A Patient-Derived Glioblastoma Organoid Model and Biobank Recapitulates Inter- and Intra-tumoral Heterogeneity.

Glioblastomas exhibit vast inter- and intra-tumoral heterogeneity, complicating the development of effective therapeutic strategies. Current in vitro models are limited in preserving the cellular and mutational diversity of parental tumors and require a prolonged generation time. Here, we report methods for generating and biobanking patient-derived glioblastoma organoids (GBOs) that recapitulate the histological features, cellular diversity, gene expression, and mutational profiles of their corresponding parental tumors. GBOs can be generated quickly with high reliability and exhibit rapid, aggressive infiltration when transplanted into adult rodent brains. We further demonstrate the utility of GBOs to test personalized therapies by correlating GBO mutational profiles with responses to specific drugs and by modeling chimeric antigen receptor T cell immunotherapy. Our studies show that GBOs maintain many key features of glioblastomas and can be rapidly deployed to investigate patient-specific treatment strategies. Additionally, our live biobank establishes a rich resource for basic and translational glioblastoma research.

Effect of Temperature on Microwave Permeability of an Air-Stable Composite Filled with Gadolinium Powder.

A composite containing about 30% volume of micrometer-size powder of gadolinium in paraffin wax is synthesized mechanochemically. The composite permittivity and permeability are measured within the frequency range from 0.01 to 15 GHz and the temperature range from ~0 °C to 35 °C. The permittivity is constant within the measured ranges. Curie temperature of the composite is close to 15.5 °C, the phase transition is shown to take place within a temperature range about ±10 °C. The effect of temperature deviation from Curie point on reflection and transmission of a composite layer filled with Gd powder is studied experimentally and via simulation. Constitutive parameters of the composite are measured in cooled coaxial lines applying reflection-transmission and open-circuit-short-circuit techniques, and the measured low-frequency permeability is in agreement with the values retrieved from the published magnetization curves. The effect of temperature on permeability spectrum of the composite is described in terms of cluster magnetization model based on the Wiener mixing formula. The model is applied to design a microwave screen with variable attenuation; the reflectivity attenuation of 4.5 mm-thick screen increases from about -2 dB to -20 dB at 3.5 GHz if the temperature decreases from 25 °C to 5 °C.

Physics of Composites for Low-Frequency Magnetoelectric Devices.

The article discusses the physical foundations of the application of the linear magnetoelectric (ME) effect in composites for devices in the low-frequency range, including the electromechanical resonance (EMR) region. The main theoretical expressions for the ME voltage coefficients in the case of a symmetric and asymmetric composite structure in the quasi-static and resonant modes are given. The area of EMR considered here includes longitudinal, bending, longitudinal shear, and torsional modes. Explanations are given for finding the main resonant frequencies of the modes under study. Comparison of theory and experimental results for some composites is given.

The Size Dependence of Microwave Permeability of Hollow Iron Particles.

Hollow ferromagnetic powders of iron were obtained by means of ultrasonic spray pyrolysis. A variation in the conditions of the synthesis allows for the adjustment of the mean size of the hollow iron particles. Iron powders were obtained by this technique, starting from the aqueous solution of iron nitrate of two different concentrations: 10 and 20 wt.%. This was followed by a reduction in hydrogen. An increase in the concentration of the solution increased the mean particle size from 0.6 to 1.0 microns and widened particle size distribution, but still produced hollow particles. Larger particles appeared problematic for the reduction, although admixture of iron oxides did not decrease the microwave permeability of the material. The paraffin wax-based composites filled with obtained powders demonstrated broadband magnetic loss with a complex structure for lesser particles, and single-peak absorption for particles of 1 micron. Potential applications are 5G technology, electromagnetic compatibility designs, and magnetic field sensing.

Surgical Management of Trauma-Related Intracranial Hemorrhage-a Review.

PURPOSE OF REVIEW: The surgical management of trauma-related intracranial hemorrhage is characterized by marked heterogeneity. Large prospective randomized trials have generally been prohibited by the ubiquity of concordant pathology, diversity of trauma systems, and paucity of clinical equipoise among providers. RECENT FINDINGS: To date, the results of retrospective studies and surgeon preference have driven the indications, modality, extent, and timing of surgical intervention in the global neurosurgical community. With advances in our understanding of the pathophysiology of hemorrhagic TBI and the advent of novel surgical techniques, a reevaluation of surgical indication, timing, and approach is warranted. In this way, we can work to optimize surgical outcomes, achieving maximal functional recovery while minimizing surgical morbidity.

Engineered Axonal Tracts as "Living Electrodes" for Synaptic-Based Modulation of Neural Circuitry.

Brain-computer interface and neuromodulation strategies relying on penetrating non-organic electrodes/optrodes are limited by an inflammatory foreign body response that ultimately diminishes performance. A novel "biohybrid" strategy is advanced, whereby living neurons, biomaterials, and microelectrode/optical technology are used together to provide a biologically-based vehicle to probe and modulate nervous-system activity. Microtissue engineering techniques are employed to create axon-based "living electrodes", which are columnar microstructures comprised of neuronal population(s) projecting long axonal tracts within the lumen of a hydrogel designed to chaperone delivery into the brain. Upon microinjection, the axonal segment penetrates to prescribed depth for synaptic integration with local host neurons, with the perikaryal segment remaining externalized below conforming electrical-optical arrays. In this paradigm, only the biological component ultimately remains in the brain, potentially attenuating a chronic foreign-body response. Axon-based living electrodes are constructed using multiple neuronal subtypes, each with differential capacity to stimulate, inhibit, and/or modulate neural circuitry based on specificity uniquely afforded by synaptic integration, yet ultimately computer controlled by optical/electrical components on the brain surface. Current efforts are assessing the efficacy of this biohybrid interface for targeted, synaptic-based neuromodulation, and the specificity, spatial density and long-term fidelity versus conventional microelectronic or optical substrates alone.

Pediatric cerebral sinovenous thrombosis following cranial surgery.

PURPOSE: Pediatric cerebral sinovenous thrombosis (CSVT) is an important, though less common subtype of pediatric stroke. It has been linked to several risk factors, including cranial procedures, with few studies highlighting this relationship. The aim of this study was to characterize the diagnosis and treatment of CSVT after cranial surgery. METHODS: An institutional pediatric stroke research database was used to identify all CSVT cases diagnosed within 30 days of cranial surgery from November 2004 to December 2014. Thirteen subjects were retrospectively analyzed for clinical presentation, surgical details, radiographic characteristics, laboratory study results, treatment, and outcome. Diagnostic testing and treatment adhered to a consensus-based institutional stroke protocol. RESULTS: Cranial vault reconstruction, subdural empyema evacuation, and tumor resection were each observed in three subjects. Eleven (85%) subjects had sinus exposure during surgery, and eight (73%) developed thrombus in a sinus within or adjacent to the operative field. Two (15%) had documented iatrogenic sinus injury. On post-operative testing, ten (77%) subjects had prothrombotic abnormalities. Seven (54%) were treated with anti-coagulation therapy (ACT) starting on a median of post-operative day (POD) 3 (IQR 1-3) for a median of 2.9 months (IQR 2.4-5.4). Median time to imaging evidence of partial or complete recanalization was 2.4 months (IQR 0.7-5.1). No symptomatic hemorrhagic complications were encountered. CONCLUSIONS: Pediatric CSVT may be encountered after cranial surgery, and decisions related to anti-coagulation are challenging. The risk of CSVT should be considered in pre-surgical planning and post-operative evaluation of cases with known risk factors. In our study, judicious use of ACT was safe in the post-operative period.

Porcine Models of Neurotrauma and Neurological Disorders.

The translation of therapeutics from lab to clinic has a dismal record in the fields of neurotrauma and neurological disorders [...].

Management of Traumatic Atlantooccipital Dissociation at a Level 1 Trauma Center: A Retrospective Case Series.

OBJECTIVE: Atlantooccipital dislocation (AOD) is a highly unstable and often neurologically devastating injury to the craniocervical junction that typically results from high-energy trauma. Management of these devastating injuries is complex, with prognostication difficult due to high rates of concomitant intracranial and systemic injuries. This report highlights advances in management of AOD and appropriate implementation of operative adjuncts including neuronavigation and the use of intraoperative neuromonitoring. METHODS: All patients with AOD presenting to a high-volume, level 1 trauma center between January 2015 and August 2021 were retrospectively identified through a prospectively maintained database of patients presenting with traumatic spine injuries. Medical records, including imaging reports, clinical documentation, and intraoperative neurophysiological reports were reviewed. RESULTS: A total of 11 patients were identified with patterns of injury consistent with AOD. Fifty-five percent of patients survived until discharge. 73% of patients underwent surgery for stabilization. All 4 patients with preoperative neurologic deficits who underwent surgery had monitorable transcranial motor evoked potentials and somatosensory evoked potentials. Two experienced significant motor recovery postoperatively, and 2 did not survive to discharge. Blunt cerebrovascular injuries were identified in 73% of patients. CONCLUSION: AOD is encountered with increasing frequency. The identification and management of this specific injury is complicated by the volume and severity of associated injuries, especially concomitant traumatic brain injury. Timely recognition is critical and the use of surgical adjuncts including intraoperative neurophysiologic monitoring and surgical navigation can increase the safety and success of these procedures while also providing prognostic information on potential for motor recovery.

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.

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.

Prediction of intracranial pressure crises after severe traumatic brain injury using machine learning algorithms.

OBJECTIVE: Avoiding intracranial hypertension after traumatic brain injury (TBI) is a foundation of neurocritical care, to minimize secondary brain injury related to elevated intracranial pressure (ICP). However, this approach at best is reactive to episodes of intracranial hypertension, allowing for periods of elevated ICP before therapies can be initiated. Accurate prediction of ICP crises before they occur would permit clinicians to implement preventive strategies, minimize total time with ICP above threshold, and potentially avoid secondary injury. The objective of this study was to develop an algorithm capable of predicting the onset of ICP crises with sufficient lead time to enable application of preventative therapies. METHODS: Thirty-six patients admitted to a level I trauma center with severe TBI (Glasgow Coma Scale score < 8) between April 2015 and January 2019 who underwent continuous intraparenchymal ICP monitor placement were retrospectively identified. Continuous ICP data were extracted from each monitoring period (range 4-96 hours of monitoring). An ICP crisis was treated as a binary outcome, defined as ICP > 22 mm Hg for at least 75% of the data within a 5-minute interval. ICP data preceding each ICP crisis were grouped into four total data sets of 1- and 2-hour epochs, each with 10- to 20-minute lead-time intervals before an ICP crisis. Crisis and noncrisis events were identified from continuous time-series data and randomly split into 70% for training and 30% for testing, from a subset of 30 patients. Machine learning algorithms were trained to predict ICP crises, including light gradient boosting, extreme gradient boosting, and random forest. Accuracy and area under the receiver operating characteristic curve (AUC) were measured to compare performance. The most predictive algorithm was optimized using feature selection and hyperparameter tuning to avoid overfitting, and then tested on a validation subset of 5 patients. Precision, recall, F1 score, and accuracy were measured. RESULTS: The random forest model demonstrated the highest accuracy (range 0.82-0.88) and AUC (range 0.86-0.88) across all four data sets. Further validation testing revealed high precision (0.76), relatively low recall (0.46), and overall strong predictive performance (F1 score 0.57, accuracy 0.86) for ICP crises. Decision curve analysis showed that the model provided net benefit at probability thresholds above 0.1 and below 0.9. CONCLUSIONS: The presented model can provide accurate and timely forecasts of ICP crises in patients with severe TBI 10-20 minutes prior to their occurrence. If validated and implemented in clinical workflows, this algorithm can enable earlier intervention for ICP crises, more effective treatment of intracranial hypertension, and potentially improved outcomes following severe TBI.

Longitudinal Abnormalities in White Matter Extracellular Free Water Volume Fraction and Neuropsychological Functioning in Patients with Traumatic Brain Injury.

Traumatic brain injury is a global public health problem associated with chronic neurological complications and long-term disability. Biomarkers that map onto the underlying brain pathology driving these complications are urgently needed to identify individuals at risk for poor recovery and to inform design of clinical trials of neuroprotective therapies. Neuroinflammation and neurodegeneration are two endophenotypes potentially associated with increases in brain extracellular water content, but the nature of extracellular free water abnormalities after neurotrauma and its relationship to measures typically thought to reflect traumatic axonal injury are not well characterized. The objective of this study was to describe the relationship between a neuroimaging biomarker of extracellular free water content and the clinical features of a cohort with primarily complicated mild traumatic brain injury. We analyzed a cohort of 59 adult patients requiring hospitalization for non-penetrating traumatic brain injury of all severities as well as 36 healthy controls. Patients underwent brain magnetic resonance imaging (MRI) at 2 weeks (n = 59) and 6 months (n = 29) post-injury, and controls underwent a single MRI. Of the participants with TBI, 50 underwent clinical neuropsychological assessment at 2 weeks and 28 at 6 months. For each subject, we derived a summary score representing deviations in whole brain white matter extracellular free water volume fraction (VF) and free water-corrected fractional anisotropy (fw-FA). The summary specific anomaly score (SAS) for VF was significantly higher in TBI patients at 2 weeks and 6 months post-injury relative to controls. SAS for VF exhibited moderate correlation with neuropsychological functioning, particularly on measures of executive function. These findings indicate abnormalities in whole brain white matter extracellular water fraction in patients with TBI and are an important step toward identifying and validating noninvasive biomarkers that map onto the pathology driving disability after TBI.

Neurosurgeons Deliver Similar Quality Care Regardless of First Assistant Type: Resident Physician versus Nonphysician Surgical Assistant.

OBJECTIVE: There are limited data evaluating the outcomes of attending neurosurgeons with different types of first assistants. This study considers a common neurosurgical procedure (single-level, posterior-only lumbar fusion surgery) and examines whether attending surgeons deliver equal patient outcomes, regardless of the type of first assistant (resident physician vs. nonphysician surgical assistant [NPSA]), among otherwise exact-matched patients. METHODS: The authors retrospectively analyzed 3395 adult patients undergoing single-level, posterior-only lumbar fusion at a single academic medical center. Primary outcomes included readmissions, emergency department visits, reoperation, and mortality within 30 and 90 days after surgery. Secondary outcome measures included discharge disposition, length of stay, and length of surgery. Coarsened exact matching was used to match patients on key demographics and baseline characteristics known to independently affect neurosurgical outcomes. RESULTS: Among exact-matched patients (n = 1402), there was no significant difference in adverse postsurgical events (readmission, emergency department visits, reoperation, or mortality) within 30 days or 90 days of the index operation between patients who had resident physicians and those who had NPSAs as first assistants. Patients who had resident physicians as first assistants demonstrated a longer length of stay (mean: 100.0 vs. 87.4 hours, P < 0.001) and a shorter duration of surgery (mean: 187.4 vs. 213.8 minutes, P < 0.001). There was no significant difference between the two groups in the percentage of patients discharged home. CONCLUSIONS: For single-level posterior spinal fusion, in the setting described, there are no differences in short-term patient outcomes delivered by attending surgeons assisted by resident physicians versus NPSAs.

Performance of the frailty index in predicting complete remission, intensive care unit admission, and overall mortality in older and younger patients with acute myeloid leukemia receiving intensive chemotherapy.

The frailty index (FI) predicts clinical outcomes in oncology. However, in the acute myeloid leukemia (AML) setting, its predictive ability is poorly understood. We assessed whether the FI predicts complete remission (CR), intensive care unit (ICU) admission, and 1-year all-cause mortality in younger and older adults with AML receiving intensity chemotherapy. This was a secondary analysis of a prospective study. In total, 237 patients (n = 140 younger and n = 97 older adults) were classified as non-frail, prefrail, or frail. Frail younger adults were less likely to achieve CR compared with non-frail younger adults. Pre-frail and frail younger adults were more likely to be admitted to the ICU compared with their non-frail counterparts. The FI was not predictive of 1-year all-cause mortality. The FI predicts CR and ICU admission in younger but not older adults. Disease biology may be more important than frailty in predicting 1-year overall mortality in patients with AML undergoing chemotherapy.

Effectiveness of Oral Antibiotic Therapy in Prevention of Postoperative Wound Infection Requiring Surgical Washout In Spine Surgery.

BACKGROUND: Surgical site infections (SSIs) after spine surgery are a significant cause of morbidity. Surgeons often prescribe oral antibiotics in the postoperative setting for infected-appearing wounds to prevent reoperation for infection; however, the efficacy of this practice has not been well studied. METHODS: Neurosurgical spine patients with clinical concerns for SSI at the University of Pennsylvania were retrospectively studied from 2014 to 2018. Clinical predictors of 90-day reoperation for infection despite antibiotic treatment and variables that influenced antibiotic prescription were analyzed. RESULTS: Three hundred and ninety-two patients were included in the study. Preoperative albumin level, days elapsed to antibiotic prescription from index surgery, preoperative hemoglobin level, surgical location, gender, discharge disposition, and level of wound concern were significant predictors of reoperation for infection on bivariate analysis. Days elapsed to antibiotic prescription, surgical location, and level of wound concern remained significant after multivariable logistic regression. Variables that significantly predicted prescription of an antibiotic include length of stay, cerebrospinal fluid leak, race, and level of wound concern. Length of stay, race, and level of wound concern remained significant after multivariable analysis. CONCLUSIONS: Wound infection remains a challenging problem in spine surgery and it is reasonable to perform early reoperation in patients with high clinical concerns for infection, because bacterial isolates are often resistant to common oral antibiotics. Patients with wounds with low clinical concerns for infection may undergo a trial of oral antibiotics; however, duration of treatment should not be prolonged.

Case Report: Multilevel Ossification of the Ligamentum Flavum in a Patient With Spinal Osteoblastoma.

Introduction: Spinal osteoblastomas are primary benign bone tumors most commonly presenting as diffuse back pain in young adults. Rarely, spinal osteoblastoma is associated with ossification of the ligamentum flavum (OLF), a form of ectopic bone formation, which can present with myelopathy. This report highlights a unique case of a patient with spinal osteoblastoma, associated OLF, and thoracic myelopathy. Case Description: The patient presented with subtle myelopathy consisting of mid-thoracic back pain, paresthesias, and gait instability. Imaging findings were suggestive of spinal osteoblastoma with multifocal OLF. The patient was consented for thoracic decompression and stabilization at the T6-10 levels. Histopathology confirmed osteoblastoma with associated OLF. At follow up, the patient's neurological symptoms had completely resolved. Conclusion: This case describes management for a rare presentation of osteoblastoma with associated OLF and myelopathy. Surgeons should be wary of disproportionate neurological compromise when spinal osteoblastoma is associated with OLF. Further study is required to elucidate the pathogenesis of this condition.

Neurorrhaphy in Presence of Polyethylene Glycol Enables Immediate Electrophysiological Conduction in Porcine Model of Facial Nerve Injury.

Facial nerve trauma often leads to disfiguring facial muscle paralysis. Despite several promising advancements, facial nerve repair procedures often do not lead to complete functional recovery. Development of novel repair strategies requires testing in relevant preclinical models that replicate key clinical features. Several studies have reported that fusogens, such as polyethylene glycol (PEG), can improve functional recovery by enabling immediate reconnection of injured axons; however, these findings have yet to be demonstrated in a large animal model. We first describe a porcine model of facial nerve injury and repair, including the relevant anatomy, surgical approach, and naive nerve morphometry. Next, we report positive findings from a proof-of-concept experiment testing whether a neurorrhaphy performed in conjunction with a PEG solution maintained electrophysiological nerve conduction at an acute time point in a large animal model. The buccal branch of the facial nerve was transected and then immediately repaired by direct anastomosis and PEG application. Immediate electrical conduction was recorded in the PEG-fused nerves (n = 9/9), whereas no signal was obtained in a control cohort lacking calcium chelating agent in one step (n = 0/3) and in the no PEG control group (n = 0/5). Nerve histology revealed putative-fused axons across the repair site, whereas no positive signal was observed in the controls. Rapid electrophysiological recovery following nerve fusion in a highly translatable porcine model of nerve injury supports previous studies suggesting neurorrhaphy supplemented with PEG may be a promising strategy for severe nerve injury. While acute PEG-mediated axon conduction is promising, additional work is necessary to determine if physical axon fusion occurs and the longer-term fate of distal axon segments as related to functional recovery.