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Background: Traumatic brain injury is conventionally categorised as mild, moderate, or severe on the Glasgow Coma Scale (GCS). Recently developed biomarkers can provide more objective and nuanced measures of the extent of brain injury., Methods: Exposure-response relationships were investigated in 2479 patients aged ≥16 enrolled in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) prospective observational cohort study. Neurofilament protein-light (NFL), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), and glial fibrillary acidic protein (GFAP) were assayed from serum sampled in the first 24 h; concentrations were divided into quintiles within GCS severity groups. Relationships with the Glasgow Outcome Scale-Extended were examined using modified Poisson regression including age, sex, major extracranial injury, time to sample, and log biomarker concentration as covariates., Findings: Within severity groups there were associations between biomarkers and outcomes after adjustment for covariates: GCS 13-15 and negative CT imaging (relative risks [RRs] from 1.28 to 3.72), GCS 13-15 and positive CT (1.21-2.81), GCS 9-12 (1.16-2.02), GCS 3-8 (1.09-1.94). RRs were associated with clinically important differences in expectations of prognosis. In patients with GCS 3 (RRs 1.51-1.80) percentages of unfavourable outcome were 37-51% in the lowest quintiles of biomarker levels and reached 90-94% in the highest quintiles. Similarly, for GCS 15 (RRs 1.83-3.79), the percentages were 2-4% and 19-28% in the lowest and highest biomarker quintiles, respectively., Interpretation: Conventional TBI severity classification is inadequate and underestimates heterogeneity of brain injury and associated outcomes. The adoption of circulating biomarkers can add to clinical assessment of injury severity., Funding: European Union 7th Framework program (EC grant 602150), Hannelore Kohl Stiftung, One Mind, Integra LifeSciences, Neuro-Trauma Sciences, NIHR Rosetrees Trust., Competing Interests: Declaration of interests Data were obtained in CENTER-TBI, a large collaborative project with the support of the European Union 7th Framework program (EC grant 602150). Additional funding was obtained from the Hannelore Kohl Stiftung (Germany), from OneMind (USA) and from Integra LifeSciences Corporation (USA), and NeuroTrauma Sciences (USA). Data for the CENTER-TBI study has been collected through the Quesgen e-CRF (Quesgen Systems Inc, USA), hosted on the INCF platform and extracted via the INCF Neurobot tool (INCF, Sweden). VFJN holds a NIHR Rosetrees Trust Advanced Fellowship, NIHR302544, which is funded in partnership by the NIHR and Rosetrees Trust. DKM reports grants, personal fees, and non-financial support from GlaxoSmithKline outside the submitted work; personal fees from Neurotrauma Sciences, Lantmannen AB, PressuraNeuro, CSL Behring, and Invex Ltd, outside of the submitted work. Dr Maas reports receiving personal fees from NeuroTrauma Sciences, and PressuraNeuro outside the submitted work. VFJN reports a grant with ROCHE Pharmaceuticals outside the submitted work, and personal fees from Integra outside the submitted work. Dr Wilson reports receiving personal fees from Novartis, Neurotrauma Sciences, and Mass General Brigham outside the submitted work. No other disclosures were reported., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: Mild traumatic brain injury (mTBI) is a leading cause of morbidity and mortality, with approximately 1 out of 200 people each year sustaining an mTBI in Europe. There is a growing awareness that recovery may take months or years. However, the exact time frame of recovery remains ill-defined in the literature. This systematic review aims to record the range of outcome measures used for mTBI and understand the time to recovery for different outcomes., Methods and Analysis: This protocol complies with the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols guideline. A prespecified literature search for articles in the English language will be conducted from database inception to the date of searches using MEDLINE and EMBASE. A trial search was conducted on 5 October 2023 with refinement of the search criteria following this. For each study, screening of the title, abstract and full text, as well as data extraction, will be done by two reviewers, with an adjudicating third reviewer if required. The risk of bias will be assessed using the Cochrane risk of bias tool for clinical trials and the Newcastle Ottawa score for cohort studies. The primary outcome is the time to resolution of symptoms in mTBI patients who have a full recovery, using any validated outcome measure. Results will be categorised by symptom groups, including but not limited to post-concussive symptoms, mental health, functional recovery and health-related quality of life. For mTBI patients who do not recover, this review will also explore the time to the plateau of symptoms and the sequelae of these symptoms. Where possible, meta-analysis will be undertaken, with a narrative review undertaken when this is not possible. Subgroup analyses of patients aged over 64 years, and patients with repetitive head injury, are planned., Ethical Review and Dissemination: Ethical review is not required, as no original data will be collected. Results will be disseminated through peer-reviewed publications and academic conferences., Prospero Registration Number: CRD42023462797., Competing Interests: Competing interests: VN holds a grant with Roche Pharmaceuticals for a study and an honorarium from Integra. These are unrelated to this manuscript., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Sports-related concussion is a common presentation to the emergency department, with increasing evidence of short and long-term morbidity. The heterogeneity of symptoms and clinical outcomes, alongside a lack of familiarity with current guidance, can present significant challenges to clinicians. This article presents an overview of the current literature concerning assessment and management of sports-related concussion in the emergency department and outlines a framework for graduated return to activity as based upon the current national guidance., Competing Interests: DPW declares no conflicts of interest. VFJN reports holding a grant with Roche Pharmaceuticals on biomarkers which is unrelated to this article. VFJN was a member of the Update Committee for the below NICE Guideline and represented the Royal College of Emergency Medicine to review the UK Concussion Guidelines for Grassroots Sport. The head injury: assessment and early management guideline referred to in this article was produced by the National Institute for Health and Care Excellence (NICE). The views expressed in this article are those of the authors and not necessarily those of NICE.

Mild traumatic brain injury is a common presentation to the emergency department, with current management often focusing on determining whether a patient requires a CT head scan and/or neurosurgical intervention. There is a growing appreciation that approximately 20%-40% of patients, including those with a negative (normal) CT, will develop ongoing symptoms for months to years, often termed post-concussion syndrome. Owing to the requirement for improved diagnostic and prognostic mechanisms, there has been increasing evidence concerning the utility of both imaging and blood biomarkers.Blood biomarkers offer the potential to better risk stratify patients for requirement of neuroimaging than current clinical decisions rules. However, improved assessment of the clinical utility is required prior to wide adoption. MRI, using clinical sequences and advanced quantitative methods, can detect lesions not visible on CT in up to 30% of patients that may explain, at least in part, some of the ongoing problems. The ability of an acute biomarker (be it imaging, blood or other) to highlight those patients at greater risk of ongoing deficits would allow for greater personalisation of follow-up care and resource allocation.We discuss here both the current evidence and the future potential clinical usage of blood biomarkers and advanced MRI to improve diagnostic pathways and outcome prediction following mild traumatic brain injury., Competing Interests: Competing interests: VN holds a grant with ROCHE Pharmaceuticals. VN was a member of the Update Committee for the NICE head injury: assessment and early management guideline and represented the Royal College of Emergency Medicine to review the UK Concussion Guidelines for Grassroots Sport. FL was Topic Advisor for the NICE head injury: assessment and early management guideline., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Competing Interests: Competing interests: None declared.

Background: Blood biomarkers are of increasing importance in the diagnosis and assessment of traumatic brain injury (TBI). However, the relationship between them and lesions seen on imaging remains unclear., Objective: To perform a systematic review of the relationship between blood biomarkers and intracranial lesion types, intracranial lesion injury patterns, volume/number of intracranial lesions, and imaging classification systems., Methods: We searched Medical Literature Analysis and Retrieval System Online, Excerpta Medica dataBASE, and Cumulative Index to Nursing and Allied Health Literature from inception to May 2021, and the references of included studies were also screened. Heterogeneity in study design, biomarker types, imaging modalities, and analyses inhibited quantitative analysis, with a qualitative synthesis presented., Results: Fifty-nine papers were included assessing one or more biomarker to imaging comparisons per paper: 30 assessed imaging classifications or injury patterns, 28 assessed lesion type, and 11 assessed lesion volume or number. Biomarker concentrations were associated with the burden of brain injury, as assessed by increasing intracranial lesion volume, increasing numbers of traumatic intracranial lesions, and positive correlations with imaging classification scores. There were inconsistent findings associating different biomarkers with specific imaging phenotypes including diffuse axonal injury, cerebral edema, and intracranial hemorrhage., Conclusion: Blood-based biomarker concentrations after TBI are consistently demonstrated to correlate burden of intracranial disease. The relation with specific injury types is unclear suggesting a lack of diagnostic specificity and/or is the result of the complex and heterogeneous nature of TBI., (Copyright © Congress of Neurological Surgeons 2021. All rights reserved.)

Background: We aimed to understand the relationship between serum biomarker concentration and lesion type and volume found on computed tomography (CT) following all severities of TBI., Methods: Concentrations of six serum biomarkers (GFAP, NFL, NSE, S100B, t-tau and UCH-L1) were measured in samples obtained <24 hours post-injury from 2869 patients with all severities of TBI, enrolled in the CENTER-TBI prospective cohort study (NCT02210221). Imaging phenotypes were defined as intraparenchymal haemorrhage (IPH), oedema, subdural haematoma (SDH), extradural haematoma (EDH), traumatic subarachnoid haemorrhage (tSAH), diffuse axonal injury (DAI), and intraventricular haemorrhage (IVH). Multivariable polynomial regression was performed to examine the association between biomarker levels and both distinct lesion types and lesion volumes. Hierarchical clustering was used to explore imaging phenotypes; and principal component analysis and k-means clustering of acute biomarker concentrations to explore patterns of biomarker clustering., Findings: 2869 patient were included, 68% (n=1946) male with a median age of 49 years (range 2-96). All severities of TBI (mild, moderate and severe) were included for analysis with majority (n=1946, 68%) having a mild injury (GCS 13-15). Patients with severe diffuse injury (Marshall III/IV) showed significantly higher levels of all measured biomarkers, with the exception of NFL, than patients with focal mass lesions (Marshall grades V/VI). Patients with either DAI+IVH or SDH+IPH+tSAH, had significantly higher biomarker concentrations than patients with EDH. Higher biomarker concentrations were associated with greater volume of IPH (GFAP, S100B, t-tau;adj r2 range:0·48-0·49; p<0·05), oedema (GFAP, NFL, NSE, t-tau, UCH-L1;adj r2 range:0·44-0·44; p<0·01), IVH (S100B;adj r2 range:0.48-0.49; p<0.05), Unsupervised k-means biomarker clustering revealed two clusters explaining 83·9% of variance, with phenotyping characteristics related to clinical injury severity., Interpretation: Interpretation: Biomarker concentration within 24 hours of TBI is primarily related to severity of injury and intracranial disease burden, rather than pathoanatomical type of injury., Funding: CENTER-TBI is funded by the European Union 7th Framework programme (EC grant 602150)., Competing Interests: Declaration of interests DKM reports: grants from the European Union (EU), the National Institute for Health Research UK supporting the submitted work; grants from GlaxoSmithKline Ltd and Lantmannen AB, consulting fees from Calico LLC, GlaxoSmithKline Ltd, Lantmannen AB and NeuroTrauma Sciences LLC, and personal fees from Integra Neurosciences outside the submitted work. BG has received grants from European Commission and UK Research and Innovation Engineering and Physical Sciences Research Council, during the conduct of this study; and is Scientific Advisor for Kheiron Medical Technologies, Advisor and Scientific Lead of the HeartFlow-Imperial Research Team, outside the submitted work. MM reports a ERC grant agreement and consultancy fees from Triradiate Industries, outside the submitted work. ES reports a FP7 grant from the EU supporting the submitted work, and royalties for the book “Clinical Prediction Models” published by Springer. AIRM reports a FP7 grant from the EU supporting the submitted work, and grants from NeuroTrauma Sciences, Hannelore Kohl Foundation, and IntegraLife Sciences, personal fees from PresSura Neuro as DSMB chairman outside of the submitted work. KKWW reports a FP7 grant from the EU supporting the submitted work, and as a shareholder of Gryphon Bio, Inc. VFJN reports an Academy of Medical Sciences/The Health Foundation Clinician Scientist Fellowship, during the conduct of this study; a grant from Roche Pharmaceuticals, and honorarium for talks from Neurodiem, outside the submitted work. All other authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Neurological manifestations in pandemics frequently cause short and long-term consequences which are frequently overlooked. Despite advances in the treatment of infectious diseases, nervous system involvement remains a challenge, with limited treatments often available. The under-recognition of neurological manifestations may lead to an increase in the burden of acute disease as well as secondary complications with long-term consequences. Nervous system infection or dysfunction during pandemics is common and its enduring consequences, especially among vulnerable populations, are frequently forgotten. An improved understanding the possible mechanisms of neurological damage during epidemics, and increased recognition of the possible manifestations is fundamental to bring insights when dealing with future outbreaks. To reverse this gap in knowledge, we reviewed all the pandemics, large and important epidemics of human history in which neurological manifestations are evident, and described the possible physiological processes that leads to the adverse sequelae caused or triggered by those pathogens., (© 2020. The Author(s).)

An increasing number of elderly patients are being affected by traumatic brain injury (TBI) and a significant proportion are on pre-hospital antithrombotic therapy for cardio- or cerebrovascular indications. We have quantified the impact of antiplatelet/anticoagulant (APAC) agents on radiological lesion progression in acute TBI, using a novel, semi-automated approach to volumetric lesion measurement, and explored the impact of use on clinical outcomes in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. We used a 1:1 propensity-matched cohort design, matching controls to APAC users based on demographics, baseline clinical status, pre-injury comorbidities, and injury severity. Subjects were selected from a pool of patients enrolled in CENTER-TBI with computed tomography (CT) scan at admission and repeated within 7 days of injury. We calculated absolute changes in volume of intraparenchymal, extra-axial, intraventricular, and total intracranial hemorrhage (ICH) between scans, and compared volume of hemorrhagic progression, proportion of patients with significant degree of progression (>25% of initial volume), proportion with new ICH on follow-up CT, as well as clinical course and outcomes. A total of 316 patients were included (158 APAC users; 158 controls). The mean volume of progression was significantly higher in the APAC group for extra-axial (3.1 vs. 1.3 mL, p  = 0.01), but not intraparenchymal (3.8 vs. 4.6 mL, p  = 0.65), intraventricular (0.2 vs. 0.0 mL, p  = 0.79), or total intracranial hemorrhage (ICH; 7.0 vs. 6.0 mL, p  = 0.08). More patients had significant hemorrhage growth (54.1 vs. 37.0%, p  = 0.003) and delayed ICH (4 of 18 vs. none; p  = 0.04) in the APAC group compared with controls, but this was not associated with differences in length of stay (LOS), rates of neurosurgical intervention, mortality or Glasgow Outcome Scale Extended (GOS-E) score at 6 months. Pre-injury use of antithrombotic agents was associated with greater expansion of extra-axial lesions, higher rates of significant hemorrhagic progression, and higher risk of delayed traumatic ICH, but this was not associated with worse clinical course or functional outcomes.

Failure of cerebral autoregulation has been linked to unfavorable outcome after traumatic brain injury (TBI). Preliminary evidence from a small, retrospective, single-center analysis suggests that autoregulatory dysfunction may be associated with traumatic lesion expansion, particularly for pericontusional edema. The goal of this study was to further explore these associations using prospective, multi-center data from the Collaborative European Neurotrauma Effectiveness Research in TBI (CENTER-TBI) and to further explore the relationship between autoregulatory failure, lesion progression, and patient outcome. A total of 88 subjects from the CENTER-TBI High Resolution ICU Sub-Study cohort were included. All patients had an admission computed tomography (CT) scan and early repeat scan available, as well as high-frequency neurophysiological recordings covering the between-scan interval. Using a novel, semiautomated approach at lesion segmentation, we calculated absolute changes in volume of contusion core, pericontusional edema, and extra-axial hemorrhage between the imaging studies. We then evaluated associations between cerebrovascular reactivity metrics and radiological lesion progression using mixed-model regression. Analyses were adjusted for baseline covariates and non-neurophysiological factors associated with lesion growth using multi-variate methods. Impairment in cerebrovascular reactivity was significantly associated with progression of pericontusional edema and, to a lesser degree, intraparenchymal hemorrhage. In contrast, there were no significant associations with extra-axial hemorrhage. The strongest relationships were observed between RAC-based metrics and edema formation. Pulse amplitude index showed weaker, but consistent, associations with contusion growth. Cerebrovascular reactivity metrics remained strongly associated with lesion progression after taking into account contributions from non-neurophysiological factors and mean cerebral perfusion pressure. Total hemorrhagic core and edema volumes on repeat CT were significantly larger in patients who were deceased at 6 months, and the amount of edema was greater in patients with an unfavourable outcome (Glasgow Outcome Scale-Extended 1-4). Our study suggests associations between autoregulatory failure, traumatic edema progression, and poor outcome. This is in keeping with findings from a single-center retrospective analysis, providing multi-center prospective data to support those results.

Background: Failure of cerebral autoregulation and progression of intracranial lesion have both been shown to contribute to poor outcome in patients with acute traumatic brain injury (TBI), but the interplay between the two phenomena has not been investigated. Preliminary evidence leads us to hypothesize that brain tissue adjacent to primary injury foci may be more vulnerable to large fluctuations in blood flow in the absence of intact autoregulatory mechanisms. The goal of this study was therefore to assess the influence of cerebrovascular reactivity measures on radiological lesion expansion in a cohort of patients with acute TBI., Methods: We conducted a retrospective cohort analysis on 50 TBI patients who had undergone high-frequency multimodal intracranial monitoring and for which at least two brain computed tomography (CT) scans had been performed in the acute phase of injury. We first performed univariate analyses on the full cohort to identify non-neurophysiological factors (i.e., initial lesion volume, timing of scan, coagulopathy) associated with traumatic lesion growth in this population. In a subset analysis of 23 patients who had intracranial recording data covering the period between the initial and repeat CT scan, we then correlated changes in serial volumetric lesion measurements with cerebrovascular reactivity metrics derived from the pressure reactivity index (PRx), pulse amplitude index (PAx), and RAC (correlation coefficient between the pulse amplitude of intracranial pressure and cerebral perfusion pressure). Using multivariate methods, these results were subsequently adjusted for the non-neurophysiological confounders identified in the univariate analyses., Results: We observed significant positive linear associations between the degree of cerebrovascular reactivity impairment and progression of pericontusional edema. The strongest correlations were observed between edema progression and the following indices of cerebrovascular reactivity between sequential scans: % time PRx > 0.25 (r = 0.69, p = 0.002) and % time PAx > 0.25 (r = 0.64, p = 0.006). These associations remained significant after adjusting for initial lesion volume and mean cerebral perfusion pressure. In contrast, progression of the hemorrhagic core and extra-axial hemorrhage volume did not appear to be strongly influenced by autoregulatory status., Conclusions: Our preliminary findings suggest a possible link between autoregulatory failure and traumatic edema progression, which warrants re-evaluation in larger-scale prospective studies.

All drugs used for malaria prophylaxis have common adverse effects, in addition to rare and/or severe adverse effects. For many of the drugs in current use, the common adverse effects include neuropsychiatric harms. This property makes these drugs unpopular with tourists and business travellers, most of whom will be well at the start of chemoprophylaxis. Drugs available to prevent malaria have not been rigorously researched in terms of the phenomenology of their unwanted effects. Consequently, prescribers are not well placed to give useful information to travellers on the incidence, natural history and avoidability of the harms they may experience from malaria chemoprophylaxis. There is some evidence that the adverse effects of mefloquine may be a post-hepatic syndrome caused by drug-induced liver damage with, in some users, symptomatic thyroid disturbance. However, confusion in the interpretation of the scientific evidence has led to conflicting messages regarding the safety of mefloquine and other antimalaria drugs, and to incorrect self-therapy by individual travellers, sometimes with fatal outcomes. In this review, the existing knowledge base for the safety of drugs currently used to prevent malaria is described along with present designs for future studies that would allow a rigorous safety assessment of candidate chemoprophylactic agents and of new drugs introduced to prevent malaria. There is an urgent need for internationally-agreed, evidence-based malaria prevention guidelines. These guidelines should be explicitly linked to the best available research evidence (normally systematic reviews of trials and individual randomised trials) and should highlight gaps in the knowledge base as priority areas for research.

Recurrent pyogenic meningitis is uncommon. Its aetiology is often associated with impaired host defence mechanisms. Two such examples are discussed. Case 1 resulted from an anatomical defect and Case 2 a defect of the complement system.

A retrospective study was made of all 28 soldiers with chronic pancreatitis first diagnosed between 1978 and 1989. All patients were male, alcohol was the aetiological factor in 90%, the mean age at diagnosis was 30 and the commonest mode of presentation was with recurrent painful episodes of pancreatitis. Endocrine and exocrine pancreatic insufficiency occurred in a quarter and a third of patients respectively and one third required surgical intervention.