR 64-578] ng/mL), MHI (45 [IQR] 38-68) ng/mL), and POEM scores (108 [IQR 44-462] ng/mL) (all p < 0.01). Thrombomodulin was also raised within 10 hours of injury when compared to healthy controls (2.9 [IQR 2.2-3.4] ng/mL) for worse PPV (4.1 [IQR 3.4-6.2] ng/mL) and MFI (4.1 [IQR 3.4-6.2] ng/mL) (both p < 0.05)., Conclusions: Endothelial cell damage and glycocalyx shedding are associated with worse flow, density, and heterogeneity within microvessels after traumatic hemorrhagic shock. The clinical utility of these biomarkers and flow parameters at the bedside are yet to be elucidated., Level of Evidence: Prognostic study, level III.

Background: Cell free deoxyribonucleic acid (cfDNA) has been proposed as a biomarker of secondary complications following trauma. Raised thrombomodulin and syndecan-1 levels have been used to indicate endotheliopathy, and are associated with inflammation, coagulopathy, and mortality. The current study aimed to analyse the association between cfDNA and biomarkers of endotheliopathy in a cohort of trauma patients, and whether raised levels of cfDNA were associated with poorer clinical outcomes., Methods: Serum thrombomodulin and syndecan-1 were used as biomarkers of endotheliopathy and compared to plasma cfDNA in trauma patients from two prospective longitudinal observational studies. Cohort A (n = 105) had a predicted injury severity score (ISS) >8, and had blood sampled within 1h of injury and at 4-12h. Cohort B (n = 17) had evidence of haemorrhagic shock, and had blood sampled at a median time of 3.5h after injury. Relationships between biomarkers were tested using multivariable linear regression models that included the covariates of gender, age, ISS, Glasgow Coma Scale, lactate, systolic blood pressure, and heart rate. A model was fitted to investigate whether changes in cfDNA were associated with similar changes in endothelial biomarkers., Results: The mean age was 41 (SD 19), and the median ISS was 25 (IQR 12-34). There was a significant association between cfDNA levels and both syndecan-1 and thrombomodulin levels (both p<0.001). This was independent of all covariates except for ISS, which significantly correlated with cfDNA levels. 50 ng/ml change in syndecan-1 and 1 ng/ml change in thrombomodulin corresponded to 15% and 20% increases in cfDNA levels respectively (both p<0.001). Patients who died had significantly higher prehospital and in-hospital cfDNA levels (both p<0.05)., Conclusions: Raised cfDNA levels are associated with markers of endotheliopathy following trauma, and are associated with mortality. This relationship is present within the first hour of injury, and a change in one biomarker level is reflected by similar changes in the others. These findings are in keeping with the hypothesis that circulating DNA and endothelial injury share a common pathway following trauma.

Background: There is no consensus on reporting nonmortality trauma complications in a graded manner. The Clavien-Dindo scale of complications was originally for elective surgery and requires adaptation to provide meaningful data for trauma patients. In particular, the original score does not account for those treated without surgery. We report an adapted Clavien-Dindo in trauma (ACDiT) scale and apply it to patients managed operatively and nonoperatively., Methods: A combined prospective and retrospective international multicenter observational study was undertaken to apply the ACDiT scale to 484 trauma patients at three university teaching hospitals (Birmingham, England (n = 303); Houston, Texas (n = 113); and Glasgow, Scotland (n = 68)). These included both intensive care unit (ICU) and non-ICU-managed patients. The Clavien-Dindo scoring system was adapted for trauma patients based on consensus amongst an international collaboration of trauma specialists at these sites. Data included whether initial patients were managed operatively or nonoperatively. Complication grades were compared with hospital-free and ICU-free days as other outcome measures of patient morbidity., Results: Two hundred seventeen (44.8%) of 484 patients experienced complications, of whom 61 (28.1%) of 217 died (grade V). The remainder consisted of grades I (n = 20), II (n = 60), III (n = 24), and IV (n = 52). There was a strong association between higher ACDiT grade category and lower number of hospital-free and ICU-free days (p < 0.01). Eighty-eight patients with complications did not require surgery, validating the score's usefulness in patients managed nonoperatively., Conclusion: The ACDiT scale can be used to grade the severity of posttrauma complications in patients managed both operatively and nonoperatively. It provides clinically meaningful data for morbidity and mortality meetings and other quality improvement exercises., Level of Evidence: Prognostic, level IV.

Objective: Rapid sequence induction (RSI) provides prompt airway control during emergency evacuation of trauma patients. Physicians may be tasked to travel with paramedic ambulance crews to the scene of injury when RSI is more likely to be required. This study investigates whether there are any differences in the practice of prehospital RSI during emergency retrievals for trauma since the establishment of the regional Major Trauma Network (MTN) in March 2012., Methods: A retrospective observational study examined prehospital records for all trauma patients from September 2010 to January 2015 at a Major Trauma Centre in Birmingham, UK. Prehospital physician availability increased from 12 to 24 h after March 2012, and tasking became centralized. Data included demographics, mechanism of injury, crew personnel, and details of RSI. The periods before and after the establishment of the regional MTN were compared., Results: There were 5244 patients: 1432 (27.3%) before and 3812 (72.7%) after March 2012. Of the patients, 67.2% were male. The most common injuries were road traffic collisions (45.0%). Physicians were more likely to be present after (2345 missions, 61.5%) than before (529 missions, 36.9%) March 2012 (P<0.01). RSI was performed 434 (8.3%) times and was more likely during the latter than the former period [359 (9.4%) vs. 75 (5.2%), P<0.01]. Successful tracheal intubation was achieved in 99% of occasions., Conclusion: The establishment of regional MTNs enables centrally tasked, 24-h physician availability for emergency trauma patients. There has been an increase in physician presence on emergency missions and increased frequency of RSI for at-risk trauma patients at times when there may previously have been an unmet requirement.

Objectives: Sublingual microcirculatory monitoring for traumatic haemorrhagic shock (THS) may predict clinical outcomes better than traditional blood pressure and cardiac output, but is not usually performed until the patient reaches the intensive care unit (ICU), missing earlier data of potential importance. This pilot study assessed for the first time the feasibility and safety of sublingual video-microscopy for THS in the emergency department (ED), and whether it yields useable data for analysis., Setting: A safety and feasibility assessment was undertaken as part of the prospective observational MICROSHOCK study; sublingual video-microscopy was performed at the UK-led Role 3 medical facility at Camp Bastion, Afghanistan, and in the ED in 3 UK Major Trauma Centres., Participants: There were 15 casualties (2 military, 13 civilian) who presented with traumatic haemorrhagic shock with a median injury severity score of 26. The median age was 41; the majority (n=12) were male. The most common injury mechanism was road traffic accident., Primary and Secondary Outcome Measures: Safety and feasibility were the primary outcomes, as measured by lack of adverse events or clinical interruptions, and successful acquisition and storage of data. The secondary outcome was the quality of acquired video clips according to validated criteria, in order to determine whether useful data could be obtained in this emergency context., Results: Video-microscopy was successfully performed and stored for analysis for all patients, yielding 161 video clips. There were no adverse events or episodes where clinical management was affected or interrupted. There were 104 (64.6%) video clips from 14 patients of sufficient quality for analysis., Conclusions: Early sublingual microcirculatory monitoring in the ED for patients with THS is safe and feasible, even in a deployed military setting, and yields videos of satisfactory quality in a high proportion of cases. Further investigations of early microcirculatory behaviour in this context are warranted., Trial Registration Number: NCT02111109., Competing Interests: Conflicts of Interest: None declared., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Background: Increased microcirculatory flow and perfusion has been reported to improve clinical outcomes following shock. The optimal resuscitation fluid to restore the flow dynamics of the microcirculation is unknown. This review summarizes the preclinical literature to inform the direction and most important hypotheses for future clinical interventional studies., Methods: Standard systematic review methodology was utilized, and registered with the Collaborative Approach to Meta Analysis and Review of Animal Data from Experimental Studies (CAMARADES). Medline and Embase (via OVID SP) and SCOPUS were searched for all preclinical studies of haemorrhagic shock that compared fluid resuscitation of any kind (e.g., blood products, crystalloids, colloids, or haemoglobin based oxygen carriers) to another fluid or haemorrhage only, and reported at least one microcirculatory physical endpoint (such as flow rate, velocity, vessel diameter, functional capillary density, or glycocalyx thickness). Risk of bias was assessed using the Systematic Review Centre for Laboratory animal Experimentation (SYRCLE) tool. Translatability was also assessed for each study based on the most common recommendations., Results: There were 3,103 potential studies of interest, of which 71 studies fulfilled all eligibility criteria. There were 62 rodent, 5 canine, and 4 porcine studies. Flow rate, velocity, and vessel diameter were the most commonly reported endpoints. Studies reported the importance of the presence of haemoglobin, as well as osmotic potential and viscosity in providing optimal restoration of microcirculatory flow dynamics. Others reported the restoration of the endothelial glycocalyx and attenuation of inflammation as important properties for the choice of fluid. All studies were at potential risk of bias due to unclear randomization, concealment, and blinding. There were important threats to translatability for all studies., Conclusion: The ideal resuscitation fluid for restoration of the microcirculation following haemorrhagic shock is likely to contain a preparation of haemoglobin, favor higher oncotic potential, and viscosity, protect and reconstitute the endothelium, and attenuate inflammation. These hypotheses that are derived from preclinical research warrant further exploration in the clinical context.

Background: Serum lactate serves as a surrogate marker for global tissue hypoxia following traumatic injury and has potential to guide resuscitation. Portable, handheld point-of-care monitoring devices enable lactate values to be readily available in the prehospital environment. The current review examines the utility of prehospital lactate (pLa) measurement in the management of trauma., Methods: MEDLINE and EMBASE databases were searched using predefined criteria (pLa measurement, trauma patients) until March 10, 2016. Studies were examined for lactate measurement as an intervention, prognostic indicator, and utilization in the guidance of goal-directed therapy. The Newcastle-Ottawa Scale was used to assess risk of bias, and quality of evidence was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation system. Data were unsuitable for meta-analysis and are presented in narrative form., Results: Of 2,415 articles of interest, seven met the inclusion criteria, all of which were observational studies, including 2,085 trauma patients. Lactate sampling techniques, timings, and thresholds were heterogeneous. No studies used pLa to guide intervention. Elevated pLa may be an independent prognostic marker of critical illness in trauma patients, particularly in blunt trauma. Prehospital lactate measurement may be more sensitive than systolic blood pressure in determining need for resuscitative care. Early lactate measurement may be particularly useful in the detection of occult hypoperfusion, with elevated pLa detectable within 30 minutes of injury. All current studies were assessed as being of "low" or "very low" quality and were at risk of bias. Considerable logistical barriers to pLa measurement exist., Conclusions: Prehospital point-of-care lactate monitoring for trauma has been variably performed. There is a paucity of evidence relating to its use. The limited data available show feasibility and potential clinical utility, and further investigation is warranted to establish whether lactate might give meaningful guidance during prehospital triage and trauma patient resuscitation., Level of Evidence: Systematic review, level IV.

Object: In recent conflicts, many UK personnel sustained head injuries requiring damage-control surgery and aeromedical transfer to the UK. This study aims to examine indications, complications and outcomes of UK military casualties undergoing craniectomy and cranioplasty from conflicts in Afghanistan and Iraq., Methods: The UK military Joint Theatre Trauma Registry (JTTR) was searched for all UK survivors in Afghanistan and Iraq between 2004 and 2014 requiring craniectomy and cranioplasty resulting from trauma., Results: Fourteen decompressive craniectomies and cranioplasties were performed with blast and gunshot wounds equally responsible for head injury. Ten survivors (71%) had an Injury Severity Score (ISS) of 75, normally designated as 'unsurvivable'. Most were operated on the day of injury. Seventy-one percent received a reverse question mark incision and 7% received a bicoronal incision. Seventy-nine percent had bone flaps discarded. Overall infection rate was 43%. Acinetobacter spp was the causative organism in 50% of cases. Median Glasgow Outcome Scale (GOS) at final follow-up was 4. All casualties had a GOS score greater than 3., Conclusions: Timely neurosurgical intervention is imperative for military personnel given high survival rates in those sustaining what are designated 'un-survivable' injuries. Early decompression facilitates safe aeromedical evacuation of casualties. Excellent outcomes validate the UK military trauma system and the stepwise performance gains throughout recent conflicts however trauma registers most evolving to have specific relevance to military casualties. In high-energy trauma with contamination and soft-tissue destruction, surgery should be conducted with regard for future soft tissue reconstruction. Bone flaps should be discarded and cranioplasty performed according to local preference. Facilities receiving military casualties should have specialist microbiological input mindful of the difficulties treating unusual microbes.

Background: Despite over a decade of research and technological advances, sublingual microcirculatory monitoring has not yet reached clinical utility. Offline analysis is time consuming and occurs away from the patient. A system to assess the microcirculation at the point of care is desirable. We present a novel 5-point grading system (the point of care microcirculation (POEM) scoring system) that can be used at the point of care during non-invasive sublingual microcirculatory monitoring., Methods: The POEM score is an ordinal scale from 1 (worst) to 5 (best), based on a composite assessment of flow and heterogeneity of four individual sublingual video-microscopy clips. Thirty-two healthcare professionals were trained in how to assign POEM scores. Following training they assigned scores to five test sequences (each consisting of four video clips). They were blinded to clinical status. Inter-user consistency and agreement were assessed using intra-class correlation coefficient (ICC) analysis. In addition, blinded expert scores for 68 video clips were compared to offline computer analysis using traditional microcirculatory parameters including total vessel density (TVD), perfused vessel density (PVD), proportion of perfused vessels (PPV), microcirculatory flow index (MFI) and microcirculatory heterogeneity index (MHI). The time taken to assign each was recorded., Results: Participants showed good inter-rater consistency (ICC 0.83, 95 % CI 0.626, 0.976) and agreement (ICC 0.815, 95 % CI 0.602, 0.974) for assigned POEM scores. Expert scoring of videos correlated with offline values for PVD (R 2  = 0.39; p < 0.05), PPV (R 2  = 0.71; p < 0.001), MFI (R 2  = 0.75; p < 0.001), and MHI (R 2  = 0.68; p < 0.001). POEM scores took less time to assign than conventional offline computer analysis (2 minutes versus 44 minutes)., Conclusion: We present for the first time a novel 5-point ordinal scale of microcirculatory flow and heterogeneity that can be used at the point of care. It has minimal inter-user variability amongst healthcare professionals after just 1 hour of training. POEM scores take a short time to assign, and correspond well to traditional offline computer-analyzed parameters.

Introduction: Administration of high ratios of plasma to packed red blood cells is a routine practice for in-hospital trauma resuscitation. Military and civilian emergency teams are increasingly carrying prehospital blood products (PHBP) for trauma resuscitation. This study systematically reviewed the clinical literature to determine the extent to which the available evidence supports this practice., Methods: Bibliographic databases and other sources were searched to July 2015 using keywords and index terms related to the intervention, setting, and condition. Standard systematic review methodology aimed at minimizing bias was used for study selection, data extraction, and quality assessment (protocol registration, Prospero: CRD42014013794). Synthesis was mainly narrative with random effects model meta-analysis limited to mortality outcomes., Results: No prospective comparative or randomized studies were identified. Sixteen case series and 11 comparative studies were included in the review. Seven studies included mixed populations of trauma and non-trauma patients. Twenty-five of 27 studies provided only very low quality evidence. No association between PHBP and survival was found (OR for mortality: 1.29, 95% CI: 0.84-1.96, P = 0.24). A single study showed improved survival in the first 24 h. No consistent physiological or biochemical benefit was identified, nor was there evidence of reduced in-hospital transfusion requirements. Transfusion reactions were rare, suggesting the short-term safety of PHBP administration., Conclusions: While PHBP resuscitation appears logical, the clinical literature is limited, provides only poor quality evidence, and does not demonstrate improved outcomes. No conclusions as to efficacy can be drawn. The results of randomized controlled trials are awaited.

Introduction: The microcirculation is the physiological site of oxygen and substrate exchange. Its effectiveness during circulatory shock is vital for the perfusion of tissues, and has a bearing on subsequent organ function and prognosis. Microcirculatory dysfunction following traumatic haemorrhagic shock (THS) has been understudied compared with other pathologies such as sepsis. The aim of the MICROSHOCK study is to investigate changes seen in the microcirculation of patients following THS, and to assess its response to resuscitation. A greater understanding of the behaviour and mechanisms of microcirculatory dysfunction in this context may direct future avenues of goal-directed resuscitation for these patients., Methods and Analysis: This multicentre prospective longitudinal observational study includes patients who present as an emergency with THS. Microcirculatory parameters are recorded using sublingual incident dark field microscopy alongside measurements of global flow (oesophageal Doppler and transthoracic echocardiography). Patients are enrolled into the study as soon as feasible after they arrive in hospital, and then at subsequent daily time points. Blood samples are taken for investigation into the mechanisms of microcirculatory dysfunction. Sequential Organ Failure Assessment scores will be analysed with microcirculatory parameters to determine whether they correlate with greater fidelity than more conventional, global circulatory parameters., Ethics and Dissemination: Research Ethics Committee approval has been granted for this study (Reference: 14/YH/0078). Owing to the nature of THS, capacity for informed consent will be absent on patient enrolment. This will be addressed according to the Mental Health Capacity Act 2005. The physician in charge of the patient's care (nominated consultee) may consent on behalf of the patient. Consent will also be sought from a personal consultee (close relative or friend). After capacity is regained, the participant will be asked for their consent. Results will be submitted for publication in peer-reviewed journal format and presented at relevant academic meetings., Trial Registration Number: NCT02111109; Pre-results., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

The microcirculation is the anatomical location of perfusion and substrate exchange, and its functional impairment is of paramount importance during the state of shock. The difference in venous-to-arterial carbon dioxide partial pressures (Pv-aCO2) has recently been reported to correlate with microcirculatory dysfunction during early septic shock with greater fidelity than global hemodynamic parameters. This makes it a potential candidate as a point-of-care test in goal directed therapy that aims to restore microcirculatory function in an emergency clinical context. This early work needs to be explored further, and a better understanding of Pv-aCO2 during the resuscitation and subsequent patient progression is required. The quest for an ideal bedside point-of-care test for microcirculatory behavior is ongoing, and is likely to consist of a combination of non-invasive sublingual microcirculatory monitoring and biochemical tests that reflect tissue perfusion. These tools have the potential to provide more accurate and clinically relevant data with regards to the microcirculation that more conventional resuscitative monitoring such as blood pressure, cardiac output, and serum lactate.

Introduction: Trauma care delivery in England has been transformed by the development of trauma networks, and the designation of trauma centres. A specialist trauma service is a key component of such centres. The aim of this survey was to determine to which extent, and how, the new major trauma centres (MTCs) have been able to implement such services., Methods: Electronic questionnaire survey of MTCs in England., Results: All 22 MTCs submitted responses. Thirteen centres have a dedicated major trauma service or trauma surgery service, and a further four are currently developing such a service. In 7 of these 17 centres, the service is or will be provided by orthopaedic surgeons, in 2 by emergency medicine departments, in another 2 by general or vascular surgeons, and in 6 by a multidisciplinary group of consultants., Discussion: A large proportion of MTCs still do not have a dedicated major trauma service. Furthermore, the models which are emerging differ from other countries. The relative lack of involvement of surgeons in MTC trauma service provision is particularly noteworthy, and a potential concern. The impact of these different models of service delivery is not known, and warrants further study., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Background: Modern resuscitation strategies following haemorrhagic shock are influenced by global haemodynamic parameters such as blood pressure and cardiac output. Microcirculatory dysfunction in this context may persist even after restoration of satisfactory global parameters. Additional monitoring of the microcirculatory function may therefore be warranted in order to facilitate goal-directed therapy at a tissue oxygenation level. Although such a phenomenon is recognised in the case of sepsis, clinical evidence regarding the behaviour of the microcirculation following the delivery of resuscitation fluids after haemorrhagic shock is sparse. A summation of the current state of pre-clinical evidence is justified in order to direct avenues for future clinical research., Methods/design: Systematic review methodology will be utilised in order to identify relevant studies, assess for bias, and extract data for analysis. Medical databases will be searched to find pre-clinical studies that monitor the microcirculatory function following haemorrhagic shock and subsequent fluid resuscitation. Different fluid types (e.g. blood products, crystalloid, and colloid fluids) will be compared. The search strategy will combine terms for the animal model, resuscitation fluid, and microcirculatory parameters. Randomised and non-randomised experiments, as well as case series, will be eligible for inclusion. Specific quality assessment tools for pre-clinical research will be used depending on study design. A combination of narrative and meta-analysis techniques will be used for the synthesis of data., Discussion: The choice of type, sequence, and quantity of resuscitation fluid following haemorrhagic shock is controversial, and the optimal strategy for restoration of microcirculatory function is yet unknown. A detailed examination of pre-clinical data regarding the microcirculation is timely and will enable a focussed approach to clinical research for the improvement of resuscitation following haemorrhagic shock., Systematic Review Registration: Collaborative Approach to Meta Analysis and Review of Animal Data from Experimental Studies ( CAMARADES).

Background: The United Kingdom was at war in Iraq and Afghanistan for more than a decade. Despite assertions regarding advances in military trauma care during these wars, thus far, no studies have examined survival in UK troops during this sustained period of combat. The aims of this study were to examine temporal changes of injury patterns defined by body region and survival in a population of UK Military casualties between 2003 and 2012 in Iraq and Afghanistan., Methods: The UK Military Joint Theatre Trauma Registry was searched for all UK Military casualties (survivors and fatalities) sustained on operations between January 1, 2003, and December 31, 2012. The New Injury Severity Score (NISS) was used to stratify injury severity., Results: There were 2,792 UK Military casualties sustaining 14,252 separate injuries during the study period. There were 608 fatalities (22% of all casualties). Approximately 70% of casualties injured in hostile action resulted from explosive munitions. The extremities were the most commonly injured body region, involved in 43% of all injuries. The NISS associated with a 50% chance of survival rose each year from 32 in 2003 to 60 in 2012., Conclusion: An improvement in survival during the 10-year period is demonstrated. A majority of wounds are a result of explosive munitions, and the extremities are the most commonly affected body region. The authors recommend the development of more sophisticated techniques for the measuring of the performance of combat casualty care systems to include measures of morbidity and functional recovery as well as survival., Level of Evidence: Epidemiologic study, level III.

Introduction: Modern body armour clearly reduces injury incidence and severity, but evidence to actually objectively demonstrate this effect is scarce. Although the Joint Theatre Trauma Registry (JTTR) alone cannot relate injury pattern to body armour coverage, the addition of computerised Surface Wound Mapping (SWM) may enable this utility., Method: Surface wound locations of all UK and NATO coalition soldiers, Afghan National Army and Police and local nationals injured by explosively propelled fragments and treated in the Role 3 UK-led Field Hospital in Camp Bastion, Afghanistan, between 8 July and 20 October 2012 were prospectively recorded. The Abbreviated Injury Scores (AIS) and relative risk of casualties sustaining injuries under a type of body armour were compared with those that did not wear that armour., Results: Casualties wearing a combat helmet were 2.7 times less likely to sustain a fragmentation wound to the head than those that were unprotected (mean AIS of 2.9 compared with 4.1). Casualties wearing a body armour vest were 4.1 times less likely to sustain a fragmentation wound to the chest or abdomen than those that were unprotected (mean AIS of 2.9 compared with 3.9). Casualties wearing pelvic protection were 10 times less likely to sustain a fragmentation wound to the pelvis compared with those that were unprotected (mean AIS of 3.4 compared with 3.9)., Discussion: Computerised SWM has objectively demonstrated the ability of body armour worn on current operations in Afghanistan to reduce wound incidence and severity. We recognise this technique is limited in that it only records the surface wound location and may be specific to this conflict. However, gathering electronic SWM at the same time as recording injuries for the JTTR was simple, required little extra time and therefore we would recommend its collection during future conflicts., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Introduction: Prevention against head wounds from explosively propelled fragments is currently the Mark 7 general service combat helmet, although only limited evidence exists to define the coverage required for the helmet to adequately protect against such a threat. The Royal Centre for Defence Medicine was tasked by Defence Equipment and Support to provide a framework for determining the optimum coverage of future combat helmets in order to inform the VIRTUS procurement programme., Method: A systematic review of the literature was undertaken to identify potential solutions to three components felt necessary to define the ideal helmet coverage required for protection against explosively propelled fragments., Results: The brain and brainstem were identified as the structures requiring coverage by a helmet. No papers were identified that directly defined the margins of these structures to anatomical landmarks, nor how these could be related to helmet coverage., Conclusions: We recommend relating the margins of the brain to three identifiable anatomical landmarks (nasion, external auditory meatus and superior nuchal line), which can in turn be related to the coverage provided by the helmet. Early assessments using an anatomical mannequin indicate that the current helmet covers the majority of the brain and brainstem from projectiles with a horizontal trajectory but not from ones that originate from the ground. Protection from projectiles with ground-originating trajectories is reduced by helmets with increased stand-off from the skin. Future helmet coverage assessments should use a finite element numerical modelling approach with representative material properties assigned to intracranial anatomical structures to enable differences in projectile trajectory and helmet coverage to be objectively compared., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)