A randomised Trial of Autologous Blood products, leukocyte and platelet-rich fibrin (L-PRF), to promote ulcer healing in LEprosy: The TABLE trial.

INTRODUCTION: Autologous blood products like Platelet Rich Plasma (PRP) and Leukocyte and Platelets Rich Fibrin (L-PRF) have been used for many years across many types of skin ulcers. However, the effectiveness of autologous blood products on wound healing is not well established. METHODS: We evaluated the 'second generation' autologous product- Leukocyte and Platelet- Rich Fibrin (L-PRF). Our trial was undertaken on patients suffering from neuropathic leprosy ulcers at the Anandaban hospital which serves the entire country of Nepal. We conducted a 1:1 (n = 130) individually randomised trial of L-PRF (intervention) vs. normal saline dressing (control) to compare rate of healing and time to complete healing. Rate of healing was estimated using blind assessments of ulcer areas based on three different measurement methods. Time to complete healing was measured by the local unblinded clinicians and by blind assessment of ulcer images. RESULTS: The point estimates for both outcomes were favourable to L-PRF but the effect sizes were small. Unadjusted mean differences (intervention vs control) in mean daily healing rates (cm2) were respectively 0.012 (95% confidence interval 0.001 to 0.023, p = 0.027); 0.016 (0.004 to 0.027, p = 0.008) and 0.005 (-0.005 to 0.016, p = 0.313) across the three measurement methods. Time to complete healing at 42 days yielded Hazard Ratios (unadjusted) of 1.3 (0.8 to 2.1, p = 0.300) assessed by unblinded local clinicians and 1.2 (0.7 to 2.0, p = 0.462) on blind assessment. CONCLUSION: Any benefit from L-PRF appears insufficient to justify routine use in care of neuropathic ulcers in leprosy. TRIAL REGISTRATION: ISRCTN14933421. Date of trial registration: 16 June 2020.

Targeting patient recovery priorities in degenerative cervical myelopathy: design and rationale for the RECEDE-Myelopathy trial-study protocol.

INTRODUCTION: Degenerative cervical myelopathy (DCM) is a common and disabling condition of symptomatic cervical spinal cord compression secondary to degenerative changes in spinal structures leading to a mechanical stress injury of the spinal cord. RECEDE-Myelopathy aims to test the disease-modulating activity of the phosphodiesterase 3/phosphodiesterase 4 inhibitor Ibudilast as an adjuvant to surgical decompression in DCM. METHODS AND ANALYSIS: RECEDE-Myelopathy is a multicentre, double-blind, randomised, placebo-controlled trial. Participants will be randomised to receive either 60-100 mg Ibudilast or placebo starting within 10 weeks prior to surgery and continuing for 24 weeks after surgery for a maximum of 34 weeks. Adults with DCM, who have a modified Japanese Orthopaedic Association (mJOA) score 8-14 inclusive and are scheduled for their first decompressive surgery are eligible for inclusion. The coprimary endpoints are pain measured on a visual analogue scale and physical function measured by the mJOA score at 6 months after surgery. Clinical assessments will be undertaken preoperatively, postoperatively and 3, 6 and 12 months after surgery. We hypothesise that adjuvant therapy with Ibudilast leads to a meaningful and additional improvement in either pain or function, as compared with standard routine care. STUDY DESIGN: Clinical trial protocol V.2.2 October 2020. ETHICS AND DISSEMINATION: Ethical approval has been obtained from HRA-Wales.The results will be presented at an international and national scientific conferences and in a peer-reviewed journals. TRIAL REGISTRATION NUMBER: ISRCTN Number: ISRCTN16682024.

Concussion in Non-athletes: Assessment of Cognition and Symptomatology (CONTACTS) study protocol - an exploratory cohort study investigating the utility of sports concussion assessment tools and salivary microRNAs to diagnose concussion in NHS patients.

INTRODUCTION: Concussion is a complex pathophysiological process with a wide range of non-specific signs and symptoms. There are currently no objective diagnostic tests to identify concussion, and diagnosis relies solely on history and examination. Recent research has identified a unique panel of microRNAs (miRNAs) that distinguish between concussed and non-concussed rugby players. This study aims to assess the diagnostic utility of salivary miRNAs in concussion for a sample of UK National Health Service patients and whether well-established sports-related concussion (SRC) assessment tools may be translated into the emergency department (ED). METHODS AND ANALYSIS: Concussion in Non-athletes: Assessment of Cognition and Symptomatology is a single-centre, prospective, two-phase cohort study. The concussed cohort will consist of participants with maxillofacial trauma and concurrent concussion. The control cohort will consist of participants with isolated limb trauma and no evidence of concussion. Participants will be recruited in the ED and saliva samples will be taken to identify the presence of miRNAs. The SRC assessments being investigated include the Sports Concussion Assessment Test, Fifth Edition (SCAT5), the Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) and the ImPACT Quick. Follow-up will be at 24-48 hours in-hospital and remotely via telephone and email at 14 days and 6 months. ETHICS AND DISSEMINATION: Ethical approval was granted in February 2021 by the West Midlands Coventry & Warwickshire Research Ethics Committee (ref 20/WM/0299). The investigators intend to submit their study findings for publication in peer-reviewed journals and to disseminate study findings via presentation at academic meetings. The results will also form part of a doctorate thesis, registered at the University of Birmingham.

Estimating Risk of Chronic Pain and Disability Following Musculoskeletal Trauma in the United Kingdom.

Importance: Serious traumatic injury is a leading cause of death and disability globally, with most survivors known to develop chronic pain. Objective: To describe early variables associated with poor long-term outcome for posttrauma pain and create a clinical screening tool for this purpose. Design, Setting, and Participants: This was a prospective cohort study at a major trauma center hospital in England. Recruitment commenced in December 2018 and ceased in March 2020. Participants were followed up for 12 months. Patients aged 16 years or older who were hospitalized because of acute musculoskeletal trauma within the preceding 14 days were included. Data were analyzed from March to December 2021. Exposure: Acute musculoskeletal trauma requiring admittance to a major trauma center hospital. Main Outcomes and Measures: A poor outcome was defined as Chronic Pain Grade II or higher and measured at both 6 months (primary time point) and 12 months. A broad range of candidate variables potentially associated with outcomes were used, including surrogates for pain mechanisms, quantitative sensory testing, and psychosocial factors. Univariable models were used to identify the variables most likely to be associated with poor outcome, which were entered into multivariable models. A clinical screening tool (nomogram) was derived from 6-month results. Results: In total, 1590 consecutive patients were assessed for eligibility, of whom 772 were deemed eligible and 124 (80 male [64.5%]; mean [SD] age, 48.9 [18.8] years) were recruited. At 6 months, 19 of 82 respondents (23.2%) reported a good outcome, whereas at 12 months 27 of 44 respondents (61.4%) reported a good outcome. At 6 months on univariable analysis, an increase in total posttraumatic stress symptoms (odds ratio [OR], 2.09; 95% CI, 1.33-3.28), pain intensity average (OR, 2.87; 95% CI, 1.37-6.00), number of fractures (OR, 2.79; 95% CI, 1.02-7.64), and pain extent (OR, 4.67; 95% CI, 1.57-13.87) were associated with worse outcomes. A multivariable model including those variables had a sensitivity of 0.93, a specificity of 0.54, and C-index of 0.92. Conclusions and Relevance: A poor long-term pain outcome from musculoskeletal traumatic injuries may be estimated by measures recorded within days of injury. These findings suggest that posttraumatic stress symptoms, pain spatial distribution, perceived average pain intensity, and number of fractures are good candidates for a sensitive multivariable model and derived clinical screening tool.

Results of a pilot feasibility randomised controlled trial exploring the use of an electronic patient-reported outcome measure in the management of UK patients with advanced chronic kidney disease.

OBJECTIVES: The use of routine remote follow-up of patients with chronic kidney disease (CKD) is increasing exponentially. It has been suggested that online electronic patient-reported outcome measures (ePROMs) could be used in parallel, to facilitate real-time symptom monitoring aimed at improving outcomes. We tested the feasibility of this approach in a pilot trial of ePROM symptom monitoring versus usual care in patients with advanced CKD not on dialysis. DESIGN: A 12-month, parallel, pilot randomised controlled trial (RCT) and qualitative substudy. SETTING AND PARTICIPANTS: Queen Elizabeth Hospital Birmingham, UK. Adult patients with advanced CKD (estimated glomerular filtration rate ≥6 and ≤15 mL/min/1.73 m2, or a projected risk of progression to kidney failure within 2 years ≥20%). INTERVENTION: Monthly online ePROM symptom reporting, including automated feedback of tailored self-management advice and triggered clinical notifications in the advent of severe symptoms. Real-time ePROM data were made available to the clinical team via the electronic medical record. OUTCOMES: Feasibility (recruitment and retention rates, and acceptability/adherence to the ePROM intervention). Health-related quality of life, clinical data (eg, measures of kidney function, kidney failure, hospitalisation, death) and healthcare utilisation. RESULTS: 52 patients were randomised (31% of approached). Case report form returns were high (99.5%), as was retention (96%). Overall, 73% of expected ePROM questionnaires were received. Intervention adherence was high beyond 90 days (74%) and 180 days (65%); but dropped beyond 270 days (46%). Qualitative interviews supported proof of concept and intervention acceptability, but highlighted necessary changes aimed at enhancing overall functionality/scalability of the ePROM system. LIMITATIONS: Small sample size. CONCLUSIONS: This pilot trial demonstrates that patients are willing to be randomised to a trial assessing ePROM symptom monitoring. The intervention was considered acceptable; though measures to improve longer-term engagement are needed. A full-scale RCT is considered feasible. TRIAL REGISTRATION NUMBER: ISRCTN12669006 and the UK NIHR Portfolio (CPMS ID: 36497).

A rapid intrapartum test for group B Streptococcus to reduce antibiotic usage in mothers with risk factors: the GBS2 cluster RCT.

BACKGROUND: Mother-to-baby transmission of group B Streptococcus (Streptococcus agalactiae) is the main cause of early-onset infection. OBJECTIVES: We investigated if intrapartum antibiotic prophylaxis directed by a rapid intrapartum test reduces maternal and neonatal antibiotic use, compared with usual care (i.e. risk factor-directed antibiotics), among women with risk factors for vertical group B Streptococcus transmission, and examined the accuracy and cost-effectiveness of the rapid test. DESIGN: An unblinded cluster randomised controlled trial with a nested test accuracy study, an economic evaluation and a microbiology substudy. SETTING: UK maternity units were randomised to either a strategy of rapid test or usual care. PARTICIPANTS: Vaginal and rectal swabs were taken from women with risk factors for vertical group B Streptococcus transmission in established term labour. The accuracy of the GeneXpert® Dx IV GBS rapid testing system (Cepheid, Maurens-Scopont, France) was compared with the standard of selective enrichment culture in diagnosing maternal group B Streptococcus colonisation. MAIN OUTCOME MEASURES: Primary outcomes were rates of intrapartum antibiotic prophylaxis administered to prevent early-onset group B Streptococcus infection and accuracy estimates of the rapid test. Secondary outcomes were maternal antibiotics for any indication, neonatal antibiotic exposure, maternal antibiotic duration, neonatal group B Streptococcus colonisation, maternal and neonatal antibiotic resistance, neonatal morbidity and mortality, and cost-effectiveness of the strategies. RESULTS: Twenty-two maternity units were randomised and 20 were recruited. A total of 722 mothers (749 babies) participated in rapid test units and 906 mothers (951 babies) participated in usual-care units. There were no differences in the rates of intrapartum antibiotic prophylaxis for preventing early-onset group B Streptococcus infection in the rapid test units (41%, 297/716) compared with the usual-care units (36%, 328/906) (risk ratio 1.16, 95% confidence interval 0.83 to 1.64). There were no differences between the groups in intrapartum antibiotic administration for any indication (risk ratio 0.99, 95% confidence interval 0.81 to 1.21). Babies born in the rapid test units were 29% less likely to receive antibiotics (risk ratio 0.71, 95% confidence interval 0.54 to 0.95) than those born in usual-care units. The sensitivity and specificity of the rapid test were 86% (95% confidence interval 81% to 91%) and 89% (95% confidence interval 85% to 92%), respectively. In 14% of women (99/710), the rapid test was invalid or the machine failed to provide a result. In the economic analysis, the rapid test was shown to be both less effective and more costly and, therefore, dominated by usual care. Sensitivity analysis indicated potential lower costs for the rapid test strategy when neonatal costs were included. No serious adverse events were reported. CONCLUSIONS: The Group B Streptococcus 2 (GBS2) trial found no evidence that the rapid test reduces the rates of intrapartum antibiotic prophylaxis administered to prevent early-onset group B Streptococcus infection. The rapid test has the potential to reduce neonatal exposure to antibiotics, but economically is dominated by usual care. The accuracy of the test is within acceptable limits. FUTURE WORK: The role of routine testing for prevention of neonatal infection requires evaluation in a randomised controlled trial. TRIAL REGISTRATION: Current Controlled Trials ISRCTN74746075. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 12. See the NIHR Journals Library website for further project information.

WHAT IS THE PROBLEM?: Group B Streptococcus is a common bacterium found in the vagina and intestines of approximately one in four women. Group B Streptococcus may be passed to the baby around birth and cause severe infection. In the UK, women are offered antibiotics in labour to protect their baby from group B Streptococcus infection when specific risk factors are present. Most women with risk factors do not carry group B Streptococcus and their babies are unnecessarily exposed to antibiotics. Most women carrying group B Streptococcus do not have risk factors and so will not be offered antibiotics to protect their babies. WHAT DID WE PLAN TO DO?: We planned to find out if, for women with risk factors, a 'rapid test' in labour resulted in fewer women receiving antibiotics compared with 'usual care'. We also wanted to establish if the test correctly identified if mothers were carrying group B Streptococcus, helped reduce infections in babies and represented value for money. WHAT DID WE FIND?: We involved 1627 women (1700 babies) from 20 hospitals randomly allocated to rapid test or usual care. Using the 'rapid test' did not reduce antibiotics provided to mothers (41% in rapid test units and 36% in usual-care units). The test correctly identified 86% of women carrying group B Streptococcus, 89% of those who did not and failed to provide a result in 14% of women. A rapid test policy resulted in 13% fewer babies receiving antibiotics. The rapid test generated no cost savings when only the mothers' care was considered, but there was potential for reduced costs when including the newborns' hospital stay. WHAT DOES THIS MEAN?: The rapid test is accurate; however, using it for women with risk factors for their baby developing group B Streptococcus infection does not reduce antibiotic usage in mothers, although it does in babies. Value for money is uncertain and depends on what costs are included.

Rapid intrapartum test for maternal group B streptococcal colonisation and its effect on antibiotic use in labouring women with risk factors for early-onset neonatal infection (GBS2): cluster randomised trial with nested test accuracy study.

BACKGROUND: Mother-to-baby transmission of group B Streptococcus (GBS) is the main cause of early-onset infection. We evaluated whether, in women with clinical risk factors for early neonatal infection, the use of point-of-care rapid intrapartum test to detect maternal GBS colonisation reduces maternal antibiotic exposure compared with usual care, where antibiotics are administered due to those risk factors. We assessed the accuracy of the rapid test in diagnosing maternal GBS colonisation, against the reference standard of selective enrichment culture. METHODS: We undertook a parallel-group cluster randomised trial, with nested test accuracy study and microbiological sub-study. UK maternity units were randomised to a strategy of rapid test (GeneXpert GBS system, Cepheid) or usual care. Within units assigned to rapid testing, vaginal-rectal swabs were taken from women with risk factors for vertical GBS transmission in established term labour. The trial primary outcome was the proportion of women receiving intrapartum antibiotics to prevent neonatal early-onset GBS infection. The accuracy of the rapid test was compared against the standard of selective enrichment culture in diagnosing maternal GBS colonisation. Antibiotic resistance profiles were determined in paired maternal and infant samples. RESULTS: Twenty-two maternity units were randomised and 20 were recruited. A total of 722 mothers (749 babies) participated in rapid test units; 906 mothers (951 babies) were in usual care units. There was no evidence of a difference in the rates of intrapartum antibiotic prophylaxis (relative risk 1.16, 95% CI 0.83 to 1.64) between the rapid test (41%, 297/716) and usual care (36%, 328/906) units. No serious adverse events were reported. The sensitivity and specificity measures of the rapid test were 86% (95% CI 81 to 91%) and 89% (95% CI 85 to 92%), respectively. Babies born to mothers who carried antibiotic-resistant Escherichia coli were more likely to be colonised with antibiotic-resistant strains than those born to mothers with antibiotic-susceptible E. coli. CONCLUSION: The use of intrapartum rapid test to diagnose maternal GBS colonisation did not reduce the rates of antibiotics administered for preventing neonatal early-onset GBS infection than usual care, although with considerable uncertainty. The accuracy of the rapid test is within acceptable limits. TRIAL REGISTRATION: ISRCTN74746075 . Prospectively registered on 16 April 2015.

An individual randomised efficacy trial of autologous blood products, leukocyte and platelet-rich fibrin (L-PRF), to promote ulcer healing in leprosy in Nepal: the TABLE trial protocol.

BACKGROUND: Leprosy is curable with multidrug therapy and treatment in the early stages can prevent disability. However, local nerve damage can lead to injury and consequently recurring and disfiguring ulcers. The aim of this study is to evaluate the treatment of leprosy ulcers using an autologous blood product; leukocyte and platelet-rich fibrin (L-PRF) to promote healing. METHODS: This is a single-centre study in the Anandaban Hospital, The Leprosy Mission Nepal, Kathmandu, Nepal. Consenting patients (n=130) will be individually randomised in a single-blinded, controlled trial. Participants will be 18 years of age or older, admitted to the hospital with a clean, dry and infection-free chronic foot ulcer between 2 and 20 cm2 in size. If the ulcer is infected, it will be treated before enrolment into the study. The intervention involves the application of leukocyte and platelet-rich fibrin (L-PRF) matrix on the ulcer beds during twice-weekly dressing changes. Controls receive usual care in the form of saline dressings only during their twice-weekly dressing changes. Primary outcomes are the rate of healing assessed using standardised photographs by observers blind to allocated treatment, and time to complete re-epithelialization. Follow-up is at 6 months from randomisation. DISCUSSION: This research will provide valuable information on the clinical and cost-effectiveness of L-PRF in the treatment of leprosy ulcers. An additional benefit is the evaluation of the effects of treatment on quality of life for people living with leprosy ulcers. The results will improve our understanding of the scalability of this treatment across low-income countries for ulcer healing in leprosy and potentially other conditions such as diabetic ulcers. TRIAL REGISTRATION: ClinicalTrials.gov ISRCTN14933421 . Registered on 16 June 2020.

Development of an electronic patient-reported outcome measure (ePROM) system to aid the management of patients with advanced chronic kidney disease.

BACKGROUND: Effective management of patients with chronic kidney disease (CKD) relies on timely detection of clinical deterioration towards end stage kidney failure. We aimed to design an electronic Patient-Reported Outcome Measure (ePROM) system, which would allow patients with advanced CKD (pre-dialysis) to: (i) remotely self-report their symptoms using a simple and secure online platform; (ii) share the data with the clinical team in real-time via the electronic patient record to help optimise care. We adopted a staged development process which included: a systematic review of PROMs used in CKD; formation of a co-design team; prototype system design/development, user acceptance testing and refinement; finalisation of the system for testing in a pilot/feasibility trial. RESULTS: A co-design team was convened, including patients with lived experience of CKD; clinical team members; IT/Informatics experts; academics; and Birmingham Clinical Trials Unit representatives. A prototype system was developed and iterative changes made before finalisation during a series of operational meetings. The system allows patients to remotely self-report their symptoms; provides tailored self-management advice; allows monitoring of real-time patient ePROM data; sends automated notifications to the patient/clinical team in the advent of a severe symptom report; and incorporates longitudinal ePROM symptom data into the electronic patient record. Feasibility of the system will be evaluated as part of the National Institute for Health Research funded RePROM (Renal electronic Patient-Reported Outcome Measure) pilot trial (ISRCTN12669006). CONCLUSIONS: Routine ePROM collection with real-time feedback has the potential to improve outcomes and reduce health service costs. We have successfully developed a trial-ready ePROM system for advanced CKD, the feasibility of which is currently being explored in a pilot trial. Assuming feasibility is demonstrated, formal evaluation of efficacy will take place in a future multi-centre randomised controlled trial.

Mapping the Steroid Response to Major Trauma From Injury to Recovery: A Prospective Cohort Study.

CONTEXT: Survival rates after severe injury are improving, but complication rates and outcomes are variable. OBJECTIVE: This cohort study addressed the lack of longitudinal data on the steroid response to major trauma and during recovery. DESIGN: We undertook a prospective, observational cohort study from time of injury to 6 months postinjury at a major UK trauma centre and a military rehabilitation unit, studying patients within 24 hours of major trauma (estimated New Injury Severity Score (NISS) > 15). MAIN OUTCOME MEASURES: We measured adrenal and gonadal steroids in serum and 24-hour urine by mass spectrometry, assessed muscle loss by ultrasound and nitrogen excretion, and recorded clinical outcomes (ventilator days, length of hospital stay, opioid use, incidence of organ dysfunction, and sepsis); results were analyzed by generalized mixed-effect linear models. FINDINGS: We screened 996 multiple injured adults, approached 106, and recruited 95 eligible patients; 87 survived. We analyzed all male survivors <50 years not treated with steroids (N = 60; median age 27 [interquartile range 24-31] years; median NISS 34 [29-44]). Urinary nitrogen excretion and muscle loss peaked after 1 and 6 weeks, respectively. Serum testosterone, dehydroepiandrosterone, and dehydroepiandrosterone sulfate decreased immediately after trauma and took 2, 4, and more than 6 months, respectively, to recover; opioid treatment delayed dehydroepiandrosterone recovery in a dose-dependent fashion. Androgens and precursors correlated with SOFA score and probability of sepsis. CONCLUSION: The catabolic response to severe injury was accompanied by acute and sustained androgen suppression. Whether androgen supplementation improves health outcomes after major trauma requires further investigation.

Investigation into repetitive concussion in sport (RECOS): study protocol of a prospective, exploratory, observational cohort study.

INTRODUCTION: Sport-related concussion management remains a diagnostic dilemma to clinicians in all strata of care, coaching staff and players alike. The lack of objective diagnostic and prognostic biomarkers and over-reliance on subjective clinical assessments carries a significant health risk of undiagnosed concussive episodes and early return to play before full recovery increasing the risk of sustaining additional concussion, and leading to long-term sequelae and/or unfavourable outcome. OBJECTIVE: To identify a set of parameters (neuroimaging with neurophysiological, biological and neuropsychological tests) that may support pitch-side and outpatient clinical decision-making in order to objectively diagnose concussion, determine the severity of injury, guide a safe return to play and identify the potential predictors of the long-term sequelae of concussion. METHODS AND ANALYSIS: An exploratory, observational, prospective, cohort study recruiting between 2017 and 2020. The participants will have a baseline preseason screening (brain imaging, neuropsychological assessments, serum, urine and saliva sampling). If a screened player later suffers a concussion and/or multiple concussions then he/she will be assessed again with the same protocol within 72 hours, and their baseline data will be used as internal control as well as normative data. Inferential statistical analysis will be performed to determine correlations between biological, imaging techniques and neuropsychological assessments. ETHICS AND DISSEMINATION: This study was approved by the East of England-Essex Research Ethics Committee on 22 September 2017-REC 17/EE/0275; IRAS 216703. The results of this study will be presented at national and international conferences and submitted for publication in peer reviewed journals. TRIAL REGISTRATION NUMBER: ISRCTN16974791; Pre-results.

Impact of plasma viscosity on microcirculatory flow after traumatic haemorrhagic shock: A prospective observational study.

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.

Use of an electronic patient-reported outcome measure in the management of patients with advanced chronic kidney disease: the RePROM pilot trial protocol.

INTRODUCTION: Chronic kidney disease (CKD) affects up to 16% of adults in the UK. Patient quality of life is particularly reduced in end-stage renal disease and is strongly associated with increased hospitalisation and mortality. Thus, accurate and responsive healthcare is a key priority. Electronic patient-reported outcome measures (ePROMs) are online questionnaires which ask patients to self-rate their health status. Evidence in oncology suggests that the use of ePROM data within routine care, alongside clinical information, may enhance symptom management and improve patient outcomes. However, National Health Service (NHS)-based ePROM research in CKD is lacking. This pilot trial will assess the feasibility of undertaking a full-scale randomised controlled trial (RCT) in patients with CKD within the NHS. METHODS AND ANALYSIS: The renal ePROM pilot trial is an investigator-led single-centre, open-label, two-arm randomised controlled pilot trial of 66 participants ≥18 years with advanced CKD. Participants will be randomised to receive either usual care or usual care supplemented with an ePROM intervention. Participants within the intervention arm will be asked to submit monthly self-reports of their health status using the ePROM system. The system will provide tailored information to patients in response to each report and notify the clinical team of patient deterioration. The renal clinical team will monitor for ePROM notifications and will respond with appropriate action, in line with standard clinical practice. Measures of study feasibility, participant quality of life and CKD severity will be completed at 3 monthly intervals. Health economic outcomes will be assessed. Clinicians will record treatment decision-making. Acceptability and feasibility of the protocol will be assessed alongside outcome measure and intervention compliance rates. Qualitative process evaluation will be conducted. ETHICS AND DISSEMINATION: The findings will inform the design of a full-scale RCT and the results will be submitted for publication in peer-reviewed journals. The study has ethical approval. TRIAL REGISTRATION NUMBERS: ISRCTN12669006; Pre-results.

Prophylactic antibiotics to reduce pelvic infection in women having miscarriage surgery - The AIMS (Antibiotics in Miscarriage Surgery) trial: study protocol for a randomized controlled trial.

BACKGROUND: The estimated annual global burden of miscarriage is 33 million out of 210 million pregnancies. Many women undergoing miscarriage have surgery to remove pregnancy tissues, resulting in miscarriage surgery being one of the most common operations performed in hospitals in low-income countries. Infection is a serious consequence and can result in serious illness and death. In low-income settings, the infection rate following miscarriage surgery has been reported to be high. Good quality evidence on the use of prophylactic antibiotics for surgical miscarriage management is not available. Given that miscarriage surgery is common, and infective complications are frequent and serious, prophylactic antibiotics may offer a simple and affordable intervention to improve outcomes. METHODS: Eligible patients will be approached once the diagnosis of miscarriage has been made according to local practice. Once informed consent has been given, participants will be randomly allocated using a secure internet facility (1:1 ratio) to a single dose of oral doxycycline (400 mg) and metronidazole (400 mg) or placebo. Allocation will be concealed to both the patient and the healthcare providers. A total of 3400 women will be randomised, 1700 in each arm. The medication will be given approximately 2 hours before surgery, which will be provided according to local practice. The primary outcome is pelvic infection 2 weeks after surgery. Women will be invited to the hospital for a clinical assessment at 2 weeks. Secondary outcomes include overall antibiotic use, individual components of the primary outcome, death, hospital admission, unplanned consultations, blood transfusion, vomiting, diarrhoea, adverse events, anaphylaxis and allergy, duration of clinical symptoms, and days before return to usual activities. An economic evaluation will be performed to determine if prophylactic antibiotics are cost-effective. DISCUSSION: This trial will assess whether a single dose of doxycycline (400 mg) and metronidazole (400 mg) taken orally 2 hours before miscarriage surgery can reduce the incidence of pelvic infection in women up to 2 weeks after miscarriage surgery. TRIAL REGISTRATION: Registered with the ISRCTN (international standard randomised controlled trial number) registry: ISRCTN 97143849 . (Registered on April 17, 2013).

Routine low-dose continuous or nocturnal oxygen for people with acute stroke: three-arm Stroke Oxygen Supplementation RCT.

BACKGROUND: Stroke is a major cause of death and disability worldwide. Hypoxia is common after stroke and is associated with worse outcomes. Oxygen supplementation could prevent hypoxia and secondary brain damage. OBJECTIVES: (1) To assess whether or not routine low-dose oxygen supplementation in patients with acute stroke improves outcome compared with no oxygen; and (2) to assess whether or not oxygen given at night only, when oxygen saturation is most likely to be low, is more effective than continuous supplementation. DESIGN: Multicentre, prospective, randomised, open, blinded-end point trial. SETTING: Secondary care hospitals with acute stroke wards. PARTICIPANTS: Adult stroke patients within 24 hours of hospital admission and 48 hours of stroke onset, without definite indications for or contraindications to oxygen or a life-threatening condition other than stroke. INTERVENTIONS: Allocated by web-based minimised randomisation to: (1) continuous oxygen: oxygen via nasal cannula continuously (day and night) for 72 hours after randomisation at a flow rate of 3 l/minute if baseline oxygen saturation was ≤ 93% or 2 l/minute if > 93%; (2) nocturnal oxygen: oxygen via nasal cannula overnight (21:00-07:00) for three consecutive nights. The flow rate was the same as the continuous oxygen group; and (3) control: no routine oxygen supplementation unless required for reasons other than stroke. MAIN OUTCOME MEASURES: Primary outcome: disability assessed by the modified Rankin Scale (mRS) at 3 months by postal questionnaire (participant aware, assessor blinded). Secondary outcomes at 7 days: neurological improvement, National Institutes of Health Stroke Scale (NIHSS), mortality, and the highest and lowest oxygen saturations within the first 72 hours. Secondary outcomes at 3, 6, and 12 months: mortality, independence, current living arrangements, Barthel Index, quality of life (European Quality of Life-5 Dimensions, three levels) and Nottingham Extended Activities of Daily Living scale by postal questionnaire. RESULTS: In total, 8003 patients were recruited between 24 April 2008 and 17 June 2013 from 136 hospitals in the UK [continuous, n = 2668; nocturnal, n = 2667; control, n = 2668; mean age 72 years (standard deviation 13 years); 4398 (55%) males]. All prognostic factors and baseline characteristics were well matched across the groups. Eighty-two per cent had ischaemic strokes. At baseline the median Glasgow Coma Scale score was 15 (interquartile range 15-15) and the mean and median NIHSS scores were 7 and 5 (range 0-34), respectively. The mean oxygen saturation at randomisation was 96.6% in the continuous and nocturnal oxygen groups and 96.7% in the control group. Primary outcome: oxygen supplementation did not reduce disability in either the continuous or the nocturnal oxygen groups. The unadjusted odds ratio for a better outcome (lower mRS) was 0.97 [95% confidence interval (CI) 0.89 to 1.05; p = 0.5] for the combined oxygen groups (both continuous and nocturnal together) (n = 5152) versus the control (n = 2567) and 1.03 (95% CI 0.93 to 1.13; p = 0.6) for continuous versus nocturnal oxygen. Secondary outcomes: oxygen supplementation significantly increased oxygen saturation, but did not affect any of the other secondary outcomes. LIMITATIONS: Severely hypoxic patients were not included. CONCLUSIONS: Routine low-dose oxygen supplementation in stroke patients who are not severely hypoxic is safe, but does not improve outcome after stroke. FUTURE WORK: To investigate the causes of hypoxia and develop methods of prevention. TRIAL REGISTRATION: Current Controlled Trials ISRCTN52416964 and European Union Drug Regulating Authorities Clinical Trials (EudraCT) number 2006-003479-11. FUNDING DETAILS: This project was funded by the National Institute for Health Research (NIHR) Research for Patient Benefit and Health Technology Assessment programmes and will be published in full in Health Technology Assessment; Vol. 22, No. 14. See the NIHR Journals Library website for further project information.

Refining the Trauma and Injury Severity Score (TRISS) to Measure the Performance of the UK Combat Casualty Care System.

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.

Endotheliopathy of Trauma is an on-Scene Phenomenon, and is Associated with Multiple Organ Dysfunction Syndrome: A Prospective Observational Study.

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.

Endotheliopathy is associated with higher levels of cell-free DNA following major trauma: A prospective observational study.

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.