Citations

Abstract Glioblastoma (GBM) is the most aggressive primary brain tumor, with a dismal median survival of 12–15 months. Recent evidence shows that neurons form functional synapses with GBM cells, promoting invasion and growth. Microglia, the brain’s resident immune cells, can modulate synaptic connections; however, their role in neuron-glioma synaptic interactions remains poorly understood. Here, we co-cultured patient-derived GBM cells with either human iPSC-derived microglia-like cells or HMC3 microglia in five-month-old iPSC-derived cortical organoids, assessing GBM calcium activity over 30 minutes using GCaMP6s-based imaging. Compared to GBM-only controls, cells grown with microglia displayed elevated mean ΔF/F0 (t-test, p = 6.536×10^-6,****) and higher calcium peak counts (p = 0.0002181 by t-test, ***). Tumor region- specific single-cell transcriptomic analysis of the Darmanis et. al dataset, containing GBM samples from four patients revealed eight distinct immune subclusters and highlighted a spatial dichotomy in immune function, with upregulation of complement and phagocytic signals in the tumor core, and unique ligand–receptor interactions in the periphery. CellChat analysis identified SEMA4D–PLXNB1 as a candidate ligand–receptor pair enriched between immune and neoplastic cells at the tumor periphery. Resident microglia exhibited significantly higher SEMA4D expression, while neoplastic cells showed elevated PLXNB1. These data suggest that microglia intensify GBM calcium signaling and engage in SEMA4D–PLXNB1 signaling. Future studies will determine the impact of these observations on neuron-gioma synapses and whether genetic ablation of PLXNB1 disrupts microglia-driven calcium signaling and slows tumor progression, offering mechanistic insight into the interplay of immune cells, neurons, and GBM.

Abstract Our understanding of Alzheimer's disease (AD) and related dementias (ADRD) has grown exponentially, thanks to significant investments by the National Institute on Aging (NIA). This article celebrates the 40th anniversary of the NIA's Alzheimer's Disease Research Centers, highlighting the pivotal role of neuropathology as the bedrock for neurodegeneration research. Neuropathology has championed the key principles of proteinopathy, selective vulnerability, and stereotypic spread. Furthermore, neuropathologic studies advanced our understanding of ADRD prevalence, heterogeneity, clinical–pathological correlations, and genetic underpinnings, spurring biomarker development for target engagement and disease monitoring. Disease‐modifying therapies for AD were inspired and informed by neuropathology. The neuropathology community is poised to refine diagnostics, leveraging digital pathology and integrating genetics and pathomics to enhance subtyping for novel precision medicine approaches. Despite some common misconceptions and logistical challenges, neuropathology continues to be a critical component of the ADRD research infrastructure, serving as a key bridge between allied basic and clinical sciences. Highlights We celebrate 40 years of NIA‐funded ADRCs and their contributions through neuropathology studies that have significantly advanced our understanding and treatment of ADRD. Neuropathology uncovers principles of neurodegenerative disease: proteinopathy, selective vulnerability, and stereotypic spread, informing diagnostics and therapies. Development of AD biomarkers with reference to neuropathology enhances accuracy in diagnosis and monitoring, paving the way for targeted disease‐modifying therapies. Integration of digital pathology, genetics, and novel tools in neurodegeneration research promises advanced precision medicine approaches and refined diagnostics. Misconceptions and logistical challenges to neuropathological research are addressed to improve understanding and collaboration.

Abstract Several complications are associated with total shoulder arthroplasty (TSA), including glenoid loosening and joint instability. These complications are linked to imbalances in glenohumeral muscle forces, which cause eccentric loading that occurs on the outer edge of the glenoid component, rather than in the center of the glenoid, and can be damaging to the implant and destabilizing the joint. The purpose of this study was to develop musculoskeletal models of TSA patients using their skeletal geometry acquired from CT and their kinematics acquired with high-speed stereo radiography (HSSR) to predict glenohumeral joint loading and muscle forces for abduction and flexion and describe how these loads differ from their native contralateral side. CT data was collected for both shoulders of 6 TSA patients (three anatomic and three reverse). Models were developed using CT reconstructions of each patient’s scapula and humerus, and placed implant geometry with CT-derived alignment. Mesh morphing was used to create personalized muscle attachment sites on the scapula. Simulation of abduction and flexion to quantify muscle and joint forces was driven with limb-specific HSSR kinematics. At 90 deg abduction, reverse TSA increased superior shear force by 11.2% bodyweight (BW) and decreased medial compressive force by 27.5%BW compared to each patient’s contralateral shoulder. Lateral deltoid elevation moment arms and stability ratios increased 9.61 mm and 0.58, respectively. At 90 deg abduction, anatomic TSA patients increased humeral internal rotation by 52.7 deg and decreased rotator cuff force by 9.4%BW. Patient-specific musculoskeletal models quantified differences in glenohumeral joint mechanics. This study revealed muscle and kinematic mechanisms that could lead to edge loading and glenoid loosening in TSA and can inform personalized surgical planning for implant alignment with the goal of improving patient outcomes.

Abstract Professor Albert J. Rhoton Jr., MD, is renowned for his groundbreaking dissections, marking a monumental achievement in the field of neuroanatomy. Alongside his anatomical contributions, he also passed on his knowledge and skills to numerous fellows, leaving behind a profound legacy. Despite the widespread recognition of his influence, little quantitative work has been done to characterize the scholarly impact of his alumni. Data were collected on Rhoton fellows, including fellowship years, country of origin, current institutions, and titles, practice settings, and leadership roles. Scholarly productivity was evaluated by assessing publication counts, including publications before and after the fellowship, and publications focused on surgical anatomy. Additionally, H-indices and citation counts were recorded. Other variables analyzed included ownership of a surgical anatomy laboratory, and participation in organizing hands-on courses. We analyzed 118 alumni from diverse countries. There was a significant increase in publication output following the fellowship, with publications rising from an average of 7 to 76 (p < 0.001). Fellows from high-income countries had higher research productivity than those from middle-income countries, with greater average H-index (p = 0.003), publication count (p = 0.01), and citation score (p = 0.003). Overall, 65% of fellows pursued academic practice, with 18% owning a laboratory and 30% involved in hands-on courses. Dr. Rhoton's mentorship has shaped a generation of neurosurgeons who continue his legacy. His fellows have established careers worldwide, leading in academia, professional organizations, and surgical training. Their global impact underscores the lasting value of structured mentorship in neurosurgery.

Study Design Narrative Review. Objectives To summarize the work of the AO Spine Knowledge Forum Tumor, specifically studies from the Epidemiology, Process and Outcomes in Spine Oncology (EPOSO) study. Methods A narrative review of all published manuscripts from the EPOSO study was undertaken. EPOSO represents a multicenter, prospective registry effort across 10 North American and European sites to enroll patients with metastatic disease of the spine. Results The current review summarized all studies from the EPOSO network, divided into the following five sections: (1) quality of life and satisfaction, (2) overall survival, (3) spinal instability, (4) neurologic outcome in patients with metastatic epidural spinal cord compression or radicular pain, and (5) patient and tumor-specific factors. Several important findings were elucidated. Patient evaluation should include SINS, nutritional status, severity and duration of neurologic deficit, extent of metastatic tumor burden, and differentiation of axial from radicular pain. Moreover, SOSGOQ2.0 serves as a useful and validated instrument for patient-reported outcome instrument. Despite the palliative nature of metastatic spine surgery, clear improvement in quality-of-life is seen. Even in patients with short-survival, the remaining weeks and months of life result in improved quality-of-life. Metastatic spine surgery often improves neurologic function, potentially enhancing survival through increased performance status. Conclusions Several noteworthy results have come from the EPOSO network, highlighting important trends in metastatic spine care. The AO Spine Knowledge Forum Tumor has helped advancing metastatic spine tumor research as well as ensure these new findings reach and benefit clinicians and their patients.

Introduction: The lack of understanding about the genetic and molecular basis of young stroke (<55 years of age) has hindered development of diagnostic, management, and therapeutic approaches. Whole exome sequencing (WES) can be leveraged as a tool for studying etiological processes underlying stroke. At the time of study inception, this is the single largest WES study in this unique young stroke population to uncover elusive stroke etiologies. Methods: The Mayo Clinic TAPESTRY database is a research program conducting whole exome sequencing of 100,000 participants. Of these, 406 participants met the criteria for young stroke (18-54 years of age) based on ICD-9 and ICD-10 diagnostic codes. Controls were TAPESTRY participants without a stroke-related ICD diagnosis. Cases were matched for age, gender, and race for a 1:4 case-control ratio. Ischemic stroke etiology was classified using TOAST classification. To uncover genetic mechanisms, a gene centric approach was used to identify variants in our cohort. A list of 66 genes known to be associated with young stroke was curated based on existing genetic databases. Various filtration strategies were used to identify potentially damaging variants (graphic 1). Results: There were 406 cases (363 ischemic and 43 hemorrhagic; 291 female; age at stroke onset 39.8±10.4; 368 were White) and 3,857 controls. TOAST classification yielded 20 patients with large artery atherosclerosis, 58 cardioembolic, 10 small vessel disease, 148 other determined (58 patent foramen ovale, 50 dissection, 48 hypercoagulable state, 11 Moyamoya, 11 vasculitis, 10 fibromuscular dysplasia), and 165 undetermined etiologies. Several individuals had multiple competing etiologies. Of cerebral hemorrhages, there were 6 aneurysmal, 6 arteriovenous malformation, 5 hypertensive, 2 substance abuse, 3 trauma, and 21 other etiologies. Across the entire cohort, 35,054 variants were found within the 66 genes identified from the literature. Filtration identified 48 potentially damaging variants across 30 genes in 44 patients (20 cryptogenic and 21 other: 12 patent foramen ovale, 5 vasculitis, 4 dissection, 4 cardioembolic) that were absent in controls. Conclusion: WES is a powerful tool that can be used to uncover potential genetic mechanisms in the young stroke population. An improved understanding of etiologies would improve diagnostics and pave the way for new preventive and therapeutic approaches, thus improving the overall care of young stroke patients.

World record speeds at different distances for men and women in different age categories are used to develop a model to predict running performance as a function of race distance, age, and sex. This empirical model quantifies the decline in running speed with distance and age in a way that provides insight into the aerobic and anaerobic contributions to running speed and may help with developing training strategies for different age groups at various distances.