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The neurovascular unit provides a dynamic interface between the circulation and central nervous system. Disruption of neurovascular integrity occurs in numerous brain pathologies including neurotrauma and ischaemic stroke. Tissue plasminogen activator is a serine protease that converts plasminogen to plasmin, a protease that dissolves blood clots. Besides its role in fibrinolysis, tissue plasminogen activator is abundantly expressed in the brain where it mediates extracellular proteolysis. However, proteolytically active tissue plasminogen activator also promotes neurovascular disruption after ischaemic stroke; the molecular mechanisms of this process are still unclear. Tissue plasminogen activator is naturally inhibited by serine protease inhibitors (serpins): plasminogen activator inhibitor-1, neuroserpin or protease nexin-1 that results in the formation of serpin:protease complexes. Proteases and serpin:protease complexes are cleared through high-affinity binding to low-density lipoprotein receptors, but their binding to these receptors can also transmit extracellular signals across the plasma membrane. The matrix metalloproteinases are the second major proteolytic system in the mammalian brain, and like tissue plasminogen activators are pivotal to neurological function but can also degrade structures of the neurovascular unit after injury. Herein, we show that tissue plasminogen activator potentiates neurovascular damage in a dose-dependent manner in a mouse model of neurotrauma. Surprisingly, inhibition of activity following administration of plasminogen activator inhibitor-1 significantly increased cerebrovascular permeability. This led to our finding that formation of complexes between tissue plasminogen activator and plasminogen activator inhibitor-1 in the brain parenchyma facilitates post-traumatic cerebrovascular damage. We demonstrate that following trauma, the complex binds to low-density lipoprotein receptors, triggering the induction of matrix metalloproteinase-3. Accordingly, pharmacological inhibition of matrix metalloproteinase-3 attenuates neurovascular permeability and improves neurological function in injured mice. Our results are clinically relevant, because concentrations of tissue plasminogen activator: plasminogen activator inhibitor-1 complex and matrix metalloproteinase-3 are significantly elevated in cerebrospinal fluid of trauma patients and correlate with neurological outcome. In a separate study, we found that matrix metalloproteinase-3 and albumin, a marker of cerebrovascular damage, were significantly increased in brain tissue of patients with neurotrauma. Perturbation of neurovascular homeostasis causing oedema, inflammation and cell death is an important cause of acute and long-term neurological dysfunction after trauma. A role for the tissue plasminogen activator-matrix metalloproteinase axis in promoting neurovascular disruption after neurotrauma has not been described thus far. Targeting tissue plasminogen activator: plasminogen activator inhibitor-1 complex signalling or downstream matrix metalloproteinase-3 induction may provide viable therapeutic strategies to reduce cerebrovascular permeability after neurotrauma. [ABSTRACT FROM AUTHOR]

Abstract Best practice guidelines have advanced severe traumatic brain injury (TBI) care; however, there is little that currently informs goals of care decisions and processes despite their importance and frequency. Panelists from the S eattle I nternational severe traumatic B rain I njury C onsensus C onference (SIBICC) participated in a survey consisting of 24 questions. Questions queried use of prognostic calculators, variability in and responsibility for goals of care decisions, and acceptability of neurological outcomes, as well as putative means of improving decisions that might limit care. A total of 97.6% of the 42 SIBICC panelists completed the survey. Responses to most questions were highly variable. Overall, panelists reported infrequent use of prognostic calculators, and observed variability in patient prognostication and goals of care decisions. They felt that it would be beneficial for physicians to improve consensus on what constitutes an acceptable neurological outcome as well as what chance of achieving that outcome is acceptable. Panelists felt that the public should help to define what constitutes a good outcome and expressed some support for a "nihilism guard." More than 50% of panelists felt that if it was certain to be permanent, a vegetative state or lower severe disability would justify a withdrawal of care decision, whereas 15% felt that upper severe disability justified such a decision. Whether conceptualizing an ideal or existing prognostic calculator to predict death or an unacceptable outcome, on average a 64-69% chance of a poor outcome was felt to justify treatment withdrawal. These results demonstrate important variability in goals of care decision making and a desire to reduce this variability. Our panel of recognized TBI experts opined on the neurological outcomes and chances of those outcomes that might prompt consideration of care withdrawal; however, imprecision of prognostication and existing prognostication tools is a significant impediment to standardizing the approach to care-limiting decisions.

Giovanni Andrea Dalla Croce was a Venetian physician who lived in the 16th century and was famous for his treatment of wounds, which was surprisingly modern. He was the military surgeon of the Venetian Republic's naval fleet. In 1537, he published the Chirurgiae universalis opus absolutum (The absolute work on universal surgery) in Latin, then expanded and translated into vernacular Italian and published in 1574 with the title Cirugia universale e perfetta di tutte le parti pertinenti all'ottimo chirurgo (Universal and perfect surgery of all the parts necessary for the optimal surgeon). This monumental work was a comprehensive handbook of surgery, medicine, and the treatment of many kinds of wounds with techniques to be used on the battlefield. It is also notable for the inclusion of illustrations of various weapons and projectiles, for the most comprehensive description and illustrations of surgical instruments at that time, and for the first illustrations of a surgeon performing trephination of the skull in an operating room. Dalla Croce also considered the writings of his surgical forebears in formulating his own ideas. Dalla Croce was a leader of traumatology, a universal surgeon who exemplified the erudite Renaissance man, and left a tremendous legacy to military surgery of the 16th century and beyond.

Penetrating traumatic brain injury (pTBI) affects civilian and military populations resulting in significant morbidity, mortality, and healthcare costs. No up-to-date and evidence-based guidelines exist to assist modern medical and surgical management of these complex injuries. A preliminary literature search revealed a need for updated guidelines, supported by the Brain Trauma Foundation. Methodologists experienced in TBI guidelines were recruited to support project development alongside two cochairs and a diverse steering committee. An expert multi-disciplinary workgroup was established and vetted to inform key clinical questions, to perform an evidence review and the development of recommendations relevant to pTBI. The methodological approach for the project was finalized. The development of up-to-date evidence- and consensus-based clinical care guidelines and algorithms for pTBI will provide critical guidance to care providers in the pre-hospital and emergent, medical, and surgical settings., Competing Interests: No competing financial interests exist., (© Gregory W.J. Hawryluk et al., 2022; Published by Mary Ann Liebert, Inc.)

Video surveillance and detection of players with visible signs of concussion by experienced medical staff facilitates rapid on-field screening of suspected concussion in professional sports. This method, however has not been validated in community sports where video footage is unavailable. This study aimed to explore the utility of visible signs of concussion to identify players with decrements in performance on concussion screening measures. In this observational prospective cohort study, personnel with basic training observed live matches across a season (60 matches) of community male and female Australian football for signs of concussion outlined in the community-based Head Injury Assessment form (HIAf). Players identified to have positive signs of concussion (CoSign+) following an impact were compared with players without signs (CoSign-). Outcome measures, the Sport Concussion Assessment Tool (SCAT3) and Cogstate, were administered at baseline and post-match. CoSign+ ( n  = 22) and CoSign- ( n  = 61) groups were similar with respect to age, sex, education, baseline mood, and medical history. CoSign+ players exhibited worse orientation, concentration, and recall, and slower reaction time in attention and working memory tasks. Comparing individual change from baseline to post-match assessment revealed 100% (95% confidence interval [CI]: 84-100%) of CoSign+ players demonstrated clinically significant deficits on SCAT3 or Cogstate tasks, compared with 59% (95% CI: 46-71%) of CoSign- players. All CoSign+ players observed to have a blank/vacant look demonstrated clinically significant decline on the Standardized Assessment of Concussion (SAC). Detection of visible signs of concussion represents a rapid, real-time method for screening players suspected of concussion in community sports where video technology and medical personnel are rarely present. Consistent with community guidelines, it is recommended that all CoSign+ players be immediately removed from play for further concussion screening.

Background: There has been immense interest and debate regarding the effectiveness of antibiotic treatment for chronic low back pain. Two randomised controlled trials have examined the efficacy of antibiotics for chronic low back pain with disc herniation and Modic changes, but have reported conflicting results. The aim of this double-blind, randomised, placebo-controlled trial is to determine the efficacy of antibiotic treatment in a broader patient subgroup of chronic low back pain with disc herniation and investigate whether the presence of Modic changes predicts response to antibiotic therapy., Methods: One hundred and seventy individuals with chronic low back pain will be recruited through hospital and private medical and allied health clinics; advertising in national, community and social media; and posting of flyers in community locations. They will be randomly allocated to receive either amoxicillin-clavulanate (500 mg/125 mg) twice per day for 90 days or placebo. The primary outcome measure of pain intensity will be assessed using the Low Back Pain Rating scale and a 100-mm visual analogue scale at 12 months. Secondary measures of self-reported low back disability and work absence and hindrance will also be examined, and an economic analysis will be conducted. Intention-to-treat analyses will be performed., Discussion: There is uncertainty about whether antibiotic treatment is effective for chronic low back pain and, if effective, which patient subgroup is most likely to respond. We will conduct a clinical trial to investigate the efficacy of antibiotics compared with placebo in individuals with chronic low back pain and a disc herniation. Our findings will provide high-quality evidence to assist in answering these questions., Trial Registration: Australian New Zealand Clinical Trials Registry ACTRN12615000958583 . Registered on 11 September 2015., (© 2021. The Author(s).)

To investigate cerebral autoregulatory status in patients with severe traumatic brain injury (TBI), guidelines now suggest active manipulation of mean arterial pressure (MAP). There is a paucity of data, however, describing the effect on intracranial pressure (ICP) when MAP is raised. Consecutive patients with TBI requiring ICP monitoring were enrolled from November 2019 to April 2020. The MAP and ICP were recorded continuously, and clinical annotations were made whenever intravenous vasopressors were commenced or adjusted to defend cerebral perfusion pressure (CPP) targets. A significant change in MAP burden was defined as MAP >100min.mm Hg over 15 min. The primary outcome was the change in ICP burden over the same 15-min period. Bedside and clinical parameters were then compared between these groups. Twenty-eight patients were enrolled, providing 212 clinical events, of which 60 were deemed significant. Over the first 15 min, 65% were associated with a net negative ICP burden. A greater reduction in ICP burden was observed with events occurring in patients without a history of hypotension at scene ( p  = 0.016), after three days post-injury ( p  = 0.0018), and where the pressure-reactivity index (PRx) was <0.25 ( p  = 0.0005) or the ICP amplitude to CPP correlation coefficient (RAC) was <-0.10 ( p  = 0.0036) at the initiation of vasopressor changes. The ICP burden in the first 15 min was highly correlated with the next 15-min period. In patients with severe TBI requiring ICP monitoring, increasing MAP to pursue a CPP target was followed by a net negative ICP burden in approximately two-thirds of events. These data suggest a MAP challenge may be a useful adjunct in managing intracranial hypertension.

Exposure to repeated concussive traumatic brain injury (TBI) and to blast-induced TBI has been associated with the potential development of the neurodegenerative condition known as chronic traumatic encephalopathy (CTE). CTE is characterized by the accumulation of hyperphosphorylated tau protein, with the resultant tau tangles thought to initiate the cognitive and behavioral manifestations that appear as the condition progresses. However, the mechanisms linking concussive and blast TBI with tau hyperphosphorylation are unknown. Here we show that single moderate TBI, repeated concussive TBI and blast-induced mild TBI all result in hyperphosphorylation of tau via a substance P mediated mechanism. Post-injury administration of a substance P, NK1 receptor antagonist attenuated the injury-induced phosphorylation of tau by modulating the activity of several key kinases including Akt, ERK1/2 and JNK, and was associated with improvement in neurological outcome. We also demonstrate that inhibition of the TRPV1 mechanoreceptor, which is linked to substance P release, attenuated injury-associated tau hyperphosphorylation, but only when it was administered prior to injury. Our results demonstrate that TBI-mediated stimulation of brain mechanoreceptors is associated with substance P release and consequent tau hyperphosphorylation, with administration of an NK1 receptor antagonist attenuating tau phosphorylation and associated neurological deficits. NK1 antagonists may thus represent a pharmacological approach to attenuate the potential development of CTE following concussive and blast TBI.

This study aimed to evaluate the utility of the 11-variable modified Frailty Index (mFI) in prognosticating elderly patients with traumatic acute subdural hematomas (aSDHs). A state-service level 1 trauma center registry was interrogated to investigate consecutive patients ≥65 years of age presenting with traumatic aSDH, with or without major extracranial injury, between January 2013 and December 2017. mFI on admission, demographics, and admission details, including Glasgow Coma Scale (GCS) and pupillary status and radiological findings, were retrospectively retrieved from institutional records. Clinical outcome data were retrieved from medical records and the Victorian State Trauma Registry (VSTR). Outcome measures were 1) 30-day mortality and 2) 6-month unfavorable outcome, defined by the Extended Glasgow Outcome Scale (GOS-E). Five hundred twenty-nine consecutive cases were identified from the registry. Demographic data included: 1) age (median; interquartile range) = 80.46; 74.17-85.89; 2) mFI (mean ± standard deviation) = 1.96 ± 1.42 of 11 variables. Four hundred sixteen cases (79%) had complete outcome data. As mFI increased from 0/11 variables to ≥5/11 variables (≥0.45), 30-day mortality risk increased from 17.72% to 39.29% ( p  = 0.023) and 6-month unfavorable outcome risk increased from 40.51% to 96.43% ( p  < 0.001). Multi-variate analysis showed that greater mFI score of ≥3/11 variables (≥0.27) suggested a significantly higher risk of 30-day mortality ( p  = 0.009) and unfavorable outcome ( p  < 0.001). We conclude that increasing frailty, as measured by the mFI, was associated with significantly higher risk of 30-day mortality and 6-month unfavorable outcome in elderly patients presenting with aSDH to a level 1 neurotrauma center. Assessment of mFI in elderly patients with aSDH may be a useful determinant of outcome for this rapidly growing population.

Functional outcomes at 12 months were a secondary outcome of the randomized DECRA trial of early decompressive craniectomy for severe diffuse traumatic brain injury (TBI) and refractory intracranial hypertension. In the DECRA trial, patients were randomly allocated 1:1 to either early decompressive craniectomy or intensive medical therapies (standard care). We conducted planned secondary analyses of the DECRA trial outcomes at 6 and 12 months, including all 155 patients. We measured functional outcome using the Glasgow Outcome Scale-Extended (GOS-E). We used ordered logistic regression, and dichotomized the GOS-E using logistic regression, to assess outcomes in patients overall and in survivors. We adjusted analyses for injury severity using the International Mission for Prognosis and Analysis of Clinical Trials in TBI (IMPACT) model. At 12 months, the odds ratio (OR) for worse functional outcomes in the craniectomy group (OR 1.68; 95% confidence interval [CI]: 0.96-2.93; p  = 0.07) was no longer significant. Unfavorable functional outcomes after craniectomy were 11% higher (59% compared with 48%), but were not significantly different from standard care (OR 1.58; 95% CI: 0.84-2.99; p  = 0.16). Among survivors after craniectomy, there were fewer good (OR 0.33; 95% CI: 0.12-0.91; p  = 0.03) and more vegetative (OR 5.12; 95% CI: 1.04-25.2; p  = 0.04) outcomes. Similar outcomes in survivors were found at 6 months after injury. Vegetative (OR 5.85; 95% CI: 1.21-28.30; p  = 0.03) and severely disabled outcomes (OR 2.49; 95% CI: 1.21-5.11; p  = 0.01) were increased. Twelve months after severe diffuse TBI and early refractory intracranial hypertension, decompressive craniectomy did not improve outcomes and increased vegetative survivors.

Trauma/stroke centres optimise acute 24/7/365 surgical/critical care in high-income countries (HICs). Concepts from low-income and middle-income countries (LMICs) offer additional cost-effective healthcare strategies for limited-resource settings when combined with the trauma/stroke centre concept. Mass casualty centres (MCCs) integrate resources for both routine and emergency care-from prevention to acute care to rehabilitation. Integration of the various healthcare systems-governmental, non-governmental and military-is key to avoid both duplication and gaps. With input from LMIC and HIC personnel of various backgrounds-trauma and subspecialty surgery, nursing, information technology and telemedicine, and healthcare administration-creative solutions to the challenges of expanding care (both daily and disaster) are developed. MCCs are evolving initially in Chile and Pakistan. Technologies for cost-effective healthcare in LMICs include smartphone apps (enhance prehospital care) to electronic data collection and analysis (quality improvement) to telemedicine and drones/robots (support of remote regions and resource optimisation during both daily care and disasters) to resilient, mobile medical/surgical facilities (eg, battery-operated CT scanners). The co-ordination of personnel (within LMICs, and between LMICs and HICs) and the integration of cost-effective advanced technology are features of MCCs. Providing quality, cost-effective care 24/7/365 to the 5 billion who lack it presently makes MCCs an appealing means to achieve the healthcare-related United Nations Sustainable Development Goals for 2030., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

It has been well-documented recently that 5 billion people globally lack surgical care. Also well-documented is the need to improve mass casualty disaster response. Many of the United Nations (UN) Sustainable Development Goals (SDGs) for 2030-healthcare and economic milestones-require significant improvement in global surgical care, particularly in low-income and middle-income countries. Trauma/stroke centres evolved in high-income countries with evidence that 24/7/365 surgical and critical care markedly improved morbidity and mortality for trauma and stroke and for cardiovascular events, difficult childbirth, acute abdomen. Duplication of emergency services, especially civilian and military, often results in suboptimal, expensive care. By combining all healthcare resources within the ongoing healthcare system, more efficient care for both individual emergencies and mass casualty situations can be achieved. We describe progress in establishing mass casualty centres in Chile and Pakistan. In both locations, planning among the stakeholders (primarily civilian and military) indicates the feasibility of such integrated surgical and emergency care. We also review other programmes and initiatives to provide integrated mass casualty disaster response. Integrated mass casualty centres are a feasible means to improve both day-to-day surgical care and mass casualty disaster response. The humanitarian aspect of mass casualty disasters facilitates integration among stakeholders-from local healthcare systems to military resources to international healthcare organisations. The benefits of mass casualty centres-both healthcare and economic-can facilitate achieving the 2030 UN SDGs., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Neurosurgical residents are finding it more difficult to obtain experience as the primary operator in aneurysm surgery. The present study aimed to replicate patient-derived cranial anatomy, pathology and human tissue properties relevant to cerebral aneurysm intervention through 3D printing and 3D print-driven casting techniques. The final simulator was designed to provide accurate simulation of a human head with a middle cerebral artery (MCA) aneurysm., Methods: This study utilized living human and cadaver-derived medical imaging data including CT angiography and MRI scans. Computer-aided design (CAD) models and pre-existing computational 3D models were also incorporated in the development of the simulator. The design was based on including anatomical components vital to the surgery of MCA aneurysms while focusing on reproducibility, adaptability and functionality of the simulator. Various methods of 3D printing were utilized for the direct development of anatomical replicas and moulds for casting components that optimized the bio-mimicry and mechanical properties of human tissues. Synthetic materials including various types of silicone and ballistics gelatin were cast in these moulds. A novel technique utilizing water-soluble wax and silicone was used to establish hollow patient-derived cerebrovascular models., Results: A patient-derived 3D aneurysm model was constructed for a MCA aneurysm. Multiple cerebral aneurysm models, patient-derived and CAD, were replicated as hollow high-fidelity models. The final assembled simulator integrated six anatomical components relevant to the treatment of cerebral aneurysms of the Circle of Willis in the left cerebral hemisphere. These included models of the cerebral vasculature, cranial nerves, brain, meninges, skull and skin. The cerebral circulation was modeled through the patient-derived vasculature within the brain model. Linear and volumetric measurements of specific physical modular components were repeated, averaged and compared to the original 3D meshes generated from the medical imaging data. Calculation of the concordance correlation coefficient (ρ c : 90.2%-99.0%) and percentage difference (≤0.4%) confirmed the accuracy of the models., Conclusions: A multi-disciplinary approach involving 3D printing and casting techniques was used to successfully construct a multi-component cerebral aneurysm surgery simulator. Further study is planned to demonstrate the educational value of the proposed simulator for neurosurgery residents.

The Internet comprises a decentralized global system that serves humanity's collective effort to generate, process, and store data, most of which is handled by the rapidly expanding cloud. A stable, secure, real-time system may allow for interfacing the cloud with the human brain. One promising strategy for enabling such a system, denoted here as a "human brain/cloud interface" ("B/CI"), would be based on technologies referred to here as "neuralnanorobotics." Future neuralnanorobotics technologies are anticipated to facilitate accurate diagnoses and eventual cures for the ∼400 conditions that affect the human brain. Neuralnanorobotics may also enable a B/CI with controlled connectivity between neural activity and external data storage and processing, via the direct monitoring of the brain's ∼86 × 10 9 neurons and ∼2 × 10 14 synapses. Subsequent to navigating the human vasculature, three species of neuralnanorobots (endoneurobots, gliabots, and synaptobots) could traverse the blood-brain barrier (BBB), enter the brain parenchyma, ingress into individual human brain cells, and autoposition themselves at the axon initial segments of neurons (endoneurobots), within glial cells (gliabots), and in intimate proximity to synapses (synaptobots). They would then wirelessly transmit up to ∼6 × 10 16 bits per second of synaptically processed and encoded human-brain electrical information via auxiliary nanorobotic fiber optics (30 cm 3 ) with the capacity to handle up to 10 18 bits/sec and provide rapid data transfer to a cloud based supercomputer for real-time brain-state monitoring and data extraction. A neuralnanorobotically enabled human B/CI might serve as a personalized conduit, allowing persons to obtain direct, instantaneous access to virtually any facet of cumulative human knowledge. Other anticipated applications include myriad opportunities to improve education, intelligence, entertainment, traveling, and other interactive experiences. A specialized application might be the capacity to engage in fully immersive experiential/sensory experiences, including what is referred to here as "transparent shadowing" (TS). Through TS, individuals might experience episodic segments of the lives of other willing participants (locally or remote) to, hopefully, encourage and inspire improved understanding and tolerance among all members of the human family.

The hippocampus is a key component of emotional and memory circuits and is broadly connected throughout the brain. We tracked the whole-brain connections of white matter fibres from the hippocampus using ultra-high angular resolution diffusion MRI in both a single 1150-direction dataset and a large normal cohort (n = 94; 391-directions). Using a connectomic approach, we identified six dominant pathways in terms of strength, length and anatomy, and characterised them by their age and gender variation. The strongest individual connection was to the ipsilateral thalamus. There was a strong age dependence of hippocampal connectivity to medial occipital regions. Overall, our results concur with preclinical and ex-vivo data, confirming that meaningful in vivo characterisation of hippocampal connections is possible in an individual. Our findings extend the collective knowledge of hippocampal anatomy, highlighting the importance of the spinal-limbic pathway and the striking lack of hippocampal connectivity with motor and sensory cortices.

Acute subdural hematoma (aSDH) is among the most common injury types encountered by neurosurgeons, and carries a poor prognosis, particularly in the elderly. As the incidence of aSDH in the elderly population rises, identifying those patients who may benefit from operative intervention is crucial. This systematic review aimed to identify data on prognostic factors or indices, such as the modified frailty index, that may help predict outcome, and hence guide management. A comprehensive search of online databases was conducted by two independent authors, and data on prognostic factors and outcomes were extracted. The quality of the evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria. Of 769 studies identified in the initial search, 7 satisfied inclusion and exclusion criteria. Mortality and morbidity varied considerably among studies. Initial Glasgow Coma Scale (GCS) of 3-8 was the most consistently reported negative prognostic feature. Several studies evaluated the impact of medical comorbidities and premorbid frailty, but were limited by small sample size. A previous history of pneumonia was shown to increase the risk of Glasgow Outcome Score (GOS) 1-3 (odds ratio [OR] 6.4 [95% CI 1.6-25.2], p = 0.04) in a single study, which also reported a greater increase in GOS at 3 months in those with fewer than five comorbidities (56% vs. 19%, p < 0.01). There are limited data describing prognostic factors or the use of frailty indices within the specific group of elderly patients with aSDH. Prospective research is needed to evaluate the utility of accurate and validated assessments of frailty to enhance the neurosurgeon's ability to appropriately manage this complex and expanding patient group.

Background: Evidence-based guidelines for management of mild traumatic brain injury (mTBI) in the emergency department (ED) are now widely available; however, clinical practice remains inconsistent with these guidelines. A targeted, theory-informed implementation intervention (Neurotrauma Evidence Translation (NET) intervention) was designed to increase the uptake of three clinical practice recommendations regarding the management of patients who present to Australian EDs with mild head injuries. The intervention involved local stakeholder meetings, identification and training of nursing and medical local opinion leaders, train-the-trainer workshops and standardised education materials and interactive workshops delivered by the opinion leaders to others within their EDs during a 3 month period. This paper reports on the effects of this intervention., Methods: EDs (clusters) were allocated to receive either access to a clinical practice guideline (control) or the implementation intervention, using minimisation, a method that allocates clusters to groups using an algorithm to minimise differences in predefined factors between the groups. We measured clinical practice outcomes at the patient level using chart audit. The primary outcome was appropriate screening for post-traumatic amnesia (PTA) using a validated tool until a perfect score was achieved (indicating absence of acute cognitive impairment) before the patient was discharged home. Secondary outcomes included appropriate CT scanning and the provision of written patient information upon discharge. Patient health outcomes (anxiety, primary outcome: Hospital Anxiety and Depression Scale) were also assessed using follow-up telephone interviews. Outcomes were assessed by independent auditors and interviewers, blinded to group allocation., Results: Fourteen EDs were allocated to the intervention and 17 to the control condition; 1943 patients were included in the chart audit. At 2 months follow-up, patients attending intervention EDs (n = 893) compared with control EDs (n = 1050) were more likely to have been appropriately assessed for PTA (adjusted odds ratio (OR) 20.1, 95%CI 6.8 to 59.3; adjusted absolute risk difference (ARD) 14%, 95%CI 8 to 19). The odds of compliance with recommendations for CT scanning and provision of written patient discharge information were small (OR 1.2, 95%CI 0.8 to 1.6; ARD 3.2, 95%CI - 3.7 to 10 and OR 1.2, 95%CI 0.8 to 1.8; ARD 3.1, 95%CI - 3.0 to 9.3 respectively). A total of 343 patients at ten interventions and 14 control sites participated in follow-up interviews at 4.3 to 10.7 months post-ED presentation. The intervention had a small effect on anxiety levels (adjusted mean difference - 0.52, 95%CI - 1.34 to 0.30; scale 0-21, with higher scores indicating greater anxiety)., Conclusions: Our intervention was effective in improving the uptake of the PTA recommendation; however, it did not appreciably increase the uptake of the other two practice recommendations. Improved screening for PTA may be clinically important as it leads to appropriate periods of observation prior to safe discharge. The estimated intervention effect on anxiety was of limited clinical significance. We were not able to compare characteristics of EDs who declined trial participation with those of participating sites, which may limit the generalizability of the results., Trial Registration: Australian New Zealand Clinical Trials Registry (ACTRN12612001286831), date registered 12 December 2012.

Background: The Prophylactic hypOthermia to Lessen trAumatic bRain injury-Randomised Controlled Trial (POLAR-RCT) will evaluate whether early and sustained prophylactic hypothermia delivered to patients with severe traumatic brain injury improves patient-centred outcomes., Methods: The POLAR-RCT is a multicentre, randomised, parallel group, phase III trial of early, prophylactic cooling in critically ill patients with severe traumatic brain injury, conducted in Australia, New Zealand, France, Switzerland, Saudi Arabia and Qatar. A total of 511 patients aged 18-60 years have been enrolled with severe acute traumatic brain injury. The trial intervention of early and sustained prophylactic hypothermia to 33 °C for 72 h will be compared to standard normothermia maintained at a core temperature of 37 °C. The primary outcome is the proportion of favourable neurological outcomes, comprising good recovery or moderate disability, observed at six months following randomisation utilising a midpoint dichotomisation of the Extended Glasgow Outcome Scale (GOSE). Secondary outcomes, also assessed at six months following randomisation, include the probability of an equal or greater GOSE level, mortality, the proportions of patients with haemorrhage or infection, as well as assessment of quality of life and health economic outcomes. The planned sample size will allow 80% power to detect a 30% relative risk increase from 50% to 65% (equivalent to a 15% absolute risk increase) in favourable neurological outcome at a two-sided alpha of 0.05., Discussion: Consistent with international guidelines, a detailed and prospective analysis plan has been developed for the POLAR-RCT. This plan specifies the statistical models for evaluation of primary and secondary outcomes, as well as defining covariates for adjusted analyses and methods for exploratory analyses. Application of this statistical analysis plan to the forthcoming POLAR-RCT trial will facilitate unbiased analyses of these important clinical data., Trial Registration: ClinicalTrials.gov, NCT00987688 (first posted 1 October 2009); Australian New Zealand Clinical Trials Registry, ACTRN12609000764235 . Registered on 3 September 2009.

Background: Reducing alcohol related harms in Australian Defence Force (ADF) trainees has been identified as a priority, but there are few evidence-based prevention programs available for the military setting. The study aims to test whether the P.A.R.T.Y. program delivered in-hospital or on-base, can reduce harmful alcohol consumption among ADF trainees., Methods/design: The study is a 3-arm randomized controlled trial, involving 953 Royal Australian Navy trainees from a single base. Trainees, aged 18 to 30 years, will be randomly assigned to the study arms: i. in-hospital P.A.R.T.Y.; ii. On-base P.A.R.T.Y.; and iii., Control Group: All groups will receive the routine ADF annual alcohol awareness training. The primary outcome is the proportion of participants reporting an Alcohol Use Disorders Identification Test (AUDIT) score of 8 or above at 12 months' post-intervention. The secondary outcome is the number of alcohol related incidents reported to the Royal Australian Navy (RAN) in the 12 months' post-intervention., Discussion: This is the first trial of the use of the P.A.R.T.Y. program in the military. If the proposed intervention proves efficacious, it may be a useful program in the early education of RAN trainees., Trial Registration: Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12614001332617 , date of registration: 18/12/2014 'retrospectively registered'.

Moderate-to-severe traumatic brain injury (TBI) remains a major global challenge, with rising incidence, unchanging mortality and lifelong impairments. State-of-the-science reviews are important for research planning and clinical decision support. This review aimed to identify randomized controlled trials (RCTs) evaluating interventions for acute management of moderate/severe TBI, synthesize key RCT characteristics and findings, and determine their implications on clinical practice and future research. RCTs were identified through comprehensive database and other searches. Key characteristics, outcomes, risk of bias, and analysis approach were extracted. Data were narratively synthesized, with a focus on robust (multi-center, low risk of bias, n > 100) RCTs, and three-dimensional graphical figures also were used to explore relationships between RCT characteristics and findings. A total of 207 RCTs were identified. The 191 completed RCTs enrolled 35,340 participants (median, 66). Most (72%) were single center and enrolled less than 100 participants (69%). There were 26 robust RCTs across 18 different interventions. For 74% of 392 comparisons across all included RCTs, there was no significant difference between groups. Positive findings were broadly distributed with respect to RCT characteristics. Less than one-third of RCTs demonstrated low risk of bias for random sequence generation or allocation concealment, less than one-quarter used covariate adjustment, and only 7% employed an ordinal analysis approach. Considerable investment of resources in producing 191 completed RCTs for acute TBI management has resulted in very little translatable evidence. This may result from broad distribution of research effort, small samples, preponderance of single-center RCTs, and methodological shortcomings. More sophisticated RCT design, large multi-center RCTs in priority areas, increased focus on pre-clinical research, and alternatives to RCTs, such as comparative effectiveness research and precision medicine, are needed to fully realize the potential of acute TBI research to benefit patients.

Early decompression may improve neurological outcome after spinal cord injury (SCI), but is often difficult to achieve because of logistical issues. The aims of this study were to 1) determine the time to decompression in cases of isolated cervical SCI in Australia and New Zealand and 2) determine where substantial delays occur as patients move from the accident scene to surgery. Data were extracted from medical records of patients aged 15-70 years with C3-T1 traumatic SCI between 2010 and 2013. A total of 192 patients were included. The median time from accident scene to decompression was 21 h, with the fastest times associated with closed reduction (6 h). A significant decrease in the time to decompression occurred from 2010 (31 h) to 2013 (19 h, p = 0.008). Patients undergoing direct surgical hospital admission had a significantly lower time to decompression, compared with patients undergoing pre-surgical hospital admission (12 h vs. 26 h, p < 0.0001). Medical stabilization and radiological investigation appeared not to influence the timing of surgery. The time taken to organize the operating theater following surgical hospital admission was a further factor delaying decompression (12.5 h). There was a relationship between the timing of decompression and the proportion of patients demonstrating substantial recovery (2-3 American Spinal Injury Association Impairment Scale grades). In conclusion, the time of cervical spine decompression markedly improved over the study period. Neurological recovery appeared to be promoted by rapid decompression. Direct surgical hospital admission, rapid organization of theater, and where possible, use of closed reduction, are likely to be effective strategies to reduce the time to decompression.

Introduction: Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. Prophylactic hypothermia is effective in laboratory models, but clinical studies to date have been inconclusive, partly because of methodological limitations. Our Prophylactic Hypothermia Trial to Lessen Traumatic Brain Injury (POLAR) randomised controlled trial is currently underway comparing early, sustained hypothermia versus standard care in patients with severe TBI. We describe our study protocol and the challenges in conducting prophylactic hypothermia research in TBI., Design: We aim to randomise 500 patients to either prophylactic 33°C hypothermia initiated within 3 hours of injury and continued for at least 72 hours, or standard normothermic management. Patients will be enrolled by paramedic services in the prehospital setting, or by emergency department staff at participating sites in Australia, New Zealand and Europe. The primary outcome will be the eight-level extended Glasgow outcome scale (GOSE), dichotomised to favourable and unfavourable outcomes at 6 months after injury. Secondary outcomes will include mortality at hospital discharge and at 6 months, ordinal analyses of 6-month GOSE outcomes, quality of life with health economic evaluations and the differential proportion of adverse events. We will predefine subgroup and interaction analyses., Discussion: After a run-in phase, recruitment for our main study began in December 2010. When the study is completed, we aim to provide evidence on the efficacy of prophylactic hypothermia in TBI to guide clinicians in their management of this devastating condition.

Unlabelled: During inflammation, the kynurenine pathway (KP) metabolises the essential amino acid tryptophan (TRP) potentially contributing to excitotoxicity via the release of quinolinic acid (QUIN) and 3-hydroxykynurenine (3HK). Despite the importance of excitotoxicity in the development of secondary brain damage, investigations on the KP in TBI are scarce. In this study, we comprehensively characterised changes in KP activation by measuring numerous metabolites in cerebrospinal fluid (CSF) from TBI patients and assessing the expression of key KP enzymes in brain tissue from TBI victims. Acute QUIN levels were further correlated with outcome scores to explore its prognostic value in TBI recovery., Methods: Twenty-eight patients with severe TBI (GCS ≤ 8, three patients had initial GCS = 9-10, but rapidly deteriorated to ≤8) were recruited. CSF was collected from admission to day 5 post-injury. TRP, kynurenine (KYN), kynurenic acid (KYNA), QUIN, anthranilic acid (AA) and 3-hydroxyanthranilic acid (3HAA) were measured in CSF. The Glasgow Outcome Scale Extended (GOSE) score was assessed at 6 months post-TBI. Post-mortem brains were obtained from the Australian Neurotrauma Tissue and Fluid Bank and used in qPCR for quantitating expression of KP enzymes (indoleamine 2,3-dioxygenase-1 (IDO1), kynurenase (KYNase), kynurenine amino transferase-II (KAT-II), kynurenine 3-monooxygenase (KMO), 3-hydroxyanthranilic acid oxygenase (3HAO) and quinolinic acid phosphoribosyl transferase (QPRTase) and IDO1 immunohistochemistry., Results: In CSF, KYN, KYNA and QUIN were elevated whereas TRP, AA and 3HAA remained unchanged. The ratios of QUIN:KYN, QUIN:KYNA, KYNA:KYN and 3HAA:AA revealed that QUIN levels were significantly higher than KYN and KYNA, supporting increased neurotoxicity. Amplified IDO1 and KYNase mRNA expression was demonstrated on post-mortem brains, and enhanced IDO1 protein coincided with overt tissue damage. QUIN levels in CSF were significantly higher in patients with unfavourable outcome and inversely correlated with GOSE scores., Conclusion: TBI induced a striking activation of the KP pathway with sustained increase of QUIN. The exceeding production of QUIN together with increased IDO1 activation and mRNA expression in brain-injured areas suggests that TBI selectively induces a robust stimulation of the neurotoxic branch of the KP pathway. QUIN's detrimental roles are supported by its association to adverse outcome potentially becoming an early prognostic factor post-TBI.

Background: Recently, there has been both immense interest and controversy regarding a randomised, controlled trial which showed antibiotics to be effective in the treatment of chronic low back pain (disc herniation with Modic Type 1 change). While this research has the potential to result in a paradigm shift in the treatment of low back pain, several questions remain unanswered. This systematic review aims to address these questions by examining the role of bacteria in low back pain and the relationship between bacteria and Modic change., Methods: We conducted electronic searches of MEDLINE and EMBASE and included studies that examined the relationship between bacteria and back pain or Modic change. Studies were rated based on their methodological quality, a best-evidence synthesis was used to summarise the results, and Bradford Hill's criteria were used to assess the evidence for causation., Results: Eleven studies were identified. The median (range) age and percentage of female participants was 44.7 (41-46.4) years and 41.5% (27-59%), respectively, and in 7 of the 11 studies participants were diagnosed with disc herniation. Nine studies examined the presence of bacteria in spinal disc material and all identified bacteria, with the pooled estimate of the proportion with positive samples being 34%. Propionibacterium acnes was the most prevalent bacteria, being present in 7 of the 9 studies, with median (minimum, maximum) 45.0% (0-86.0) of samples positive. The best evidence synthesis found moderate evidence for a relationship between the presence of bacteria and both low back pain with disc herniation and Modic Type 1 change with disc herniation. There was modest evidence for a cause-effect relationship., Conclusions: We found that bacteria were common in the spinal disc material of people undergoing spinal surgery. There was moderate evidence for a relationship between the presence of bacteria and both low back pain with disc herniation and Modic Type 1 change associated with disc herniation and modest evidence for causation. However, further work is needed to determine whether these organisms are a result of contamination or represent low grade infection of the spine which contributes to chronic low back pain.

Low back pain and degenerative disc disease are a significant cause of pain and disability worldwide. Advances in regenerative medicine and cell-based therapies, particularly the transplantation of mesenchymal stem cells and intervertebral disc chondrocytes, have led to the publication of numerous studies and clinical trials utilising these biological therapies to treat degenerative spinal conditions, often reporting favourable outcomes. Stem cell mediated disc regeneration may bridge the gap between the two current alternatives for patients with low back pain, often inadequate pain management at one end and invasive surgery at the other. Through cartilage formation and disc regeneration or via modification of pain pathways stem cells are well suited to enhance spinal surgery practice. This paper will systematically review the current status of basic science studies, preclinical and clinical trials utilising cell-based therapies to repair the degenerate intervertebral disc. The mechanism of action of transplanted cells, as well as the limitations of published studies, will be discussed.

Objective Lateral sinus thrombosis is a potentially devastating but seldom studied complication of cerebellopontine angle (CPA) tumor surgery. Systemic anticoagulation in the early postoperative period has often been avoided due to the potential risks of intracranial hemorrhage. Design Retrospective review. Setting Tertiary referral center. Main Outcome Measures The goal of this study was to identify the frequency, treatment, and outcomes in patients who develop postoperative venous sinus thrombosis following CPA tumor surgery and receive early systemic anticoagulation. Results Of 43 patients with CPA tumors, we report five patients (11.6%) with transverse and/or sigmoid sinus thrombosis following resection of the tumor, four of which were detected on routine early postoperative noncontrast computed tomography (CT) scan. The thrombosis was confirmed in all cases with CT venography or magnetic resonance venography. Affected patients had significantly larger tumors than controls and tended to undergo longer operations. These patients were treated with immediate anticoagulation (intravenous heparin, followed by Coumadin for 6 months) without complication. Conclusion Venous sinus thrombosis is an underrecognized complication of CPA surgery, but it can be diagnosed in the early postoperative period by noncontrast CT imaging. Early postoperative initiation of systemic anticoagulation appears safe and effective to prevent the progression of thrombosis and its consequences.

Melatonin is an endogenous hormone mainly produced by the pineal gland whose dysfunction leads to abnormal sleeping patterns. Changes in melatonin have been reported in acute traumatic brain injury (TBI); however, the impact of environmental conditions typical of the intensive care unit (ICU) has not been assessed. The aim of this study was to compare daily melatonin production in three patient populations treated at the ICU to differentiate the role of TBI versus ICU conditions. Forty-five patients were recruited and divided into severe TBI, trauma without TBI, medical conditions without trauma, and compared to healthy volunteers. Serum melatonin levels were measured at four daily intervals at 0400 h, 1000 h, 1600 h, and 2200 h for 7 days post-ICU admission by commercial enzyme linked immunosorbent assay. The geometric mean concentrations (95% confidence intervals) of melatonin in these groups showed no difference being 8.3 (6.3-11.0), 9.3 (7.0-12.3), and 8.9 (6.6-11.9) pg/mL, respectively, in TBI, trauma, and intensive care cohorts. All of these patient groups demonstrated decreased melatonin concentrations when compared to control patients. This study suggests that TBI as well as ICU conditions, may have a role in the dysfunction of melatonin. Monitoring and possibly substituting melatonin acutely in these settings may assist in ameliorating long-term sleep dysfunction in all of these groups, and possibly contribute to reducing secondary brain injury in severe TBI.

Background: Mild head injuries commonly present to emergency departments. The challenges facing clinicians in emergency departments include identifying which patients have traumatic brain injury, and which patients can safely be sent home. Traumatic brain injuries may exist with subtle symptoms or signs, but can still lead to adverse outcomes. Despite the existence of several high quality clinical practice guidelines, internationally and in Australia, research shows inconsistent implementation of these recommendations. The aim of this trial is to test the effectiveness of a targeted, theory- and evidence-informed implementation intervention to increase the uptake of three key clinical recommendations regarding the emergency department management of adult patients (18 years of age or older) who present following mild head injuries (concussion), compared with passive dissemination of these recommendations. The primary objective is to establish whether the intervention is effective in increasing the percentage of patients for which appropriate post-traumatic amnesia screening is performed., Methods/design: The design of this study is a cluster randomised trial. We aim to include 34 Australian 24-hour emergency departments, which will be randomised to an intervention or control group. Control group departments will receive a copy of the most recent Australian evidence-based clinical practice guideline on the acute management of patients with mild head injuries. The intervention group will receive an implementation intervention based on an analysis of influencing factors, which include local stakeholder meetings, identification of nursing and medical opinion leaders in each site, a train-the-trainer day and standardised education and interactive workshops delivered by the opinion leaders during a 3 month period of time. Clinical practice outcomes will be collected retrospectively from medical records by independent chart auditors over the 2 month period following intervention delivery (patient level outcomes). In consenting hospitals, eligible patients will be recruited for a follow-up telephone interview conducted by trained researchers. A cost-effectiveness analysis and process evaluation using mixed-methods will be conducted. Sample size calculations are based on including 30 patients on average per department. Outcome assessors will be blinded to group allocation., Trial Registration: Australian New Zealand Clinical Trials Registry ACTRN12612001286831 (date registered 12 December 2012).