Pediatric Tumors as Disorders of Development: The Case for In Vitro Modeling Based on Human Stem Cells.

Despite improvements in patient outcomes, pediatric cancer remains a leading cause of non-accidental death in children. Recent genetic analysis of patients with pediatric cancers indicates an important role for both germline genetic predisposition and cancer-specific somatic driver mutations. Increasingly, evidence demonstrates that the developmental timepoint at which the cancer cell-of-origin transforms is critical to tumor identity and therapeutic response. Therefore, future therapeutic development would be bolstered by the use of disease models that faithfully recapitulate the genetic context, cell-of-origin, and developmental window of vulnerability in pediatric cancers. Human stem cells have the potential to incorporate all of these characteristics into a pediatric cancer model, while serving as a platform for rapid genetic and pharmacological testing. In this review, we describe how human stem cells have been used to model pediatric cancers and how these models compare to other pediatric cancer model modalities.

Today, pediatric cancer is a leading cause of non-accidental death in children. In order to further improve outcomes, it is important for researchers and clinicians alike to recognize how pediatric cancers are distinct from adult cancers. Inherited risk of cancer may play a greater role in pediatric cancer risk, and subsequent tumor-specific acquired driver mutations initiate tumor formation. However, there is substantial interaction between inherited and acquired mutations, which supports consideration of both simultaneously. Recent advancements in biotechnology, have improved matching between early cells of development and pediatric cancer cells, although cell-of-origin for certain pediatric central nervous system tumors remain elusive. Increasingly, evidence, particularly in pediatric medulloblastoma, demonstrates that the developmental timepoint at which the cancer cell-of-origin transforms is critical to tumor identity and therapeutic response. Therefore, future therapeutic development would be bolstered by the use of disease models that faithfully recapitulate the genetic context, cell-of-origin, and developmental window of pediatric cancers. Human stem cells have the potential to incorporate all of these characteristics into a pediatric cancer model, while serving as a platform for rapid genetic and pharmacological testing. In this review, we describe how human stem cells have been used to model pediatric cancers, how human these models compare to other pediatric cancer model modalities, and how these models can be improved in the future.

Implementation of Routine In Situ Simulation in Residency Curriculum Targeting Competency in Technical and Decision-Making Skills.

OBJECTIVE: To describe the development and implementation of a comprehensive in situ simulation-based curriculum for anesthesia residents. DESIGN: This is a prospective study. SETTING: This study was conducted at a university hospital. PARTICIPANTS: This single-center prospective study included all 53 anesthesia residents enrolled in the anesthesia residency program. INTERVENTIONS: Introduction of a routine, high-fidelity, in situ simulation program that incorporates short sessions to train residents in the necessary skill sets and decision-making processes required in the operating room. MEASUREMENTS AND MAIN RESULTS: Our team conducted 182 individual 15-minute simulation sessions over 3 months during regular working hours. All 53 residents in our program actively participated in the simulations. Most residents engaged in at least 3 sessions, with an average participation rate of 3.4 per resident (range, 1-6 sessions). Residents completed an online anonymous survey, with a response rate of 71.7% (38 of 53 residents) over the 3-month period. The survey aimed to assess their overall impression and perceived contribution of this project to their training. CONCLUSIONS: Our proposed teaching method can bridge the gap in resident training and enhance their critical reasoning to manage diverse clinical situations they may not experience during their residency.

Virtual Reality Training for Central Venous Catheter Placement: An Interventional Feasibility Study Incorporating Virtual Reality Into a Standard Training Curriculum of Novice Trainees.

OBJECTIVES: This study assess the feasibility of integrating virtual reality (VR) simulation into the central venous catheter (CVC) placement training curriculum. DESIGN: The study consists of 3 parts: (1) Evaluating current manikin-based training for CVC placement through surveys for senior first-year anesthesia residents and cardiac anesthesia faculty who supervise resident performing the procedure; (2) Interventional study training novice trainees with VR simulator and assessing their reaction satisfaction; and (3) pilot study integrating VR training sessions into CVC training curriculum for first-year anesthesia residents. SETTING: Conducted at a single academic-affiliated medical center from December 2022 to August 2023. PARTICIPANTS: Junior first-year anesthesia residents. INTERVENTIONS: VR training sessions for CVC placements using the Vantari VR system. MEASUREMENTS AND MAIN RESULTS: Primary outcome: novice trainees' satisfaction with VR training for CVC procedure. Satisfaction of resident and faculty with standard manikin-based training was also collected. Faculty expressed concerns about residents' confidence and perceived knowledge in performing CVC placement independently. Novice trainees showed high satisfaction and perceived usefulness with VR training, particularly in understanding procedural steps and developing spatial awareness. Pilot integration of VR training into the curriculum demonstrated comparable training times and emphasized structured stepwise training modules to ensure completion of vital procedural steps. CONCLUSIONS: This study underscores the potential of VR simulation as a complementary training tool for CVC placement rather than a substitution of standard manikin training. VR is offering immersive experiences and addressing limitations of traditional manikin-based training methods. The integration of VR into training curricula warrants further exploration to optimize procedural proficiency and patient safety in clinical practice.

A three-dimensional tissue-engineered rostral migratory stream as an in vitro platform for subventricular zone-derived cell migration.

In the brains of most adult mammals, neural precursor cells (NPCs) from the subventricular zone (SVZ) migrate through the rostral migratory stream (RMS) to replace olfactory bulb interneurons. Following brain injury, published studies have shown that NPCs can divert from the SVZ-RMS-OB route and migrate toward injured brain regions, but the quantity of arriving cells, the lack of survival and terminal differentiation of neuroblasts into neurons, and their limited capacity to re-connect into circuitry are insufficient to promote functional recovery in the absence of therapeutic intervention. Our lab has fabricated a biomimetic tissue-engineered rostral migratory stream (TE-RMS) that replicates some notable structural and functional components of the endogenous rat RMS. Based on the design attributes for the TE-RMS platform, it may serve as a regenerative medicine strategy to facilitate sustained neuronal replacement into an injured brain region or an in vitro tool to investigate cell-cell communication and neuroblast migration. Previous work has demonstrated that the TE-RMS replicates the basic structure, unique nuclear shape, cytoskeletal arrangement, and surface protein expression of the endogenous rat RMS. Here, we developed an enhanced TE-RMS fabrication method in hydrogel microchannels that allowed more robust and high-throughput TE-RMS assembly. We report unique astrocyte behavior, including astrocyte bundling into the TE-RMS, the presence of multiple TE-RMS bundles, and observations of discontinuities in TE-RMS bundles, when microtissues are fabricated in agarose microchannels containing different critical curved or straight geometric features. We also demonstrate that we can harvest NPCs from the SVZ of adult rat brains and that EGFP+ cells migrate in chain formation from SVZ neurospheres through the TE-RMS in vitro. Overall, the TE-RMS can be utilized as an in vitro platform to investigate the pivotal cell-cell signaling mechanisms underlying the synergy of molecular cues involved in immature neuronal migration and differentiation.

Sex differences in the extent of acute axonal pathologies after experimental concussion.

Although human females appear be at a higher risk of concussion and suffer worse outcomes than males, underlying mechanisms remain unclear. With increasing recognition that damage to white matter axons is a key pathologic substrate of concussion, we used a clinically relevant swine model of concussion to explore potential sex differences in the extent of axonal pathologies. At 24 h post-injury, female swine displayed a greater number of swollen axonal profiles and more widespread loss of axonal sodium channels than males. Axon degeneration for both sexes appeared to be related to individual axon architecture, reflected by a selective loss of small caliber axons after concussion. However, female brains had a higher percentage of small caliber axons, leading to more extensive axon loss after injury compared to males. Accordingly, sexual dimorphism in axonal size is associated with more extensive axonal pathology in females after concussion, which may contribute to worse outcomes.

Generation of contractile forces by three-dimensional bundled axonal tracts in micro-tissue engineered neural networks.

Axonal extension and retraction are ongoing processes that occur throughout all developmental stages of an organism. The ability of axons to produce mechanical forces internally and respond to externally generated forces is crucial for nervous system development, maintenance, and plasticity. Such axonal mechanobiological phenomena have typically been evaluated in vitro at a single-cell level, but these mechanisms have not been studied when axons are present in a bundled three-dimensional (3D) form like in native tissue. In an attempt to emulate native cortico-cortical interactions under in vitro conditions, we present our approach to utilize previously described micro-tissue engineered neural networks (micro-TENNs). Here, micro-TENNs were comprised of discrete populations of rat cortical neurons that were spanned by 3D bundled axonal tracts and physically integrated with each other. We found that these bundled axonal tracts inherently exhibited an ability to generate contractile forces as the microtissue matured. We therefore utilized this micro-TENN testbed to characterize the intrinsic contractile forces generated by the integrated axonal tracts in the absence of any external force. We found that contractile forces generated by bundled axons were dependent on microtubule stability. Moreover, these intra-axonal contractile forces could simultaneously generate tensile forces to induce so-called axonal "stretch-growth" in different axonal tracts within the same microtissue. The culmination of axonal contraction generally occurred with the fusion of both the neuronal somatic regions along the axonal tracts, therefore perhaps showing the innate tendency of cortical neurons to minimize their wiring distance, a phenomenon also perceived during brain morphogenesis. In future applications, this testbed may be used to investigate mechanisms of neuroanatomical development and those underlying certain neurodevelopmental disorders.

Motor neurons and endothelial cells additively promote development and fusion of human iPSC-derived skeletal myocytes.

BACKGROUND: Neurovascular cells have wide-ranging implications on skeletal muscle biology regulating myogenesis, maturation, and regeneration. Although several in vitro studies have investigated how motor neurons and endothelial cells interact with skeletal myocytes independently, there is limited knowledge about the combined effect of neural and vascular cells on muscle maturation and development. METHODS: Here, we report a triculture system comprising human-induced pluripotent stem cell (iPSC)-derived skeletal myocytes, human iPSC-derived motor neurons, and primary human endothelial cells maintained under controlled media conditions. Briefly, iPSCs were differentiated to generate skeletal muscle progenitor cells (SMPCs). These SMPCs were seeded at a density of 5 × 104 cells/well in 12-well plates and allowed to differentiate for 7 days before adding iPSC-derived motor neurons at a concentration of 0.5 × 104 cells/well. The neuromuscular coculture was maintained for another 7 days in coculture media before addition of primary human umbilical vein endothelial cells (HUVEC) also at 0.5 × 104 cells/well. The triculture was maintained for another 7 days in triculture media comprising equal portions of muscle differentiation media, coculture media, and vascular media. Extensive morphological, genetic, and molecular characterization was performed to understand the combined and individual effects of neural and vascular cells on skeletal muscle maturation. RESULTS: We observed that motor neurons independently promoted myofiber fusion, upregulated neuromuscular junction genes, and maintained a molecular niche supportive of muscle maturation. Endothelial cells independently did not support myofiber fusion and downregulated expression of LRP4 but did promote expression of type II specific myosin isoforms. However, neurovascular cells in combination exhibited additive increases in myofiber fusion and length, enhanced production of Agrin, along with upregulation of several key genes like MUSK, RAPSYN, DOK-7, and SLC2A4. Interestingly, more divergent effects were observed in expression of genes like MYH8, MYH1, MYH2, MYH4, and LRP4 and secretion of key molecular factors like amphiregulin and IGFBP-4. CONCLUSIONS: Neurovascular cells when cultured in combination with skeletal myocytes promoted myocyte fusion with concomitant increase in expression of various neuromuscular genes. This triculture system may be used to gain a deeper understanding of the effects of the neurovascular niche on skeletal muscle biology and pathophysiology.

Artificial Intelligence for Anesthesiology Board-Style Examination Questions: Role of Large Language Models.

New artificial intelligence tools have been developed that have implications for medical usage. Large language models (LLMs), such as the widely used ChatGPT developed by OpenAI, have not been explored in the context of anesthesiology education. Understanding the reliability of various publicly available LLMs for medical specialties could offer insight into their understanding of the physiology, pharmacology, and practical applications of anesthesiology. An exploratory prospective review was conducted using 3 commercially available LLMs--OpenAI's ChatGPT GPT-3.5 version (GPT-3.5), OpenAI's ChatGPT GPT-4 (GPT-4), and Google's Bard--on questions from a widely used anesthesia board examination review book. Of the 884 eligible questions, the overall correct answer rates were 47.9% for GPT-3.5, 69.4% for GPT-4, and 45.2% for Bard. GPT-4 exhibited significantly higher performance than both GPT-3.5 and Bard (p = 0.001 and p < 0.001, respectively). None of the LLMs met the criteria required to secure American Board of Anesthesiology certification, according to the 70% passing score approximation. GPT-4 significantly outperformed GPT-3.5 and Bard in terms of overall performance, but lacked consistency in providing explanations that aligned with scientific and medical consensus. Although GPT-4 shows promise, current LLMs are not sufficiently advanced to answer anesthesiology board examination questions with passing success. Further iterations and domain-specific training may enhance their utility in medical education.

Cell Replacement Therapy for Brain Repair: Recent Progress and Remaining Challenges for Treating Parkinson's Disease and Cortical Injury.

Neural transplantation represents a promising approach to repairing damaged brain circuitry. Cellular grafts have been shown to promote functional recovery through "bystander effects" and other indirect mechanisms. However, extensive brain lesions may require direct neuronal replacement to achieve meaningful restoration of function. While fetal cortical grafts have been shown to integrate with the host brain and appear to develop appropriate functional attributes, the significant ethical concerns and limited availability of this tissue severely hamper clinical translation. Induced pluripotent stem cell-derived cells and tissues represent a more readily scalable alternative. Significant progress has recently been made in developing protocols for generating a wide range of neural cell types in vitro. Here, we discuss recent progress in neural transplantation approaches for two conditions with distinct design needs: Parkinson's disease and cortical injury. We discuss the current status and future application of injections of dopaminergic cells for the treatment of Parkinson's disease as well as the use of structured grafts such as brain organoids for cortical repair.

Hippocampal interneuronal dysfunction and hyperexcitability in a porcine model of concussion.

Cognitive impairment is a common symptom following mild traumatic brain injury (mTBI or concussion) and can persist for years in some individuals. Hippocampal slice preparations following closed-head, rotational acceleration injury in swine have previously demonstrated reduced axonal function and hippocampal circuitry disruption. However, electrophysiological changes in hippocampal neurons and their subtypes in a large animal mTBI model have not been examined. Using in vivo electrophysiology techniques, we examined laminar oscillatory field potentials and single unit activity in the hippocampal network 7 days post-injury in anesthetized minipigs. Concussion altered the electrophysiological properties of pyramidal cells and interneurons differently in area CA1. While the firing rate, spike width and amplitude of CA1 interneurons were significantly decreased post-mTBI, these parameters were unchanged in CA1 pyramidal neurons. In addition, CA1 pyramidal neurons in TBI animals were less entrained to hippocampal gamma (40-80 Hz) oscillations. Stimulation of the Schaffer collaterals also revealed hyperexcitability across the CA1 lamina post-mTBI. Computational simulations suggest that reported changes in interneuronal physiology may be due to alterations in voltage-gated sodium channels. These data demonstrate that a single concussion can lead to significant neuronal and circuit level changes in the hippocampus, which may contribute to cognitive dysfunction following mTBI.

Signal processing and stimulation potential within the ascending auditory pathway: a review.

The human auditory system encodes sound with a high degree of temporal and spectral resolution. When hearing fails, existing neuroprosthetics such as cochlear implants may partially restore hearing through stimulation of auditory neurons at the level of the cochlea, though not without limitations inherent to electrical stimulation. Novel approaches to hearing restoration, such as optogenetics, offer the potential of improved performance. We review signal processing in the ascending auditory pathway and the current state of conventional and emerging neural stimulation strategies at various levels of the auditory system.

Bedside to bench: the outlook for psychedelic research.

There has recently been a resurgence of interest in psychedelic compounds based on studies demonstrating their potential therapeutic applications in treating post-traumatic stress disorder, substance abuse disorders, and treatment-resistant depression. Despite promising efficacy observed in some clinical trials, the full range of biological effects and mechanism(s) of action of these compounds have yet to be fully established. Indeed, most studies to date have focused on assessing the psychological mechanisms of psychedelics, often neglecting the non-psychological modes of action. However, it is important to understand that psychedelics may mediate their therapeutic effects through multi-faceted mechanisms, such as the modulation of brain network activity, neuronal plasticity, neuroendocrine function, glial cell regulation, epigenetic processes, and the gut-brain axis. This review provides a framework supporting the implementation of a multi-faceted approach, incorporating in silico, in vitro and in vivo modeling, to aid in the comprehensive understanding of the physiological effects of psychedelics and their potential for clinical application beyond the treatment of psychiatric disorders. We also provide an overview of the literature supporting the potential utility of psychedelics for the treatment of brain injury (e.g., stroke and traumatic brain injury), neurodegenerative diseases (e.g., Parkinson's and Alzheimer's diseases), and gut-brain axis dysfunction associated with psychiatric disorders (e.g., generalized anxiety disorder and major depressive disorder). To move the field forward, we outline advantageous experimental frameworks to explore these and other novel applications for psychedelics.

Orally administered boldine reduces muscle atrophy and promotes neuromuscular recovery in a rodent model of delayed nerve repair.

Peripheral nerve injury often results in poor functional recovery due to a prolonged period of muscle denervation. In particular, absent axonal contact, denervated muscle can undergo irrevocable atrophy and diminished receptiveness for reinnervation over time, ultimately reducing the likelihood for meaningful neuromuscular recovery. While innovative surgical approaches can minimize the harmful effects of denervation by re-routing neighboring-otherwise uninjured-axons, there are no clinically-available approaches to preserve the reinnervation capacity of denervated muscles. Blocking intramuscular connexin hemichannel formation has been reported to improve muscle innervation in vitro and prevent atrophy in vivo. Therefore, the current study investigated the effects of orally administered boldine, a connexin hemichannel inhibitor, on denervated-related muscle changes and nerve regeneration in a rat model of delayed peripheral nerve repair. We found that daily boldine administration significantly enhanced an evoked response in the tibialis anterior muscle at 2 weeks after common peroneal nerve transection, and decreased intramuscular connexin 43 and 45 expression, intraneural Schwann cell expression of connexin 43, and muscle fiber atrophy up to 4 weeks post transection. Additional animals underwent a cross nerve repair procedure (tibial to common peroneal neurorrhaphy) at 4 weeks following the initial transection injury. Here, we found elevated nerve electrophysiological activity and greater muscle fiber maturation at 6 weeks post repair in boldine treated animals. These findings suggest that boldine may be a promising pharmacological approach to minimize the deleterious effects of prolonged denervation and, with further optimization, may improve levels of functional recovery following nerve repair.

Determination of the Terbium-152 half-life from mass-separated samples from CERN-ISOLDE and assessment of the radionuclide purity.

Terbium-152 is one of four terbium radioisotopes that together form a potential theranostic toolbox for the personalised treatment of tumours. As 152 Tb decay by positron emission it can be utilised for diagnostics by positron emission tomography. For use in radiopharmaceuticals and for activity measurements by an activity calibrator a high radionuclide purity of the material and an accurate and precise knowledge of the half-life is required. Mass-separation and radiochemical purification provide a production route of high purity 152Tb. In the current work, two mass-separated samples from the CERN-ISOLDE facility have been assayed at the National Physical Laboratory to investigate the radionuclide purity. These samples have been used to perform four measurements of the half-life by three independent techniques: high-purity germanium gamma-ray spectrometry, ionisation chamber measurements and liquid scintillation counting. From the four measurement campaigns a half-life of 17.8784(95) h has been determined. The reported half-life shows a significant difference to the currently evaluated half-life (ζ-score = 3.77), with a relative difference of 2.2 % and an order of magnitude improvement in the precision. This work also shows that under controlled conditions the combination of mass-separation and radiochemical separation can provide high-purity 152Tb.

Porcine Models of Spinal Cord Injury.

Large animal models of spinal cord injury may be useful tools in facilitating the development of translational therapies for spinal cord injury (SCI). Porcine models of SCI are of particular interest due to significant anatomic and physiologic similarities to humans. The similar size and functional organization of the porcine spinal cord, for instance, may facilitate more accurate evaluation of axonal regeneration across long distances that more closely resemble the realities of clinical SCI. Furthermore, the porcine cardiovascular system closely resembles that of humans, including at the level of the spinal cord vascular supply. These anatomic and physiologic similarities to humans not only enable more representative SCI models with the ability to accurately evaluate the translational potential of novel therapies, especially biologics, they also facilitate the collection of physiologic data to assess response to therapy in a setting similar to those used in the clinical management of SCI. This review summarizes the current landscape of porcine spinal cord injury research, including the available models, outcome measures, and the strengths, limitations, and alternatives to porcine models. As the number of investigational SCI therapies grow, porcine SCI models provide an attractive platform for the evaluation of promising treatments prior to clinical translation.

Neuronal somatic plasmalemmal permeability and dendritic beading caused by head rotational traumatic brain injury in pigs-An exploratory study.

Closed-head traumatic brain injury (TBI) is induced by rapid motion of the head, resulting in diffuse strain fields throughout the brain. The injury mechanism(s), loading thresholds, and neuroanatomical distribution of affected cells remain poorly understood, especially in the gyrencephalic brain. We utilized a porcine model to explore the relationships between rapid head rotational acceleration-deceleration loading and immediate alterations in plasmalemmal permeability within cerebral cortex, sub-cortical white matter, and hippocampus. To assess plasmalemmal compromise, Lucifer yellow (LY), a small cell-impermeant dye, was delivered intraventricularly and diffused throughout the parenchyma prior to injury in animals euthanized at 15-min post-injury; other animals (not receiving LY) were survived to 8-h or 7-days. Plasmalemmal permeability preferentially occurred in neuronal somata and dendrites, but rarely in white matter axons. The burden of LY+ neurons increased based on head rotational kinematics, specifically maximum angular velocity, and was exacerbated by repeated TBI. In the cortex, LY+ cells were prominent in both the medial and lateral gyri. Neuronal membrane permeability was observed within the hippocampus and entorhinal cortex, including morphological changes such as beading in dendrites. These changes correlated with reduced fiber volleys and synaptic current alterations at later timepoints in the hippocampus. Further histological observations found decreased NeuN immunoreactivity, increased mitochondrial fission, and caspase pathway activation in both LY+ and LY- cells, suggesting the presence of multiple injury phenotypes. This exploratory study suggests relationships between plasmalemmal disruptions in neuronal somata and dendrites within cortical and hippocampal gray matter as a primary response in closed-head rotational TBI and sets the stage for future, traditional hypothesis-testing experiments.

Persistence of Hyper-Ramified Microglia in Porcine Cortical Gray Matter after Mild Traumatic Brain Injury.

Traumatic brain injury (TBI) is a major contributor to morbidity and mortality in the United States as several million people visit the emergency department every year due to TBI exposures. Unfortunately, there is still no consensus on the pathology underlying mild TBI, the most common severity sub-type of TBI. Previous preclinical and post-mortem human studies have detailed the presence of diffuse axonal injury following TBI, suggesting that white matter pathology is the predominant pathology of diffuse brain injury. However, the inertial loading produced by TBI results in strain fields in both gray and white matter. In order to further characterize gray matter pathology in mild TBI, our lab used a pig model (n = 25) of closed-head rotational acceleration-induced TBI to evaluate blood-brain barrier disruptions, neurodegeneration, astrogliosis, and microglial reactivity in the cerebral cortex out to 1 year post-injury. Immunohistochemical staining revealed the presence of a hyper-ramified microglial phenotype-more branches, junctions, endpoints, and longer summed process length-at 30 days post injury (DPI) out to 1 year post injury in the cingulate gyrus (p < 0.05), and at acute and subacute timepoints in the inferior temporal gyrus (p < 0.05). Interestingly, we did not find neuronal loss or astroglial reactivity paired with these chronic microglia changes. However, we observed an increase in fibrinogen reactivity-a measure of blood-brain barrier disruption-predominately in the gray matter at 3 DPI (p = 0.0003) which resolved to sham levels by 7 DPI out to chronic timepoints. Future studies should employ gene expression assays, neuroimaging, and behavioral assays to elucidate the effects of these hyper-ramified microglia, particularly related to neuroplasticity and responses to potential subsequent insults. Further understanding of the brain's inflammatory activity after mild TBI will hopefully provide understanding of pathophysiology that translates to clinical treatment for TBI.

Multimodal Neuromonitoring and Neurocritical Care in Swine to Enhance Translational Relevance in Brain Trauma Research.

Neurocritical care significantly impacts outcomes after moderate-to-severe acquired brain injury, but it is rarely applied in preclinical studies. We created a comprehensive neurointensive care unit (neuroICU) for use in swine to account for the influence of neurocritical care, collect clinically relevant monitoring data, and create a paradigm that is capable of validating therapeutics/diagnostics in the unique neurocritical care space. Our multidisciplinary team of neuroscientists, neurointensivists, and veterinarians adapted/optimized the clinical neuroICU (e.g., multimodal neuromonitoring) and critical care pathways (e.g., managing cerebral perfusion pressure with sedation, ventilation, and hypertonic saline) for use in swine. Moreover, this neurocritical care paradigm enabled the first demonstration of an extended preclinical study period for moderate-to-severe traumatic brain injury with coma beyond 8 h. There are many similarities with humans that make swine an ideal model species for brain injury studies, including a large brain mass, gyrencephalic cortex, high white matter volume, and topography of basal cisterns, amongst other critical factors. Here we describe the neurocritical care techniques we developed and the medical management of swine following subarachnoid hemorrhage and traumatic brain injury with coma. Incorporating neurocritical care in swine studies will reduce the translational gap for therapeutics and diagnostics specifically tailored for moderate-to-severe acquired brain injury.

Intelligent Virtual Operating Room for Enhancing Nontechnical Skills.

This article discusses an intelligent immersive virtual operating room to enable teams to train in a distributed fashion wearing head-mounted displays.

Understanding microglial responses in large animal models of traumatic brain injury: an underutilized resource for preclinical and translational research.

Traumatic brain injury (TBI) often results in prolonged or permanent brain dysfunction with over 2.8 million affected annually in the U.S., including over 56,000 deaths, with over 5 million total survivors exhibiting chronic deficits. Mild TBI (also known as concussion) accounts for over 75% of all TBIs every year. Mild TBI is a heterogeneous disorder, and long-term outcomes are dependent on the type and severity of the initial physical event and compounded by secondary pathophysiological consequences, such as reactive astrocytosis, edema, hypoxia, excitotoxicity, and neuroinflammation. Neuroinflammation has gained increasing attention for its role in secondary injury as inflammatory pathways can have both detrimental and beneficial roles. For example, microglia-resident immune cells of the central nervous system (CNS)-influence cell death pathways and may contribute to progressive neurodegeneration but also aid in debris clearance and neuroplasticity. In this review, we will discuss the acute and chronic role of microglia after mild TBI, including critical protective responses, deleterious effects, and how these processes vary over time. These descriptions are contextualized based on interspecies variation, sex differences, and prospects for therapy. We also highlight recent work from our lab that was the first to describe microglial responses out to chronic timepoints after diffuse mild TBI in a clinically relevant large animal model. The scaled head rotational acceleration of our large animal model, paired with the gyrencephalic architecture and appropriate white:gray matter ratio, allows us to produce pathology with the same anatomical patterns and distribution of human TBI, and serves as an exemplary model to examine complex neuroimmune response post-TBI. An improved understanding of microglial influences in TBI could aid in the development of targeted therapeutics to accentuate positive effects while attenuating detrimental post-injury responses over time.