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.

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.

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.

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.

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.

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.

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.

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.

Pápulas planas labiales en un adulto joven / Flat Papules on the Lip of a Young Adult

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