Contusion Progression in Traumatic Brain Injury

Cerebral contusions that result from brain trauma have the propensity to enlarge over the days following injury, including extension of the haemorrhage core and swelling of the surrounding peri-contusional brain. This secondary injury increases the likelihood of death and severe disabil- ity, and interventions to prevent or limit contusion progression may improve clinical outcomes. In preclinical studies a number of pathophysiological process have been identified that contribute to brain oedema including blood brain barrier (BBB) disruption, neuroinflammation, and cerebral metabolic dysfunction. This work has set out to measure and quantify contusion progression in TBI patients, characterise BBB permeability with computed tomography imaging, and identify key mediators of this process using intracerebral microdialysis. • Study I: A robust and effective stereological method for measuring the volume of brain lesions was validated and applied to a cohort of TBI patients to examine the temporal course of contusion progression. Intracranial pressure and brain lactate/pyruvate ratio were found to be associated with the magnitude of contusion expansion. • Study II: Dynamic contrast enhanced computed tomography (DCE-CT) was applied in pa- tients with brain contusions to quantify BBB permeability. The imaging showed profound reduction in cerebral blood flow associated with contusions but did not show evidence of contrast extravasation or BBB permeability. • Study III: Paired microdialysis catheters, one inserted in proximity to a contusion and an- other in non-injured brain, were used to characterise the peri-contusional inflammatory response with a multiplex assay of 42 cytokines, chemokines, and growth factors. Peri- contusional tissue was found to exhibit an early pro-inflammatory signature. • Study IV: A paired microdialysis study of pericontusional expression of matrix metalloproteinases (MMP). Specific increase in the expression of MMP-9 was identified in pericontusional brain. • Study V: Nitric oxide (NOx) concentrations were assayed in pericontusional and uninjured brain with paired microdialysis. NOx levels were lower in pericontusional brain and exhibited significant correlations with brain glucose, pyruvate, and lactate. • Study VI: Microdialysis data from 619 TBI patients with collated to explore the physiological correlates of deranged metabolism and elevated LPR. Cerebral glucose was found to a key determinant of LPR. The implications of these findings in the context of existing knowledge of BBB permeability, in- flammation, and cerebral metabolism in TBI are discussed. Future investigations to clarify the mechanisms highlighted, and potential therapeutic studies directed at reducing contusion pro- gression and brain oedema are suggested

Multimodal and autoregulation monitoring in the neurointensive care unit

Given the complexity of cerebral pathology in patients with acute brain injury, various neuromonitoring strategies have been developed to better appreciate physiologic relationships and potentially harmful derangements. There is ample evidence that bundling several neuromonitoring devices, termed “multimodal monitoring,” is more beneficial compared to monitoring individual parameters as each may capture different and complementary aspects of cerebral physiology to provide a comprehensive picture that can help guide management. Furthermore, each modality has specific strengths and limitations that depend largely on spatiotemporal characteristics and complexity of the signal acquired. In this review we focus on the common clinical neuromonitoring techniques including intracranial pressure, brain tissue oxygenation, transcranial doppler and near-infrared spectroscopy with a focus on how each modality can also provide useful information about cerebral autoregulation capacity. Finally, we discuss the current evidence in using these modalities to support clinical decision making as well as potential insights into the future of advanced cerebral homeostatic assessments including neurovascular coupling

Integrative Neuroinformatics for Precision Prognostication and Personalized Therapeutics in Moderate and Severe Traumatic Brain Injury.

Despite changes in guideline-based management of moderate/severe traumatic brain injury (TBI) over the preceding decades, little impact on mortality and morbidity have been seen. This argues against the "one-treatment fits all" approach to such management strategies. With this, some preliminary advances in the area of personalized medicine in TBI care have displayed promising results. However, to continue transitioning toward individually-tailored care, we require integration of complex "-omics" data sets. The past few decades have seen dramatic increases in the volume of complex multi-modal data in moderate and severe TBI care. Such data includes serial high-fidelity multi-modal characterization of the cerebral physiome, serum/cerebrospinal fluid proteomics, admission genetic profiles, and serial advanced neuroimaging modalities. Integrating these complex and serially obtained data sets, with patient baseline demographics, treatment information and clinical outcomes over time, can be a daunting task for the treating clinician. Within this review, we highlight the current status of such multi-modal omics data sets in moderate/severe TBI, current limitations to the utilization of such data, and a potential path forward through employing integrative neuroinformatic approaches, which are applied in other neuropathologies. Such advances are positioned to facilitate the transition to precision prognostication and inform a top-down approach to the development of personalized therapeutics in moderate/severe TBI

Posterior Versus Anterior Circulation Strokes: Comparison of Treatment Costs, and Outcomes for Medicare Patients

This study used a 5% sample of Medicare billing records from 2012 to identify cost differences between posterior circulation (PCS) and anterior circulation strokes (ACS). We examined ICD-9 codes related to these stroke types at hospital admission, records for six months post stroke, or until death, and identified mean payment and charges by type of care received. The Charlson Comorbidity Score was used to control for the effects of comorbid conditions on cost, survival, and the use of tPA during the Index admission. We identified 105 PCS and a comparison group of 5230 subjects with ACS and compared mean Medicare payment data from initial hospital admission, physician hospital payments, inpatient rehabilitation, outpatient rehabilitation, physician office visits, home healthcare, DME, nursing home care, hospital readmissions, and hospice care. As hypothesized, PCS have greater costs than ACS during early recovery from an ischemic stroke

Head impact effects in Small Remotely Piloted Aircraft System (sRPAS) collisions: Gender specific risks and vulnerable population protection

This study focuses on supporting the development of safety regulations for vulnerable populations during drone to head impacts. First, the small female head and neck model was compared to cadaveric data. Then, combined with lab’s previous work, gender-based disparities in head impact responses were highlighted, with small females experiencing higher injury risk metrics, despite lower skull von Mises stress. Beyond small females, children of various ages and their head responses during impacts were also analyzed. In addition to the previously developed quadcopter drone model, a new Mavic Pro drone model was developed, and this model was integrated with human head models during comparison against cadaveric data. The Mavic Pro, despite its lower weight, demonstrated higher injury risks compared to the previously studied Phantom 3. Overall, in this study head kinematics, head injury criteria (HIC), rotational velocities, and brain strains were analyzed, indicating potential risks for vulnerable populations. These findings underscore the need for tailored safety measures, regulatory guidelines, and comprehensive injury prevention strategies in the field of drone operations

An investigation into the effects of commencing haemodialysis in the critically ill

<b>Introduction:</b> We have aimed to describe haemodynamic changes when haemodialysis is instituted in the critically ill. 3 hypotheses are tested: 1)The initial session is associated with cardiovascular instability, 2)The initial session is associated with more cardiovascular instability compared to subsequent sessions, and 3)Looking at unstable sessions alone, there will be a greater proportion of potentially harmful changes in the initial sessions compared to subsequent ones. <b>Methods:</b> Data was collected for 209 patients, identifying 1605 dialysis sessions. Analysis was performed on hourly records, classifying sessions as stable/unstable by a cutoff of >+/-20% change in baseline physiology (HR/MAP). Data from 3 hours prior, and 4 hours after dialysis was included, and average and minimum values derived. 3 time comparisons were made (pre-HD:during, during HD:post, pre-HD:post). Initial sessions were analysed separately from subsequent sessions to derive 2 groups. If a session was identified as being unstable, then the nature of instability was examined by recording whether changes crossed defined physiological ranges. The changes seen in unstable sessions could be described as to their effects: being harmful/potentially harmful, or beneficial/potentially beneficial. <b>Results:</b> Discarding incomplete data, 181 initial and 1382 subsequent sessions were analysed. A session was deemed to be stable if there was no significant change (>+/-20%) in the time-averaged or minimum MAP/HR across time comparisons. By this definition 85/181 initial sessions were unstable (47%, 95% CI SEM 39.8-54.2). Therefore Hypothesis 1 is accepted. This compares to 44% of subsequent sessions (95% CI 41.1-46.3). Comparing these proportions and their respective CI gives a 95% CI for the standard error of the difference of -4% to 10%. Therefore Hypothesis 2 is rejected. In initial sessions there were 92/1020 harmful changes. This gives a proportion of 9.0% (95% CI SEM 7.4-10.9). In the subsequent sessions there were 712/7248 harmful changes. This gives a proportion of 9.8% (95% CI SEM 9.1-10.5). Comparing the two unpaired proportions gives a difference of -0.08% with a 95% CI of the SE of the difference of -2.5 to +1.2. Hypothesis 3 is rejected. Fisher’s exact test gives a result of p=0.68, reinforcing the lack of significant variance. <b>Conclusions:</b> Our results reject the claims that using haemodialysis is an inherently unstable choice of therapy. Although proportionally more of the initial sessions are classed as unstable, the majority of MAP and HR changes are beneficial in nature

14th International Symposium on Thrombolysis, Thrombectomy and Acute Stroke Therapy: proceedings and summary of discussions

The 14th International Symposium on Thrombolysis, Thrombectomy and Acute Stroke Therapy (TTST) took place in Houston, Texas on 21–22 October 2018. Attended by 150þ invited global experts, the objectives of TTST 2018 were to explore the changing landscape of acute ischemic stroke therapy and to address current controversies in thrombolysis and thrombectomy, including expanding access and systems of care with global relevance. This article summarizes the proceedings of TTST 2018. The key points of each session are listed below, the full text of presentations and discussion areavailable in the online supplement, and the full list of contributing authors appear in the Appendix at the end of this article

Novel methods of malignant brain tumor treatment utilizing the tumor microenvironment

Malignant brain tumors constitute a disaster in the lives of patients, either in the form of extremely low survival in glioblastoma, or the serious long-term adverse effects of therapy in medulloblastoma. These two tumor types represent the most common malignant brain entities in adults and children, respectively. Ever since the early 2000’s, no major improvement of patient outcomes occurred. Immunotherapy, which recorded revolutionary successes in several tumor types, has so far failed in brain tumors. This disappointing phenomenon is the result of intrinsic characteristics of glioblastoma and medulloblastoma and their microenvironment. Therefore, other treatment modalities that exploit the distinct attributes of malignant brain tumors are urgently needed.In this thesis, I describe the features of both tumor types and the development of their therapy until today. Moreover, general features of tumor microenvironment are contrasted to the unique aspects of the brain tumor counterpart. Next, I outline the underlying mechanisms of conventional immunotherapy and recount the natural features of both tumors that prevent its effective deployment. Finally, I suggest alternative approaches that circumvent the challenges encountered so far, such as avoiding the blood brain barrier via local treatment administration or focusing on macrophages as the principal agent of immunotherapy instead of T cells. Antisecretory factor (AF), a new agent in cancer treatment, as well as modulation of CD24/Siglec10 “don’t eat me” signaling are examples of the latter.Following is a summary of the four projects. In publication I, the concept of intratumoral temozolomide treatment is investigated from the perspective of tumor immune microenvironment. Publication II describes the effects of AF16 on macrophages and glioblastoma cells. Publication III is a pilot clinical trial of an AF preparation in patients with newly diagnosed glioblastoma. Manuscript IV examines the modulation of CD24 and Siglec10 to reduce antiphagocytic signaling in glioblastoma and medulloblastoma. The impact of this research is represented by the first published immunological effects of local delivery of temozolomide through convection-enhanced delivery in murine glioblastoma; first investigation of AF16, macrophages and tumor cells; first Salovum human cancer trial; laying the groundwork for CD24-Siglec10 signaling modulation in human glioblastoma and medulloblastoma