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This introduction offers a survey of some important critical approaches to the ways in which the First World War and its aftermath have been studied, conceptualized, represented and commemorated. In particular, it notes recent scholarly interest in issues of gender, as well as a focus on widening the geographical range of the conflict beyond a dominant European paradigm. A recurrent theme is the emergence of new types of modernity in the post-war era, and the ways in which literature and the arts do not merely reflect that modernity, but actively shape and constitute it.

Despite the significant clinical consequences and socioeconomic costs of gun-shot wounds to the head (GSWH), studies examining pre-hospital risk factors, geo-spatial patterns, and economic cost are lacking.A retrospective analysis was performed for GSWH patients (single or multiple injuries) presenting to the level one Ryder Trauma Center (hospital patients) as well as the Miami Dade County Medical Examiner (ME) Department, from October 2013 to October 2015. Additionally, ME data was queried from the previous decade (2008-2017) to analyze longitudinal trends.402 consecutive cases met inclusion criteria: 297 (74%) presented to the ME and 105 (26%) presented to the hospital. GSWH in our cohort had a case fatality rate of 89%, predominantly afflicting males, Caucasians, and victims of suicide, with a mean age of 41.9 ± 20.6 years. Hospital patients were more likely to be Black males from low socioeconomic (SES) regions involved in assault. Older, Caucasian males were overrepresented in patients attempting and completing suicide, thus comprised a higher percentage of ME cases. Geo-spatial analysis of hospital patient injury zip-codes illustrates GSWH are significantly clustered in low-income urban centers with greater poverty rates. In Miami-Dade County, the economic burden of GSWH, as measured by total healthcare costs and lifetime productivity losses, was estimated to be $11,867,415 and $246,179,498 respectively.In the first analysis of GSWH with the inclusion of both hospital and ME data in a representative urban setting, our findings demonstrate pre-hospital risk factors and the unequal distribution of the significant economic costs of GSWH.

Traumatic brain injuries (TBI) often produce disability in survivors due to unresolved inflammation and progressive neurodegeneration. The central nervous system in mammals is incapable of self-repair. Two decades of preclinical studies and clinical trials have provided insights into TBI pathophysiology that could be utilized to develop clinically relevant therapy. Our laboratory recently reported efficacy of clinical trial grade fetal human neural stem cells (hNSCs) in immunosuppressed rats with penetrating traumatic brain injury (pTBI). Next, in compliance with the United States Food and Drug Administration (USFDA) guidance, this study explores safety by assessing the tumorigenicity potential of intracranial hNSC transplants in athymic rats with pTBI. First, the maximum tolerated dose (MTD) was determined. Then, forty athymic pTBI rats were randomized to either: Group A. pTBI + vehicle or Group B. pTBI + hNSCs at MTD one week after injury with 6-months survival, sufficient time to uncover transplant associated tumorigenicity. A board-certified Pathologist examined hematoxylin-eosin (HE), Ki67 immunostained brain and spinal cord, serial sections along with several abnormal peripheral masses for evidence of lesion, transplant, and oncogenesis. There was no evidence of transplant derived tumors or oncogenic tissue necrosis. Consistent with athymic literature, the lesion remained unchanged even after robust hNSC engraftment. This safety study supports the conclusion that hNSCs are safe for transplantation in pTBI. The differences in lesion expansion between immunosuppressed and athymic rats in the presence of hNSCs suggests an unexpected role for thymus derived cells in resolution of trauma induced inflammation.

Although Shakespeare’s literary reception in nineteenth-century Russia has been well mapped, less attention has been given to his musical afterlife. This chapter examines Shakespeare’s place in nineteenth-century Russian music from three complementary perspectives. First, it will consider how Shakespeare’s characters and plots were taken up in the mid-century tone poem, with a particular focus on Balakirev’s overture to King Lear. Second, it will examine the use of music in stage productions of Shakespeare’s plays, taking by way of example not just Balakirev’s incidental music for King Lear, but also Tchaikovsky’s music for Hamlet (rather than his better-known tone poems, Romeo and Juliet and The Tempest). Finally, a third model of reception is explored in the form of a discussion of Musorgsky’s treatment of Pushkin’s Boris Godunov. Rather than setting Shakespeare directly, Musorgsky engages in a triangulation of literary influence, drawing on Pushkin’s historical drama (widely regarded as an attempt to import Shakespearean principles as a way of distancing himself from the precepts of French neo-classicism) as a way of distancing himself from Italian models of operatic action (including many on Shakespearean themes).

Acute spinal cord injury (SCI) results in catastrophic neurological impairment. We aimed to examine the temporal profile and severity correlation of biomarkers, and their relationship with the American Spinal Injury Association Scale (AIS) improvement in human SCI. 15 SCI and 10 non-SCI healthy subjects were classified according to the initial and discharge AIS grade. Serial cerebrospinal fluid (CSF) and serum samples were collected. Spectrin breakdown products (SBDP) 150, SBDP145, glial fibrillary acidic protein (GFAP), and GFAP breakdown product (GBDP) 38/44K were found to be elevated in the acute phase CSF samples in SCI patients on immunoblotting. SBDP150, ubiquitin C-terminal hydrolase-L1 (UCH-L1), GFAP, S100B, neurofilament light chain protein (NF-L), Tau & interleukin (IL) -6 were elevated in the acute phase CSF and serum samples on ELISA. CSF SBDP150, UCH-L1, GFAP, S100B and Tau were seen to peak on day 1 after injury, while CSF IL-6 and NF-L peaked on day 5. Serum SBDP150, IL-6, S100B, GFAP, UCHL-1 and Tau peaked on day 1, while serum NF-L peaked on day 5 post-injury. CSF alpha II-spectrin, SBDP150/145, and GBDP 44-38K levels (by immunoblots), CSF SBDP150, S100B, GFAP, UCHL-1 and Tau (ELISA) and serum UCHL-1 and Tau (ELISA) at specific time points showed SCI severity-correlation. CSF SBDP150, GFAP, and Tau and serum UCHL-1 and Tau (ELISA) were seen to have the best correlation with the severity at discharge. Receiver Operating Characteristic Curve analysis showed that CSF and serum biomarkers (SBDP150, IL-6, S100B, GFAP, NF-L, UCHL-1 and Tau) were associated with the severity of SCI.

In Russia, the impact of the end of World War I was subsumed under the far greater impact of the October Revolution, which led to a bifurcation of Russian culture into Soviet and émigré branches. This article examines a hybrid literary and musical work from the interwar period: Viacheslav Ivanov’s nine Roman Sonnets ( Rimskie sonety, 1924) and the musical settings that the composer Aleksandr Grechaninov made of five of these as his Sonetti Romani in 1939. Here, both poet and composer seek to convey the experience of finding oneself in one of Europe’s most evocative historical and cultural locations. At the same time, their evocation of Rome forges a powerful historical narrative of the city’s prior inhabitants. Accordingly, Rome emerges as an intertextual palimpsest of literary and artistic references, which together create a powerful sense of cultural continuity to offset the loss of the artist’s original homeland.

Importance Moderate to severe traumatic brain injury (msTBI) is a major cause of death and disability in the US and worldwide. Few studies have enabled prospective, longitudinal outcome data collection from the acute to chronic phases of recovery after msTBI. Objective To prospectively assess outcomes in major areas of life function at 2 weeks and 3, 6, and 12 months after msTBI. Design, Setting, and Participants This cohort study, as part of the Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) study, was conducted at 18 level 1 trauma centers in the US from February 2014 to August 2018 and prospectively assessed longitudinal outcomes, with follow-up to 12 months postinjury. Participants were patients with msTBI (Glasgow Coma Scale scores 3-12) extracted from a larger group of patients with mild, moderate, or severe TBI who were enrolled in TRACK-TBI. Data analysis took place from October 2019 to April 2021. Exposures Moderate or severe TBI. Main Outcomes and Measures The Glasgow Outcome Scale–Extended (GOSE) and Disability Rating Scale (DRS) were used to assess global functional status 2 weeks and 3, 6, and 12 months postinjury. Scores on the GOSE were dichotomized to determine favorable (scores 4-8) vs unfavorable (scores 1-3) outcomes. Neurocognitive testing and patient reported outcomes at 12 months postinjury were analyzed. Results A total of 484 eligible patients were included from the 2679 individuals in the TRACK-TBI study. Participants with severe TBI (n = 362; 283 men [78.2%]; median [interquartile range] age, 35.5 [25-53] years) and moderate TBI (n = 122; 98 men [80.3%]; median [interquartile range] age, 38 [25-53] years) were comparable on demographic and premorbid variables. At 2 weeks postinjury, 36 of 290 participants with severe TBI (12.4%) and 38 of 93 participants with moderate TBI (41%) had favorable outcomes (GOSE scores 4-8); 301 of 322 in the severe TBI group (93.5%) and 81 of 103 in the moderate TBI group (78.6%) had moderate disability or worse on the DRS (total score ≥4). By 12 months postinjury, 142 of 271 with severe TBI (52.4%) and 54 of 72 with moderate TBI (75%) achieved favorable outcomes. Nearly 1 in 5 participants with severe TBI (52 of 270 [19.3%]) and 1 in 3 with moderate TBI (23 of 71 [32%]) reported no disability (DRS score 0) at 12 months. Among participants in a vegetative state at 2 weeks, 62 of 79 (78%) regained consciousness and 14 of 56 with available data (25%) regained orientation by 12 months. Conclusions and Relevance In this study, patients with msTBI frequently demonstrated major functional gains, including recovery of independence, between 2 weeks and 12 months postinjury. Severe impairment in the short term did not portend poor outcomes in a substantial minority of patients with msTBI. When discussing prognosis during the first 2 weeks after injury, clinicians should be particularly cautious about making early, definitive prognostic statements suggesting poor outcomes and withdrawal of life-sustaining treatment in patients with msTBI.

‘TO JEWS, I’M a Christian; to Christians, I’m a Jew. To Russians, I’m a German; to Germans, I’m a Russian. To classicists, I’m a moderniser; to modernisers, I’m a reactionary, and so on. What to make of this? I’m neither fish, nor fowl, just a pitiful individual!’...

The Russian arts were as fascinated by exotic languages, cultures, and locales as their Western European counterparts, and at first glance, Russian settings of the poetry of Hafiz appears to form part of the broader field of musical exoticism in general, and Russian orientalism in particular. This chapter begins by examining the relationship between empire and music, before setting out a rather different account of Russian musical orientalism, one marked by a complex transnational flow of literary and musical influences, as well as practices of translation, imitation, cultural appropriation, and cross-border artistic exchange. Whilst forming part of a broader tendency to imagine visions of a supposed ‘orient’ that had little to do with any documented anthropological, ethnographic, philological, or linguistic reality, Russian settings of Hafiz’s poetry are ultimately the result of the import of elements of German romanticism. Here, writers, translators, and commentators co-opted a range of ‘exotic’ literatures in an attempt to distinguish themselves from the dominance of French classicism and fashion an autonomous form of German nationalism, key elements of which were then incorporated into mid-nineteenth-century Russian culture (as in the case of Afanasy Fet’s translations of Georg Daumer’s well-known ‘versions’ of Hafiz). Accordingly, Hafiz figures not so much as the object of orientalist representation (although there is certainly a strong element of that to the songs discussed here), but as an exemplary figure within a complex network of literary mediation.

BACKGROUND Penetrating traumatic brain injury induces chronic inflammation that drives persistent tissue loss long after injury. Absence of endogenous reparative neurogenesis and effective neuroprotective therapies render injury-induced disability an unmet need. Cell replacement via neural stem cell transplantation could potentially rebuild the tissue and alleviate penetrating traumatic brain injury disability. The optimal transplant location remains to be determined. METHODS To test if subacute human neural stem cell (hNSC) transplant location influences engraftment, lesion expansion, and motor deficits, rats (n = 10/group) were randomized to the following four groups (uninjured and three injured): group 1 (Gr1), uninjured with cell transplants (sham+hNSCs), 1-week postunilateral penetrating traumatic brain injury, after establishing motor deficit; group 2 (Gr2), treated with vehicle (media, no cells); group 3 (Gr3), hNSCs transplanted into lesion core (intra); and group 4 (Gr4), hNSCs transplanted into tissue surrounding the lesion (peri). All animals were immunosuppressed for 12 weeks and euthanized following motor assessment. RESULTS In Gr2, penetrating traumatic brain injury effect manifests as porencephalic cyst, 22.53 ± 2.87 (% of intact hemisphere), with p value of

Background Hypothermia is neuroprotective in some ischemia–reperfusion injuries. Ischemia–reperfusion injury may occur with traumatic subdural hematoma (SDH). This study aimed to determine whether early induction and maintenance of hypothermia in patients with acute SDH would lead to decreased ischemia–reperfusion injury and improve global neurologic outcome. Methods This international, multicenter randomized controlled trial enrolled adult patients with SDH requiring evacuation of hematoma within 6 h of injury. The intervention was controlled temperature management of hypothermia to 35 °C prior to dura opening followed by 33 °C for 48 h compared with normothermia (37 °C). Investigators randomly assigned patients at a 1:1 ratio between hypothermia and normothermia. Blinded evaluators assessed outcome using a 6-month Glasgow Outcome Scale Extended score. Investigators measured circulating glial fibrillary acidic protein and ubiquitin C-terminal hydrolase L1 levels. Results Independent statisticians performed an interim analysis of 31 patients to assess the predictive probability of success and the Data and Safety Monitoring Board recommended the early termination of the study because of futility. Thirty-two patients, 16 per arm, were analyzed. Favorable 6-month Glasgow Outcome Scale Extended outcomes were not statistically significantly different between hypothermia vs. normothermia groups (6 of 16, 38% vs. 4 of 16, 25%; odds ratio 1.8 [95% confidence interval 0.39 to ∞], p = .35). Plasma levels of glial fibrillary acidic protein (p = .036), but not ubiquitin C-terminal hydrolase L1 (p = .26), were lower in the patients with favorable outcome compared with those with unfavorable outcome, but differences were not identified by temperature group. Adverse events were similar between groups. Conclusions This trial of hypothermia after acute SDH evacuation was terminated because of a low predictive probability of meeting the study objectives. There was no statistically significant difference in functional outcome identified between temperature groups.

Contains fulltext : 238746.pdf (Publisher’s version ) (Closed access) Recent biomarker innovations hold potential for transforming diagnosis, prognostic modeling, and precision therapeutic targeting of traumatic brain injury (TBI). However, many biomarkers, including brain imaging, genomics, and proteomics, involve vast quantities of high-throughput and high-content data. Management, curation, analysis, and evidence synthesis of these data are not trivial tasks. In this review, we discuss data management concepts and statistical and data sharing strategies when dealing with biomarker data in the context of TBI research. We propose that application of biomarkers involves three distinct steps-discovery, evaluation, and evidence synthesis. First, complex/big data has to be reduced to useful data elements at the stage of biomarker discovery. Second, inferential statistical approaches must be applied to these biomarker data elements for assessment of biomarker clinical utility and validity. Last, synthesis of relevant research is required to support practice guidelines and enable health decisions informed by the highest quality, up-to-date evidence available. We focus our discussion around recent experiences from the International Traumatic Brain Injury Research (InTBIR) initiative, with a specific focus on four major clinical projects (Transforming Research and Clinical Knowledge in TBI, Collaborative European NeuroTrauma Effectiveness Research in TBI, Collaborative Research on Acute Traumatic Brain Injury in Intensive Care Medicine in Europe, and Approaches and Decisions in Acute Pediatric TBI Trial), which are currently enrolling subjects in North America and Europe. We discuss common data elements, data collection efforts, data-sharing opportunities, and challenges, as well as examine the statistical techniques required to realize successful adoption and use of biomarkers in the clinic as a foundation for precision medicine in TBI.

Background Brain volumes in regions such as the hippocampus and amygdala have been associated with risk for the development of posttraumatic stress disorder (PTSD). The objective of this study was to determine whether a set of regional brain volumes, measured by magnetic resonance imaging at 2 weeks following mild traumatic brain injury, were predictive of PTSD at 3 and 6 months after injury. Methods Using data from TRACK-TBI (Transforming Research and Clinical Knowledge in TBI), we included patients (N = 421) with Glasgow Coma Scale scores 13–15 assessed after evaluation in the emergency department and at 2 weeks, 3 months, and 6 months after injury. Probable PTSD diagnosis (PTSD Checklist for DSM-5 score, ≥33) was the outcome. FreeSurfer 6.0 was used to perform volumetric analysis of three-dimensional T1-weighted magnetic resonance images at 3T obtained 2 weeks post injury. Brain regions selected a priori for volumetric analyses were insula, hippocampus, amygdala, superior frontal cortex, rostral and caudal anterior cingulate, and lateral and medial orbitofrontal cortices. Results Overall, 77 (18.3%) and 70 (16.6%) patients had probable PTSD at 3 and 6 months. A composite volume derived as the first principal component incorporating 73.8% of the variance in insula, superior frontal cortex, and rostral and caudal cingulate contributed to the prediction of 3-month (but not 6-month) PTSD in multivariable models incorporating other established risk factors. Conclusions Results, while needing replication, provide support for a brain reserve hypothesis of PTSD and proof of principle for how prediction of at-risk individuals might be accomplished to enhance prognostic accuracy and enrich clinical prevention trials for individuals at the highest risk of PTSD following mild traumatic brain injury.

Chapter 4 investigates interaction between languages in the performing arts – theatre, stand-up comedy, grime, rap, opera – and the types of creativity this generates in response to cultural contexts and audiences, drawing on media and performance studies, and working with artists ranging from Russian dramatists to Black British and British Asian musicians from Birmingham and Leicester.

Realism, as the prevailing aesthetic in mid-nineteenth-century Russia, shaped the artistic practice of even those artists who may not have seen themselves as realists. In this regard, the case of Tchaikovsky is particularly instructive. Tchaikovsky’s songs enjoyed considerable popularity; however, César Cui, for example, denounced them for failing to respect the literary values of the words they set. Tchaikovsky’s views about the ability of music to access a form of truth that lay beyond verbal language might suggest a belief in the fundamental primacy of music over text. His songs play a crucial role in literary, as well as musical, culture, and in some cases are the only known source for otherwise unpublished poetry. He composed songs to his own lyrics, and also wrote poems not intended to be set to music. One of these, ‘Lilies of the Valley’ (‘Landyshi’), was set in part by Arensky, arguably misrepresenting the poem. Tchaikovsky particularly admired the work of the poet Afanasy Fet, comparing him to Beethoven. In the work of Tchaikovsky and of other song-composers of the nineteenth century, music plays a crucial role in the formation and dissemination of the literary canon.

Traumatic brain injury (TBI) is a leading cause of death and disability globally. No drug treatments are available, so interest has turned to endogenous neural stem cells (NSCs) as alternative strategies for treatment. We hypothesized that regulation of cell proliferation through modulation of the sonic hedgehog pathway, a key NSC regulatory pathway, could lead to functional improvement. We assessed sonic hedgehog (Shh) protein levels in the cerebrospinal fluid (CSF) of patients with TBI. Using the cortical contusion injury (CCI) model in rodents, we used pharmacological modulators of Shh signaling to assess cell proliferation within the injured cortex using the marker 5-Ethynyl-2’-deoxyuridine (EdU); 50mg/mL. The phenotype of proliferating cells was determined and quantified. Motor function was assessed using the rotarod test. In patients with TBI there is a reduction of Shh protein in CSF compared with control patients. In rodents, following a severe CCI, quiescent cells become activated. Pharmacologically modulating the Shh signaling pathway leads to changes in the number of newly proliferating injury-induced cells. Upregulation of Shh signaling with Smoothened agonist (SAG) results in an increase of newly proliferating cells expressing glial fibrillary acidic protein (GFAP), whereas the Shh signaling inhibitor cyclopamine leads to a reduction. Some cells expressed doublecortin (DCX) but did not mature into neurons. The SAG-induced increase in proliferation is associated with improved recovery of motor function. Localized restoration of Shh in the injured rodent brain, via increased Shh signaling, has the potential to sustain endogenous cell proliferation and the mitigation of TBI-induced motor deficits albeit without the neuronal differentiation.

Importance Advances in treatment of traumatic brain injury are hindered by the inability to monitor pathological mechanisms in individual patients for targeted neuroprotective treatment. Spreading depolarizations, a mechanism of lesion development in animal models, are a novel candidate for clinical monitoring in patients with brain trauma who need surgery. Objective To test the null hypothesis that spreading depolarizations are not associated with worse neurologic outcomes. Design, Setting, and Participants This prospective, observational, multicenter cohort study was conducted from February 2009 to August 2013 in 5 level 1 trauma centers. Consecutive patients who required neurological surgery for treatment of acute brain trauma and for whom research consent could be obtained were enrolled; participants were excluded because of technical problems in data quality, patient withdrawal, or loss to follow-up. Primary statistical analysis took place from April to December 2018. Evaluators of outcome assessments were blinded to other measures. Interventions A 6-contact electrode strip was placed on the brain surface during surgery for continuous electrocorticography during intensive care. Main Outcomes and Measures Electrocorticography was scored for depolarizations, following international consensus procedures. Six-month outcomes were assessed by the Glasgow Outcome Scale–Extended score. Results A total of 157 patients were initially enrolled; 19 were subsequently excluded. The 138 remaining patients (104 men [75%]; median [interquartile range] age, 45 [29-64] years) underwent a median (interquartile range) of 75.5 (42.2-117.1) hours of electrocorticography. A total of 2837 spreading depolarizations occurred in 83 of 138 patients (60.1% incidence) who, compared with patients who did not have spreading depolarizations, had lower prehospital systolic blood pressure levels (mean [SD], 133 [31] mm Hg vs 146 [33] mm Hg;P = .03), more traumatic subarachnoid hemorrhage (depolarization incidences of 17 of 37 [46%], 18 of 32 [56%], 22 of 33 [67%], and 23 of 30 patients [77%] for Morris-Marshall Grades 0, 1, 2, and 3/4, respectively;P = .047), and worse radiographic pathology (in 38 of 73 patients [52%] and 42 of 60 patients [70%] for Rotterdam Scores 2-4 vs 5-6, respectively;P = .04). Of patients with depolarizations, 32 of 83 (39%) had only sporadic events that induced cortical spreading depression of spontaneous electrical activity, whereas 51 of 83 patients (61%) exhibited temporal clusters of depolarizations (≥3 in a 2-hour span). Nearly half of those with clusters (23 of 51 [45%]) also had depolarizations in an electrically silent area of the cortex (isoelectric spreading depolarization). Patients with clusters did not improve in motor neurologic examinations from presurgery to postelectrocorticography, while other patients did improve. In multivariate ordinal regression adjusting for baseline prognostic variables, the occurrence of depolarization clusters had an odds ratio of 2.29 (95% CI, 1.13-4.65;P = .02) for worse outcomes. Conclusions and Relevance In this cohort study of patients with acute brain trauma, spreading depolarizations were predominant but heterogeneous and independently associated with poor neurologic recovery. Monitoring the occurrence of spreading depolarizations may identify patients most likely to benefit from targeted management strategies.

OBJECTIVETraumatic brain injuries (TBIs) are a significant disease burden worldwide. It is imperative to improve neurosurgeons’ training during and after their medical residency with appropriate neurotrauma competencies. Unfortunately, the development of these competencies during neurosurgeons’ careers and in daily practice is very heterogeneous. This article aimed to describe the development and evaluation of a competency-based international course curriculum designed to address a broad spectrum of needs for taking care of patients with neurotrauma with basic and advanced interventions in different scenarios around the world.METHODSA committee of 5 academic neurosurgeons was involved in the task of building this course curriculum. The process started with the identification of the problems to be addressed and the subsequent performance needed. After this, competencies were defined. In the final phase, educational activities were designed to achieve the intended learning outcomes. In the end, the entire process resulted in competency and outcomes-based education strategy, including a definition of all learning activities and learning outcomes (curriculum), that can be integrated with a faculty development process, including training. Further development was completed by 4 additional academic neurosurgeons supported by a curriculum developer specialist and a project manager. After the development of the course curriculum, template programs were developed with core and optional content defined for implementation and evaluation.RESULTSThe content of the course curriculum is divided into essentials and advanced concepts and interventions in neurotrauma care. A mixed sample of 1583 neurosurgeons and neurosurgery residents attending 36 continuing medical education activities in 30 different cities around the world evaluated the course. The average satisfaction was 97%. The average usefulness score was 4.2, according to the Likert scale.CONCLUSIONSAn international competency-based course curriculum is an option for creating a well-accepted neurotrauma educational process designed to address a broad spectrum of needs that a neurotrauma practitioner faces during the basic and advanced care of patients in different regions of the world. This process may also be applied to other areas of the neurosurgical knowledge spectrum. Moreover, this process allows worldwide standardization of knowledge requirements and competencies, such that training may be better benchmarked between countries regardless of their income level.

Clinical trials examining neuroprotective strategies after brain injury, including those targeting cell death mechanisms, have been underwhelming. This may be in part due to an incomplete understanding of the signalling mechanisms that induce cell death after traumatic brain injury. The recent identification of a new family of death receptors that initiate pro-cell death signals in the absence of their ligand, called dependence receptors, provides new insight into the factors that contribute to brain injury. Here, we show that blocking the dependence receptor signalling of EphB3 improves oligodendrocyte cell survival in a murine controlled cortical impact injury model, which leads to improved myelin sparing, axonal conductance and behavioural recovery. EphB3 also functions as a cysteine-aspartic protease substrate, where the recruitment of injury-dependent adaptor protein Dral/FHL-2 together with capsase-8 or -9 leads to EphB3 cleavage to initiate cell death signals in murine and human traumatic brain-injured patients, supporting a conserved mechanism of cell death. These pro-apoptotic responses can be blocked via exogenous ephrinB3 ligand administration leading to improved oligodendrocyte survival. In short, our findings identify a novel mechanism of oligodendrocyte cell death in the traumatically injured brain that may reflect an important neuroprotective strategy in patients., Following cellular stress, the dependence receptor EphB3 is cleaved by caspase-8 or -9 and the adaptor protein Dral/FHL-2 to regulate oligodendrocyte survival after traumatic brain injury. These pro-apoptotic responses can be blocked via exogenous ephrinB3 ligand administration leading to improved oligodendrocyte survival., Graphical Abstract Graphical Abstract

OBJECTIVE The objectives of this study were to evaluate levels of inflammasome-signaling proteins in serum and CSF of patients with traumatic brain injury (TBI), and to correlate these protein levels with intracranial pressure (ICP) and clinical outcomes at 6 months after injury. METHODS This is a prospective and observational study in patients with moderate and severe TBI who required an external ventricular drain as part of their treatment. Serum and CSF samples were collected 3 times a day for the first 5 days after TBI. The authors have determined the protein concentration of caspase-1 in the CSF and serum of patients with TBI by using commercially available enzyme-linked immunosorbent assays. The ICP value was recorded hourly. The 6-month outcome was assessed using the Glasgow Outcome Scale–Extended. RESULTS A total of 21 patients were included in this study, and a total of 234 paired serum-CSF samples were analyzed. The area under the curve (AUC) value of caspase-1 in CSF during the 5-day period was 2452.9 pg/mL·hr in the group of patients with high ICP vs 617.6 pg/mL·hr in the patients with low ICP. The differences were mainly on day 2 (19.7 pg/mL vs 1.8 pg/mL; p = 0.06) and day 3 (13.9 pg/mL vs 1 pg/mL; p = 0.05). The AUC value of caspase in CSF during the 5-day period was 1918.9 pg/mL·hr in the group of patients with poor outcome versus 924.5 pg/mL·hr in the patients with good outcome. The protein levels of caspase-1 in CSF were higher in patients with unfavorable outcomes during the first 96 hours after TBI. CONCLUSIONS In this cohort of patients with TBI who were admitted to the neurosurgical ICU, the inflammasome protein caspase-1 is increased in the CSF of patients with high ICP, especially on days 2 and 3 after TBI. Also the protein levels of caspase-1 in CSF were higher in patients with poor outcome during the first 96 hours after TBI. Moreover, not only the absolute value of caspase-1 in CSF but also its trend is associated with poor outcomes.

Penetrating traumatic brain injury (PTBI) is a significant cause of death and disability in the United States. Inflammasomes are one of the key regulators of the interleukin (IL)-1β mediated inflammatory responses after traumatic brain injury. However, the contribution of inflammasome signaling after PTBI has not been determined. In this study, adult male Sprague-Dawley rats were subjected to sham procedures or penetrating ballistic-like brain injury (PBBI) and sacrificed at various time-points. Tissues were assessed by immunoblot analysis for expression of IL-1β, IL-18, and components of the inflammasome: apoptosis-associated speck-like protein containing a caspase-activation and recruitment domain (ASC), caspase-1, X-linked inhibitor of apoptosis protein (XIAP), nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3), and gasdermin-D (GSDMD). Specific cell types expressing inflammasome proteins also were evaluated immunohistochemically and assessed quantitatively. After PBBI, expression of IL-1β, IL-18, caspase-1, ASC, XIAP, and NLRP3 peaked around 48 h. Brain protein lysates from PTBI animals showed pyroptosome formation evidenced by ASC laddering, and also contained increased expression of GSDMD at 48 h after injury. ASC-positive immunoreactive neurons within the perilesional cortex were observed at 24 h. At 48 h, ASC expression was concentrated in morphologically activated cortical microglia. This expression of ASC in activated microglia persisted until 12 weeks following PBBI. This is the first report of inflammasome activation after PBBI. Our results demonstrate cell-specific patterns of inflammasome activation and pyroptosis predominantly in microglia, suggesting a sustained pro-inflammatory state following PBBI, thus offering a therapeutic target for this type of brain injury.

After traumatic brain injury, decompressive craniectomy (DC) is a second-tier, late therapy for refractory intracranial hypertension. We hypothesize that early DC, based on CT evidence of intracranial hypertension, improves intracranial pressure (ICP) and cerebral perfusion pressure (CPP). From September 2008 to January 2015, 286 traumatic brain injury patients requiring invasive ICP monitoring at a single Level I trauma center were reviewed. DC and non-DC patients were propensity score matched 1:1, based on demographics, hemodynamics, injury severity score (ISS), Glasgow Coma Scale (GCS), transfusion requirements, and need for vasopressor therapy. Data are presented as M ± SD or median (IQR) and compared at P ≤ 0.05. The study population was 42 ± 17 years, 84 per cent male, ISS = 29 ± 11, GCS = 6 (5), length of stay (LOS) = 32(40) days, and 28 per cent mortality. There were 116/286 (41%) DC, of which 105/116 (91%) were performed at the time of ICP placement. For 50 DC propensity matched to 50 non-DC patients, the midline shift was 7(11) versus 0(5) mm ( P < 0.001), abnormal ICP (hours > 20 mm Hg) was 1(10) versus 8(16) ( P = 0.017), abnormal CPP (hours < 60 mm Hg) was 0(6) versus 4(9) ( P = 0.008), daily minimum CPP (mm Hg) was 67(13) versus 62(17) ( P = 0.010), and daily maximum ICP (mm Hg) was 18(9) versus 22(11) ( P < 0.001). However, LOS [33(37) versus 25(34) days], mortality (24 versus 30%), and Glasgow Outcome Score Extended [3.0(3.0) versus 3.0(4.0)] did not improve significantly. Early DC for CT evidence of intracranial hypertension decreased abnormal ICP and CPP time and improved ICP and CPP thresholds, but had no obvious effect on the outcome.

Arginine vasopressin (AVP) is often used as an alternative pressor to catecholamines (CATs). However, unlike CATs, AVP is a powerful antidiuretic that could promote edema. We tested the hypothesis that AVP promoted cerebral edema and/or increased requirements for osmotherapy, relative to those who received CATs, for cerebral perfusion pressure (CPP) management after traumatic brain injury (TBI). This is a retrospective review of 286 consecutive TBI patients with intracranial pressure monitoring at a single institution from September 2008 to January 2015. Cerebral edema was quantitated using CT attenuation in prespecified areas of gray and white matter. Results: To maintain CPP >60 mm Hg, 205 patients required no vasopressors, 41 received a single CAT, 12 received AVP, and 28 required both. Those who required no pressors were generally less injured; required less hyperosmolar therapy and less total fluid; and had lower plasma Na, lower intracranial pressure, less edema, and lower mortality (all P < 0.05). Edema; daily mean, minimum, and maximum Na levels; and mortality were similar with AVP versus CATs, but the daily requirement of mannitol and 3 per cent NaCl were reduced by 45 and 35 per cent (both P < 0.05). In patients with TBI who required CPP therapy, AVP reduced the requirements for hyperosmolar therapy and did not delay resolution or increase cerebral edema compared with CATs.

Penetrating traumatic brain injury (PTBI) is one of the major cause of death and disability worldwide. Previous studies with penetrating ballistic-like brain injury (PBBI), a PTBI rat model revealed widespread perilesional neurodegeneration, similar to that seen in humans following gunshot wound to the head, which is unmitigated by any available therapies to date. Therefore, we evaluated human neural stem cell (hNSC) engraftment to putatively exploit the potential of cell therapy that has been seen in other central nervous system injury models. Toward this objective, green fluorescent protein (GFP) labeled hNSC (400,000 per animal) were transplanted in immunosuppressed Sprague–Dawley (SD), Fisher, and athymic (ATN) PBBI rats 1 week after injury. Tacrolimus (3 mg/kg 2 days prior to transplantation, then 1 mg/kg/day), methylprednisolone (10 mg/kg on the day of transplant, 1 mg/kg/week thereafter), and mycophenolate mofetil (30 mg/kg/day) for 7 days following transplantation were used to confer immunosuppression. Engraftment in SD and ATN was comparable at 8 weeks post-transplantation. Evaluation of hNSC differentiation and distribution revealed increased neuronal differentiation of transplanted cells with time. At 16 weeks post-transplantation, neither cell proliferation nor glial lineage markers were detected. Transplanted cell morphology was similar to that of neighboring host neurons, and there was relatively little migration of cells from the peritransplant site. By 16 weeks, GFP-positive processes extended both rostrocaudally and bilaterally into parenchyma, spreading along host white matter tracts, traversing the internal capsule, and extending ∼13 mm caudally from transplantation site reaching into the brainstem. In a Morris water maze test at 8 weeks post-transplantation, animals with transplants had shorter latency to platform than vehicle-treated animals. However, weak injury-induced cognitive deficits in the control group at the delayed time point confounded benefits of durable engraftment and neuronal differentiation. Therefore, these results justify further studies to progress towards clinical translation of hNSC therapy for PTBI.

Traumatic brain injury (TBI) leads to a series of pathological events that can have profound influences on motor, sensory and cognitive functions. Conversely, TBI can also stimulate neural stem/progenitor cell proliferation leading to increased numbers of neuroblasts migrating outside their restrictive neurogenic zone to areas of damage in support of tissue integrity. Unfortunately, the factors that regulate migration are poorly understood. Here, we examine whether ephrinB3 functions to restrict neuroblasts from migrating outside the subventricular zone (SVZ) and rostral migratory stream (RMS). We have previously shown that ephrinB3 is expressed in tissues surrounding these regions, including the overlying corpus callosum (CC), and is reduced after controlled cortical impact (CCI) injury. Our current study takes advantage of ephrinB3 knockout mice to examine the influences of ephrinB3 on neuroblast migration into CC and cortex tissues after CCI injury. Both injury and/or ephrinB3 deficiency led to increased neuroblast numbers and enhanced migration outside the SVZ/RMS zones. Application of soluble ephrinB3-Fc molecules reduced neuroblast migration into the CC after injury and limited neuroblast chain migration in cultured SVZ explants. Our findings suggest that ephrinB3 expression in tissues surrounding neurogenic regions functions to restrict neuroblast migration outside the RMS by limiting chain migration.