Severe thermal and major traumatic injury results in elevated plasma concentrations of total heme that are associated with poor clinical outcomes and systemic immune suppression.

Background: Traumatic and thermal injuries result in a state of systemic immune suppression, yet the mechanisms that underlie its development are poorly understood. Released from injured muscle and lysed red blood cells, heme is a damage associated molecular pattern with potent immune modulatory properties. Here, we measured plasma concentrations of total heme in over 200 traumatic and thermally-injured patients in order to examine its relationship with clinical outcomes and post-injury immune suppression. Methods: Blood samples were collected from 98 burns (≥15% total body surface area) and 147 traumatically-injured (injury severity score ≥8) patients across the ultra-early (≤1 hour) and acute (4-72 hours) post-injury settings. Pro-inflammatory cytokine production by lipopolysaccharide (LPS) challenged whole blood leukocytes was studied, and plasma concentrations of total heme, and its scavengers haptoglobin, hemopexin and albumin measured, alongside the expression of heme-oxygenase-1 (HO-1) in peripheral blood mononuclear cells (PBMCs). LPS-induced tumour necrosis factor-alpha (TNF-α) production by THP-1 cells and monocytes following in vitro heme treatment was also examined. Results: Burns and traumatic injury resulted in significantly elevated plasma concentrations of heme, which coincided with reduced levels of hemopexin and albumin, and correlated positively with circulating levels of pro and anti-inflammatory cytokines. PBMCs isolated from trauma patients 4-12 and 48-72 hours post-injury exhibited increased HO-1 gene expression. Non-survivors of burn injury and patients who developed sepsis, presented on day 1 with significantly elevated heme levels, with a difference of 6.5 µM in heme concentrations corresponding to a relative 52% increase in the odds of post-burn mortality. On day 1 post-burn, heme levels were negatively associated with ex vivo LPS-induced TNF-α and interleukin-6 production by whole blood leukocytes. THP-1 cells and monocytes pre-treated with heme exhibited significantly reduced TNF-α production following LPS stimulation. This impairment was associated with decreased gene transcription, reduced activation of extracellular signal-regulated kinase 1/2 and an impaired glycolytic response. Conclusions: Major injury results in elevated plasma concentrations of total heme that may contribute to the development of endotoxin tolerance and increase the risk of poor clinical outcomes. Restoration of the heme scavenging system could be a therapeutic approach by which to improve immune function post-injury.

Rising Incidence of Inflammatory Bowel Disease in South Asian Children in New Zealand-A Retrospective Population-Based Study.

OBJECTIVES: High rates of inflammatory bowel disease (IBD) are reported in children of South Asian (SA) descent in some western countries. This population-based study describes the incidence and clinical course of IBD in SA children compared to non-South Asian (NSA) children in New Zealand (NZ). METHODS: Children (≤15 years) with new-onset IBD presenting to a centralized tertiary referral center in Auckland, NZ from 2010 to 2020 were identified. Disease phenotype, clinical characteristics, response to exclusive enteral nutrition, clinical remission rates at 3 and 12 months, biologic use, corticosteroid exposure, and disease complications were compared by ethnicity; IBD incidence was calculated. RESULTS: There were 127 (26 SA; 101 NSA) children with Crohn disease, 41 (10 SA; 31 NSA) with ulcerative colitis, and 10 (3 SA; 7 NSA) with IBD-unclassified. IBD incidence in SA and NSA children was 14.1 per 100,000 and 4.3 per 100,000 respectively ( P < 0.001). IBD incidence increased by 5.6% per year ( P = 0.022), due to a greater rise in incidence in SA (SA 16.8% per year, P = 0.015; NSA 4.5% per year, P = 0.317). At presentation, SA children had worse biochemical parameters, severe colitis, and vitamin D deficiency. SA children had lower rates of remission following exclusive enteral nutrition (28.5% vs 65.0%, P < 0.001) or biologic induction (35.7% vs 70.8%, P = 0.020), at 3-month (35.3% vs 69.8%, P < 0.001) and 12-month follow-up (29.4% vs 55.0%, P = 0.005). No significant differences were found in disease location or corticosteroid burden. CONCLUSIONS: Increasing incidence of IBD was disproportionately represented by SA children with more severe disease and lower remission rates following exclusive enteral nutrition or biologic therapy.

Atopy and allergy following solid organ transplantation: A 15-year experience.

AIM: There are increasing reports of atopy/allergy following solid organ transplantation, especially paediatric liver transplantation (LT) with minimal New Zealand (NZ) data. We describe the prevalence of transplant-acquired atopy and allergy (TAA) in NZ paediatric liver transplant recipients, compared to paediatric kidney and adult liver transplants. METHODS: TAA focussed health questionnaires were sent to patients selected from the NZ transplant registry (transplanted between January 2003 and December 2017). Demographic and clinical data were also obtained from electronic health records and follow-up phone calls. RESULTS: A total of 232 patients (62% male) participated (111 adult liver, 82 paediatric liver, 39 paediatric kidney transplant recipients). Tacrolimus was primary immunosuppression for all LT patients; with combined tacrolimus, mycophenolate and corticosteroids for kidney transplants. The number of patients who developed TAA was significantly higher (P < 0.001) in the paediatric LT group (36/82, 44%) compared to adult liver (12/111, 11%) and paediatric kidney transplants (4/39, 10%). Eczema was most common (73%), then IgE-mediated food allergy (FA, 33%), allergic rhinitis (19%) and asthma (17%). Six paediatric LT recipients developed eosinophilic oesophagitis (EoE). Egg was the most common allergen in the IgE-mediated FA group. TAAs were severe enough to warrant a switch from tacrolimus to another agent in seven paediatric LT patients. For paediatric LT patients, female gender and younger age at transplant were risk factors for developing TAA. CONCLUSIONS: TAA is common in paediatric liver transplant recipients, with female gender and younger age at transplant being risk factors identified. This highlights the need for detailed atopic and allergy history to be incorporated in all pre-transplant assessments.

Resuscitation with blood products in patients with trauma-related haemorrhagic shock receiving prehospital care (RePHILL): a multicentre, open-label, randomised, controlled, phase 3 trial.

BACKGROUND: Time to treatment matters in traumatic haemorrhage but the optimal prehospital use of blood in major trauma remains uncertain. We investigated whether use of packed red blood cells (PRBC) and lyophilised plasma (LyoPlas) was superior to use of 0·9% sodium chloride for improving tissue perfusion and reducing mortality in trauma-related haemorrhagic shock. METHODS: Resuscitation with pre-hospital blood products (RePHILL) is a multicentre, allocation concealed, open-label, parallel group, randomised, controlled, phase 3 trial done in four civilian prehospital critical care services in the UK. Adults (age ≥16 years) with trauma-related haemorrhagic shock and hypotension (defined as systolic blood pressure <90 mm Hg or absence of palpable radial pulse) were assessed for eligibility by prehospital critial care teams. Eligible participants were randomly assigned to receive either up to two units each of PRBC and LyoPlas or up to 1 L of 0·9% sodium chloride administered through the intravenous or intraosseous route. Sealed treatment packs which were identical in external appearance, containing PRBC-LyoPlas or 0·9% sodium chloride were prepared by blood banks and issued to participating sites according to a randomisation schedule prepared by the co-ordinating centre (1:1 ratio, stratified by site). The primary outcome was a composite of episode mortality or impaired lactate clearance, or both, measured in the intention-to-treat population. This study is completed and registered with ISRCTN.com, ISRCTN62326938. FINDINGS: From Nov 29, 2016 to Jan 2, 2021, prehospital critical care teams randomly assigned 432 participants to PRBC-LyoPlas (n=209) or to 0·9% sodium chloride (n=223). Trial recruitment was stopped before it achieved the intended sample size of 490 participants due to disruption caused by the COVID-19 pandemic. The median follow-up was 9 days (IQR 1 to 34) for participants in the PRBC-LyoPlas group and 7 days (0 to 31) for people in the 0·9% sodium chloride group. Participants were mostly white (62%) and male (82%), had a median age of 38 years (IQR 26 to 58), and were mostly involved in a road traffic collision (62%) with severe injuries (median injury severity score 36, IQR 25 to 50). Before randomisation, participants had received on average 430 mL crystalloid fluids and tranexamic acid (90%). The composite primary outcome occurred in 128 (64%) of 199 participants randomly assigned to PRBC-LyoPlas and 136 (65%) of 210 randomly assigned to 0·9% sodium chloride (adjusted risk difference -0·025% [95% CI -9·0 to 9·0], p=0·996). The rates of transfusion-related complications in the first 24 h after ED arrival were similar across treatment groups (PRBC-LyoPlas 11 [7%] of 148 compared with 0·9% sodium chloride nine [7%] of 137, adjusted relative risk 1·05 [95% CI 0·46-2·42]). Serious adverse events included acute respiratory distress syndrome in nine (6%) of 142 patients in the PRBC-LyoPlas group and three (2%) of 130 in 0·9% sodium chloride group, and two other unexpected serious adverse events, one in the PRBC-LyoPlas (cerebral infarct) and one in the 0·9% sodium chloride group (abnormal liver function test). There were no treatment-related deaths. INTERPRETATION: The trial did not show that prehospital PRBC-LyoPlas resuscitation was superior to 0·9% sodium chloride for adult patients with trauma related haemorrhagic shock. Further research is required to identify the characteristics of patients who might benefit from prehospital transfusion and to identify the optimal outcomes for transfusion trials in major trauma. The decision to commit to routine prehospital transfusion will require careful consideration by all stakeholders. FUNDING: National Institute for Health Research Efficacy and Mechanism Evaluation.

COVID-19 risk, attitudes and behaviour study (CRAB study): A knowledge, attitudes, and practise qualitative study of COVID-19 in the Royal Navy.

Introduction: Outbreaks of SARS-CoV-2 onboard maritime platforms spread rapidly and have high attack rates. The aim of the COVID-19 Risk, Attitudes and Behaviour (CRAB) study was to investigate the knowledge, attitudes, and practises in the Royal Navy in relation to COVID-19 prevention. Methods: The CRAB study was a cross-sectional survey, using a census sampling method, conducted in May and June 2021. An online questionnaire was distributed to all serving Royal Navy regular personnel using either the MyNavy application or via a QR code through email for a continuous 14 day period. The questionnaire was based on an existing validated questionnaire used for avian influenza epidemics. Questions investigated individual perceptions of COVID-19 seriousness, compliance with prevention methods, explored vaccination intention and vaccine hesitancy (unvaccinated individuals who declined or were unsure about receiving a COVID-19 vaccine). The chi-squared test of best fit was used to compare the demographic responses against the whole organisation, with p-value < 0.05 deemed significant. Odds ratios were used to investigate associations between demographic groups and responses to questions, with an odds ratio crossing 1.0 deemed non-significant. Results: The response rate was 6% (2,080/33,200), with 315 responses collated in the pilot phase and 1,765 in the main study phase. Male participants were less likely to rate COVID-19 as serious (OR 0.34; 95% CI: 0.23-0.49). BAME ethnicity (OR 2.41; 95% CI: 1.12-5.17) rated it as more serious. At the time of the study 62% of respondents had received one dose of a COVID-19 vaccine. In the 797 unvaccinated personnel, vaccine hesitancy accounted for 24.2% (193/797), of whom 136 were white males. Those who had a higher COVID-19 serious rating, the most significant factor for non-adherence to COVID-19 prevention measures in both vaccinated (OR 1.61 [95%CI: 1.20-2.17]) and vaccine-hesitant (OR 3.24 [95%CI: 1.63-6.41]) individuals was colleagues' non-adherence. The most trusted source of information on vaccines was provided by the Defence Medical Services (77.2% [1,606/2,080]). Conclusion: This study has identified reasons for COVID-19 protective measure adherence, sources of information trusted by respondents and vaccine hesitancy, in the Royal Navy. The questionnaire can be used to investigate attitudes and behaviours in future emerging infectious diseases.

Multicentre, longitudinal, observational cohort study to examine the relationship between neutrophil function and sepsis in adults and children with severe thermal injuries: a protocol for the Scientific Investigation of the Biological Pathways Following Thermal Injury-2 (SIFTI-2) study.

INTRODUCTION: Burn-induced changes in the phenotype and function of neutrophils, cells which provide front-line protection against rapidly dividing bacterial infections, are emerging as potential biomarkers for the early prediction of sepsis. In a longitudinal study of adult burns patients, we recently demonstrated that a combined measurement of neutrophil phagocytic capacity, immature granulocyte (IG) count and plasma cell-free DNA (cfDNA) levels on the day of injury gave good discriminatory power for the prediction of later sepsis development. However, limited by a small sample size, single-centre design and focus on adult burns patients, these biomarkers require prospective validation in a larger patient cohort. The Scientific Investigation of the Biological Pathways Following Thermal Injury-2 study aims to prospectively validate neutrophil phagocytic activity, IG count and plasma cfDNA levels as early prognostic biomarkers of sepsis in thermally injured adult and paediatric patients. METHODS AND ANALYSIS: This multicentre, longitudinal, observational cohort study will enrol 245 paediatric and adult patients with moderate to severe burns within 24 hours of injury. Blood samples will be obtained at 19 postinjury time points (days 1-14, day 28, months 3, 6, 12 and 24) and analysed for neutrophil phagocytic activity, IG count and cfDNA levels. Patients will be screened daily for sepsis using the 2007 American Burn Association diagnostic criteria for sepsis. In addition, daily multiple organ dysfunction syndrome and Sequential Organ Failure Assessment Scores will be recorded relationships between neutrophil phagocytic activity, IG count and plasma cfDNA levels on day 1 of injury and the development of sepsis will be examined using logistic regression models. ETHICS AND DISSEMINATION: This study received ethics approval from the West Midlands, Coventry and Warwickshire Research Ethics Committee (REC reference:16/WM/0217). Findings will be presented at national and international conferences, and submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04693442.

Heparin resistance in severe thermal injury: A prospective cohort study.

BACKGROUND: Low molecular-weight heparin (LMWH) is routinely administered to burn patients for thromboprophylaxis. Some studies have reported heparin resistance, yet the mechanism(s) and prevalence have not been systematically studied. We hypothesized that nucleosomes, composed of histone structures with associated DNA released from injured tissue and activated immune cells in the form of neutrophil extracellular traps (NETs or NETosis), neutralize LMWH resulting in suboptimal anticoagulation, assessed by reduction in anti-factor Xa activity. METHODS: Blood was sampled from >15% total body surface area (TBSA) burn patients receiving LMWH on days 5, 10 and 14. Peak anti-factor Xa (AFXa) activity, anti-thrombin (ATIII) activity, cell-free DNA (cfDNA) levels and nucleosome levels were measured. Mixed effects regression was adjusted for multiple confounders, including injury severity and ATIII activity, and was used to test the association between nucleosomes and AFXa. RESULTS: A total of 30 patients with severe burns were included. Mean TBSA 43% (SD 17). Twenty-three (77%) patients were affected by heparin resistance (defined by AFXa activity <0.2 IU/mL). Mean peak AFXa activity across samples was 0.18 IU/mL (SD 0.11). Mean ATIII was 81.9% activity (SD 20.4). Samples taken at higher LWMH doses were found to have significantly increased AFXa activity, though the effect was not observed at all doses, at 8000 IU no samples were heparin resistant. Nucleosome levels were negatively correlated with AFXa (r = -0.29, p = 0.050) consistent with the hypothesis. The final model, with peak AFXa as the response variable, was adjusted for nucleosome levels (p = 0.0453), ATIII activity (p = 0.0053), LMWH dose pre-sample (p = 0.0049), drug given (enoxaparin or tinzaparin) (p = 0.03), and other confounders including severity of injury, age, gender, time point of sample. CONCLUSIONS: Heparin resistance is a prevalent issue in severe burns. Nucleosome levels were increased post-burn, and showed an inverse association with AFXa consistent with the hypothesis that they may interfere with the anticoagulant effect of heparin in vivo and contribute to heparin resistance. Accurate monitoring of AFXa activity with appropriate therapy escalation plans are recommended with dose adjustment following severe burn injury.

Stability of OCT and OCTA in the Intensive Therapy Unit Setting.

To assess the stability of retinal structure and blood flow measures over time and in different clinical settings using portable optical coherence tomography angiography (OCTA) as a potential biomarker of central perfusion in critical illness, 18 oesophagectomy patients completed retinal structure and blood flow measurements by portable OCT and OCTA in the eye clinic and intensive therapy unit (ITU) across three timepoints: (1) pre-operation in a clinic setting; (2) 24-48 h post-operation during ITU admission; and (3) seven days post-operation, if the patient was still admitted. Blood flow and macular structural measures were stable between the examination settings, with no consistent variation between pre- and post-operation scans, while retinal nerve fibre layer thickness increased in the post-operative scans (+2.31 µm, p = 0.001). Foveal avascular zone (FAZ) measurements were the most stable, with an intraclass correlation coefficient of up to 0.92 for right eye FAZ area. Blood flow and structural measures were lower in left eyes than right eyes. Retinal blood flow assessed in patients before and during an ITU stay using portable OCTA showed no systematic differences between the clinical settings. The stability of retinal blood flow measures suggests the potential for portable OCTA to provide clinically useful measures in ITU patients.

A new syndrome of moyamoya disease, kidney dysplasia, aminotransferase elevation, and skin disease associated with de novo variants in RNF213.

Ring-finger protein 213 (RNF213) encodes a protein of unknown function believed to play a role in cellular metabolism and angiogenesis. Gene variants are associated with susceptibility to moyamoya disease. Here, we describe two children with moyamoya disease who also demonstrated kidney disease, elevated aminotransferases, and recurrent skin lesions found by exome sequencing to have de novo missense variants in RNF213. These cases highlight the ability of RNF213 to cause Mendelian moyamoya disease in addition to acting as a genetic susceptibility locus. The cases also suggest a new, multi-organ RNF213-spectrum disease characterized by liver, skin, and kidney pathology in addition to severe moyamoya disease caused by heterozygous, de novo C-terminal RNF213 missense variants.

Traumatic injury is associated with reduced deoxyribonuclease activity and dysregulation of the actin scavenging system.

BACKGROUND: Traumatic injury is associated with increased concentrations of cell-free DNA (cfDNA) in the circulation, which contribute to post-injury complications. The endonuclease deoxyribonuclease 1 (DNase-1) is responsible for removing 90% of circulating cfDNA. Recently, DNase activity was reported to be significantly reduced following major non-traumatic brain injury (TBI), but the processes responsible were not investigated. Moreover, it is not known how quickly following injury DNase activity is reduced and whether this also occurs after TBI. METHODS: At 3 post-injury time points (≤1, 4-12 and 48-72 hours), blood samples were obtained from 155 adult trauma patients that had sustained an isolated TBI (n = 21), TBI with accompanying extracranial injury (TBI+) (n = 53) or an extracranial injury only (ECI) (n = 81). In addition to measuring cfDNA levels and the activity and expression of DNase, circulating concentrations of monomeric globular action (G-actin), an inhibitor of DNase-1, and the actin scavenging proteins gelsolin (GSN) and vitamin D binding protein (VDBP) were determined and values compared to a cohort of healthy controls. RESULTS: Significantly elevated concentrations of plasma cfDNA were seen in TBI, TBI+ and ECI patients at all study time points when compared to healthy controls. cfDNA levels were significantly higher at ≤1 hour post-injury in ECI patients who subsequently developed multiple organ dysfunction syndrome when compared to those who did not. Plasma DNase-1 protein was significantly elevated in all patient groups at all sampling time points. In contrast, DNase enzyme activity was significantly reduced, with this impaired function evident in TBI+ patients within minutes of injury. Circulating concentrations of G-actin were elevated in all patient cohorts in the immediate aftermath of injury and this was accompanied by a significant reduction in the levels of GSN and VDBP. CONCLUSIONS: The post-traumatic increase in circulating cfDNA that occurs following extracranial trauma and TBI is accompanied by reduced DNase activity. We propose that, secondary to reduced GSN and VDBP levels, elevated circulating concentrations of G-actin underlie the post-injury reduction in DNase activity. Reducing circulating cfDNA levels via therapeutic restoration of DNase-1 activity may improve clinical outcomes post-injury.

A Randomized Trial of Prophylactic Antibiotics for Miscarriage Surgery.

BACKGROUND: Surgical intervention is needed in some cases of spontaneous abortion to remove retained products of conception. Antibiotic prophylaxis may reduce the risk of pelvic infection, which is an important complication of this surgery, particularly in low-resource countries. METHODS: We conducted a double-blind, placebo-controlled, randomized trial investigating whether antibiotic prophylaxis before surgery to complete a spontaneous abortion would reduce pelvic infection among women and adolescents in low-resource countries. We randomly assigned patients to a single preoperative dose of 400 mg of oral doxycycline and 400 mg of oral metronidazole or identical placebos. The primary outcome was pelvic infection within 14 days after surgery. Pelvic infection was defined by the presence of two or more of four clinical features (purulent vaginal discharge, pyrexia, uterine tenderness, and leukocytosis) or by the presence of one of these features and the clinically identified need to administer antibiotics. The definition of pelvic infection was changed before the unblinding of the data; the original strict definition was two or more of the clinical features, without reference to the administration of antibiotics. RESULTS: We enrolled 3412 patients in Malawi, Pakistan, Tanzania, and Uganda. A total of 1705 patients were assigned to receive antibiotics and 1707 to receive placebo. The risk of pelvic infection was 4.1% (68 of 1676 pregnancies) in the antibiotics group and 5.3% (90 of 1684 pregnancies) in the placebo group (risk ratio, 0.77; 95% confidence interval [CI], 0.56 to 1.04; P = 0.09). Pelvic infection according to original strict criteria was diagnosed in 1.5% (26 of 1700 pregnancies) and 2.6% (44 of 1704 pregnancies), respectively (risk ratio, 0.60; 95% CI, 0.37 to 0.96). There were no significant between-group differences in adverse events. CONCLUSIONS: Antibiotic prophylaxis before miscarriage surgery did not result in a significantly lower risk of pelvic infection, as defined by pragmatic broad criteria, than placebo. (Funded by the Medical Research Council and others; AIMS Current Controlled Trials number, ISRCTN97143849.).

The potential of visible blue light (405 nm) as a novel decontamination strategy for carbapenemase-producing enterobacteriaceae (CPE).

Background: Carbapenemase-producing Enterobacteriaceae (CPE) pose a considerable threat to modern medicine. New treatment options and methods to limit spread need to be investigated. Blue light (BL) is intrinsically antimicrobial, and we have previously demonstrated significant antimicrobial effects on biofilms of a panel of isolates, including two CPEs.This study was performed to assess the antibacterial activity of 405 nm BL against a panel of CPE isolates (four encoding blaNDM, three blaKPC, two blaOXA-48, and three encoding both NDM and OXA-48 carbapenemases). Methods: In vitro experiments were conducted on 72 h old biofilms of CPEs which were exposed to 60 mW/cm2 of BL. Changes to biofilm seeding were assessed by measuring the optical density of treated and untreated biofilms. Results: Twelve bacterial clinical isolates (comprising eight Klebsiella pnemoniae, one K. oxytoca, and three Escherichia coli) were tested. BL was delivered for 5, 15 and 30 min, achieving doses of 162, 54, and 108 J/cm2, respectively.All of the CPEs were susceptible to BL treatment, with increasing reductions in seeding with increasing durations of exposure. At 30 min, reductions in biofilm seeding of ≥80% were observed for 11 of the 12 isolates, compared to five of 12 after 15 min. CPE_8180 was less susceptible than the rest, with a maximum reduction in seeding of 66% at 30 min. Conclusions: BL is effective at reducing the seeding of mature CPE biofilms in vitro, and offers great promise as a topical decontamination/treatment agent for both clinical and environmental applications.

Study of Concussion in Rugby Union through MicroRNAs (SCRUM): a study protocol of a prospective, observational cohort study.

INTRODUCTION: The diagnosis of mild traumatic brain injury or sports-related concussion is a challenge for all clinicians, players, coaches and parents involved in contact sports. Currently, there is no validated objective biomarker available to assess the presence or severity of concussion in sport, and so it is necessary to rely on subjective measures like self-reporting of symptoms which depend on the cooperation of the athlete. There is a significant health risk associated with repetitive injury if the diagnosis is missed, and so there is great value in an objective biomarker to assist diagnostic and prognostic decisions. OBJECTIVE: To establish a panel of non-invasive MicroRNA biomarkers in urine and saliva for the rapid diagnosis of sports-related concussion and investigate the kinetics and clinical utility of these biomarkers in assisting diagnostic, prognostic and return-to-play decisions. METHODS AND ANALYSIS: Observational, prospective, multicentre cohort study recruiting between the 2017-2018 and 2018-2019 Rugby Union seasons. Professional rugby players in the two highest tiers of senior professional domestic rugby competition in England will be recruited prospectively to the study. During the season, three groups will be identified: athletes entering the World Rugby Head Injury Assessment (HIA) protocol, uninjured control athletes and control athletes with musculoskeletal injuries. Saliva and urine will be collected from these athletes at multiple timepoints, coinciding with key times in the HIA protocol and return-to-play process. ETHICS AND DISSEMINATION: Ethics approval has been obtained. The compiled and analysed results will be presented at national and international conferences concerning the care of patients with traumatic brain injury. Results will also be submitted for peer review and publication in the subject journals/literature.

Combined liver and pancreas transplantation in two children with cystic fibrosis-First experience in Australia and New Zealand.

We report the first two pediatric patients with CF who underwent successful combined liver-pancreas transplantation in Australia and New Zealand for CF liver disease and CF-related diabetes mellitus.

Platelet count: A predictor of sepsis and mortality in severe burns.

BACKGROUND: Platelet cells, or thrombocytes, have additional roles to haemostasis. After burn injury, platelet counts drop to a nadir at days 2-5 then rise to a peak between days 10-18. The nadir has previously been associated with mortality but there is currently no thorough investigation of its potential to predict sepsis in adults. The primary objective of this study is to assess whether platelet count can predict survival and sepsis in adults with severe burn injuries. METHODS AND FINDINGS: A retrospective cohort analysis of platelet count and other blood parameters in 145 burn patients with a TBSA greater than 20%. AUROC analysis revealed that the platelet count and rBaux score together produce moderate discrimination for survival at less than 24h after injury (AUROC=0.848, 95%CI 0.765-0.930). Platelet count at day 3 combined with TBSA has a modest association with sepsis (AUROC=0.779, 95%CI 0.697-0.862). Multivariable Cox regression analysis revealed platelet peak was the strongest predictor of mortality. CONCLUSIONS: A reduced peak platelet count is a strong predictor of 50-day mortality. Platelet count nadir may have some association with sepsis.

Prehospital immune responses and development of multiple organ dysfunction syndrome following traumatic injury: A prospective cohort study.

BACKGROUND: Almost all studies that have investigated the immune response to trauma have analysed blood samples acquired post-hospital admission. Thus, we know little of the immune status of patients in the immediate postinjury phase and how this might influence patient outcomes. The objective of this study was therefore to comprehensively assess the ultra-early, within 1-hour, immune response to trauma and perform an exploratory analysis of its relationship with the development of multiple organ dysfunction syndrome (MODS). METHODS AND FINDINGS: The immune and inflammatory response to trauma was analysed in 89 adult trauma patients (mean age 41 years, range 18-90 years, 75 males) with a mean injury severity score (ISS) of 24 (range 9-66), from whom blood samples were acquired within 1 hour of injury (mean time to sample 42 minutes, range 17-60 minutes). Within minutes of trauma, a comprehensive leukocytosis, elevated serum pro- and anti-inflammatory cytokines, and evidence of innate cell activation that included neutrophil extracellular trap generation and elevated surface expression of toll-like receptor 2 and CD11b on monocytes and neutrophils, respectively, were observed. Features consistent with immune compromise were also detected, notably elevated numbers of immune suppressive CD16BRIGHT CD62LDIM neutrophils (82.07 x 106/l ± 18.94 control versus 1,092 x 106/l ± 165 trauma, p < 0.0005) and CD14+HLA-DRlow/- monocytes (34.96 x 106/l ± 4.48 control versus 95.72 x 106/l ± 8.0 trauma, p < 0.05) and reduced leukocyte cytokine secretion in response to lipopolysaccharide stimulation. Exploratory analysis via binary logistic regression found a potential association between absolute natural killer T (NKT) cell numbers and the subsequent development of MODS. Study limitations include the relatively small sample size and the absence of data relating to adaptive immune cell function. CONCLUSIONS: Our study highlighted the dynamic and complex nature of the immune response to trauma, with immune alterations consistent with both activation and suppression evident within 1 hour of injury. The relationship of these changes, especially in NKT cell numbers, to patient outcomes such as MODS warrants further investigation.

Reviewing deaths in British and US hospitals: a study of two scales for assessing preventability.

BACKGROUND: Standardised mortality ratios do not provide accurate measures of preventable mortality. This has generated interest in using case notes to assess the preventable component of mortality. But, different methods of measurement have not been compared. We compared the reliability of two scales for assessing preventability and the correspondence between them. METHODS: Medical specialists reviewed case notes of patients who had died in hospital, using two instruments: a five-point Likert scale and a continuous (0-100) scale of preventability. To enhance generalisability, we used two different hospital datasets with different types of acute medical patients across different epochs, and in two jurisdictions (UK and USA). We investigated the reliability of measurement and correspondence of preventability estimates across the two scales. Ordinal mixed effects regression methods were used to analyse the Likert scale and to calibrate it against the continuous scale. We report the estimates of the probability a death could have been prevented, accounting for reviewer inconsistency. RESULTS: Correspondence between the two scales was strong; the Likert categories explained most of the variation (76% UK, 73% USA) in the continuous scale. Measurement reliability was low, but similar across the two instruments in each dataset (intraclass correlation: 0.27, UK; 0.23, USA). Adjusting for the inconsistency of reviewer judgements reduced the proportion of cases with high preventability, such that the proportion of all deaths judged probably or definitely preventable on the balance of probability was less than 1%. CONCLUSIONS: The correspondence is high between a Likert and a continuous scale, although the low reliability of both would suggest careful measurement design would be needed to use either scale. Few to no cases are above the threshold when using a balance of probability approach to determining a preventable death, and in any case, there is little evidence supporting anything more than an ordinal correspondence between these reviewer estimates of probability and the true probability. Thus, it would be more defensible to use them as an ordinal measure of the quality of care received by patients who died in the hospital.