bluuebunny/crossref_metadata_2025_split huggingface dataset:
236 Bilateral Intrathalamic Infusion of rAAVrh8-Hexa/Hexb in a Phase 1/2 Clinical Trial for Gene Therapy in Infantile and Juvenile Tay-Sachs and Sandhoff Disease; Surgical Technique
Authors: Cataltepe Oguz , Daci Rrita , Owusu-Adjei Thomson Brittany , Mietus Constance Jennifer , Shazeeb Mohammed , Kuhn Anna , Sena-Esteves Miguel , Flotte Terrence 
Published: March 2024

INTRODUCTION:
Tay-Sachs (TSD) and Sandhoff (SD) diseases are rare,monogenic and severe neurodegenerative disorders due to Hexosaminidase A deficiency. We performed the first-in-human bilateral thalamic (BiTh) delivery of rAAVrh8-HEXA/HEXB in 8 children in a Phase 1/2 clinical trial.

METHODS:
Stereotactic infusion cannula placement was performed using ROSA robotic platform. Bilateral trajectories were planned via the trans-frontal route..Head stabilization was accomplished using radiolucent horse-shoe head rest and radiolucent pin-skull clamps. Flexible infusion cannulas were placed through small drill holes using ROSA guidance. Cannula stabilization was achieved using a construct which combined the Navigus brain biopsy platform and flexible cannula bolt. Insertion accuracy was verified with intraoperative CT images. Patients received one of the three doses in each thalamus: 180 mcl (5.87E + 12vg), 360 mcl (1.17E + 13vg) or 720 mcl (2.35E + 13vg). Drug infusion rate was 4 mcl/minute and completed in 90-360 minutes depending on drug dosage.

RESULTS:
Eight patients received treatment; 5 infants (6, 11, 13, 17, and 20 months) and 3 juvenile (5, 6, 12 years). Duration of follow up was 2-28 months. Outcome assessments included safety, CSF biochemistry, MRI/MRS/DTI, and neurodevelopmental observations. Surgery and drug infusions were well-tolerated. Post-infusion MRIs showed signal enhancement volume coverage in thalamus from 8%-44% parallel to escalating doses. The only surgery related complication was superficial wound dehiscence in two patients. Infants showed partial stabilization or improvement, including in oral feeding and myelination. In juveniles, dystonic posturing worsened after dosing in all 3 patients treated. Two patients died much later from reasons unrelated to surgery or drug infusion.

CONCLUSIONS:
Surgery for BiTh infusion of rAAVrh8-HEXA/HEXB for gene therapy in infants with TSD and SD is well-tolerated. Patients respond well to treatment with some stabilization or improvement.
241 Disparities in Access to Epilepsy Surgery Care in Children With Drug Resistant Epilepsy: Implications For Long-Term Survival Outcomes
Authors: Scoville Jonathan , Zhang Lu , Hall Matt , Lam Sandi 
Published: March 2024

INTRODUCTION:
Our recent publication in Lancet Child and Adolescent Health examined long-term survival rates for pediatric patients with drug-resistant epilepsy (DRE) treated with antiseizure medications (ASMs) only, ASMs plus vagus nerve stimulation (VNS), and ASMs plus cranial epilepsy surgery in a large United States (US) administrative database. The difference in survival probabilities was statistically significant (p < .001). Adjusted probabilities of survival beyond 10 years were 89.27% for the ASMs only cohort (95%CI, 87.71%-90.85%), 92.65% for VNS cohort (95%CI, 90.62%-94.72%), and 98.45% for cranial surgery cohort (95%CI, 97.53%-99.38%).

METHODS:
Patients aged 0-17 years with DRE between 01/01/2004-31/12/2020 were identified from the Pediatric Health Information System data set across 49 US pediatric hospitals. Patients treated with ASMs only or ASMs plus VNS or ASMs plus cranial epilepsy surgery were included. Chi-square tests determined associations between treatment time and preoperative factors such as treatment type, age, sex, race/ethnicity, insurance type, geographic region, epilepsy type, and medical complexity (presence of pediatric complex chronic conditions [PCCCs]).

RESULTS:
18,292 total patients were included: 10,240 patients treated with ASMs only, 5,019 patients with ASMs plus VNS, 3,033 patients with ASMs plus cranial epilepsy surgery. There were significant differences in age, geographic region, race/ethnicity, presence of PCCCs, diagnosis, and insurance type (p < 0.001). Those treated surgically, either with VNS implantation or cranial epilepsy surgery, were 2 years older than ASMs only. ASMs only patients were less ikely to be reported as non-Hispanic white (51.78%), less likely have a focal/partial epilepsy diagnosis (8.74%), and less likely carry private medical insurance (35.82%).

CONCLUSIONS:
We show a link of disparities in pediatric epilepsy surgery care and survival outcomes. Focused strategies are needed to expand access to comprehensive epilepsy care with neurosurgical evaluation and offerings when appropriate.
248 Isolated Traumatic Subarachnoid Hemorrhage on Head Computed Tomography Scan May Not Be Isolated
Authors: Yue John K. , Yuh Esther , Elguindy Mahmoud , Sun Xiaoying , van Essen Thomas , Deng Hansen , Satris Gabriela , Wong Justin , DiGiorgio Anthony Michael , Tarapore Phiroz E. , Huang Michael C. , Markowitz Amy , Mukherjee Pratik , Jain Sonia , Manley Geoffrey T. 
Published: March 2024

INTRODUCTION:
Isolated traumatic subarachnoid hemorrhage (tSAH) after traumatic brain injury (TBI) on head computed tomography (CT) is often regarded as a “mild” injury, with reduced need for additional workup. However, tSAH is also a predictor of unfavorable outcomes. Magnetic resonance imaging (MRI) and blood-based biomarkers may improve the diagnosis of concurrent intracranial injury.

METHODS:
The prospective, 18-center Transforming Research and Clinical Knowledge in Traumatic Brain Injury study enrolled patients presenting to ED within 24 hours (h) of TBI who received a clinically-indicated head CT. A subset underwent venipuncture within 24h for plasma glial fibrillary acidic protein (GFAP) analysis, and 2-week research MRI. Participants aged = 17-years with GCS 13-15, isolated tSAH on initial CT, GFAP, and MRI data were analyzed.

RESULTS:
In 57 patients, median age was 46.0-years [quartile 1 to 3 (Q1-Q3): 34-57] and 53% were male. At ED disposition, 12.3% were discharged home, 61.4% admitted to hospital ward, and 26.3% to intensive care.MRI identified additional traumatic intracranial lesions in 45.6% of patients (1 type: 31.6%; 2 types: 14.0%); of these, 65.4% had axonal injury, 42.3% subdural hematoma, and 23.1% contusion. GFAP levels were higher in patients with additional MRI lesions (median: 630.6-pg/ml, Q1-Q3: [172.4-941.2] vs. 226.4 [105.8-436.1], p = 0.049), and correlated with axonal injury severity (none: median 226.7 [109.6-435.1], traumatic axonal injury: 716.3 [304.0-892.3], diffuse axonal injury: 873.2 [407.2-1321.4], p = 0.034).

CONCLUSIONS:
Isolated tSAH on head CT is insufficient to rule out additional traumatic injuries in GCS 13-15 TBI. Forty-six percent of patients had additional traumatic lesions on MRI. Plasma GFAP may be an important biomarker for the identification of additional injuries, including axonal injury. Patients with isolated tSAH on CT may require close clinical surveillance and follow-up.
250 Harnessing the Endogenous Stem Cell Response After Spinal Cord Injury: A Novel and Translationally Relevant Therapeutic Strategy
Authors: Hachem Laureen D. , Hong James , Velumian Alexander , Mothe Andrea , Tator Charles , Fehlings Michael G. 
Published: March 2024

INTRODUCTION:
The adult spinal cord contains a population of endogenous ependymal-derived neural stem/progenitor cells (epNSPCs) that hold the potential to promote regeneration and repair after injury. epNSPCs are normally quiescent but are acutely activated after spinal cord injury (SCI). Despite this, the activation of these cells remains insufficient to promote robust neural regeneration and recovery. Understanding the mechanisms that govern the biology of epNSPCs is critical in developing a therapeutic strategy to harness their regenerative potential after SCI.

METHODS:
epNSPCs isolated from the adult spinal cord were used for in vitro mechanistic analysis. In vivo, cervical SCI was induced in adult rodents using a clinically relevant compression-contusion model of cervical SCI. FoxJ1-Cre-tdT reporter mice were used for lineage tracing studies. One-week post-SCI, animals (n = 15/group) were randomized to receive CX546 (a positive AMPA receptor modulator), or vehicle-control. Animals underwent weekly behavioural testing and spinal cords were extracted for histological/molecular analysis.

RESULTS:
Glutamate excitotoxicity, a hallmark in the pathogenesis of acute SCI, leads to calcium influx in spinal cord epNSPCs via AMPA receptors (AMPARs) and this change in calcium in concert with Notch signaling drives their proliferation and astrocytic differentiation. Blockade of AMPARs in vivo inhibits the activation of epNSPCs post-SCI. Positive modulation of AMPARs after SCI using the clinically relevant class of drugs known as ampakines, enhances epNSPC proliferation, increases pro-regenerative astrocytes and neurotrophic factor production, and promotes neuronal survival and motor recovery.

CONCLUSIONS:
We report on a novel mechanism by which AMPARs regulate the growth and phenotype of endogenous epNSPCs. Pharmacological targeting of this mechanism could be used to harness the regenerative potential of endogenous neural stem cells and improve motor recovery after SCI.
254 Initiation of Low Molecular Weight Heparin Within 24 Hours Is Safe and Effective for VTE Prophylaxis in Spinal Cord Injury Patients
Authors: Lui Austin , Chryssikos Timothy , Patel Arati , Park Christine , Torres Abel , Kyritsis Nikolaos , Hemmerle Debra P. , Fernandez Xuan Duong , Saigal Rajiv , Talbott Jason , Pan Jonathan S. , Ferguson Adam , Whetstone William , Singh Vineeta , Weinstein Philip R. , Dhall Sanjay S. , Mummaneni Praveen V. , Huie J. Russell , Pascual Lisa U. , Manley Geoffrey , Bresnahan Jacqueline , Beattie Michael , DiGiorgio Anthony Michael 
Published: March 2024

INTRODUCTION:
Venous thromboembolism (VTE) following traumatic spinal cord injury (SCI) is a major clinical concern. Current guidelines recommend initiation of chemical prophylaxis within 72 hours of injury or surgery. Given the high reported incidence of VTE in this population, the safety and efficacy of earlier initiation is an important clinical question.

METHODS:
We analyzed prospectively collected data in a cohort of 162 SCI patients from a single quaternary center. Demographic and clinical data were recorded. Univariate and multivariate logistic regression analyses were performed to identify predictors of VTE in SCI patients treated with LMWH within 24 hours of injury or surgery.

RESULTS:
Mean age was 56.9 years (28% females). One hundred and thirty (87.8%) patients underwent SCI surgery. There was an extremity fracture in 18.2% and lumbar drain was placed in 22.3%. DVT occurred in 7.4%, PE in 6.1%, and any VTE in 12.2%. A multivariable regression model including age, sex, race, injury severity score, level of SCI, SCI surgery status, admission lower extremity motor score, and extremity fracture showed that only lower extremity motor score (OR 0.94, p=0.03) was significantly associated with VTE. There were 1.5% patients with post-SCI surgery-related bleeds requiring surgery takeback. There were 5.6% non-surgery related bleeds, and 1.2% wound dehiscence.

CONCLUSIONS:
Initiation of LMWH within 24 hours of injury or surgery maintained the incidence of any VTE event within the lower end of previously reported ranges with 1.5% of patients who underwent SCI surgery requiring surgery takeback due to bleeding complications. Admission lower extremity motor score was the sole predictor of VTE in this patient cohort.
273 A Direct Domparative Analysis of Pediatric Traumatic Brain Injury Presentation and Outcomes in the United States and Uganda
Authors: Seas Andreas , Yoon Angela , Adil Syed M , Satyadev Nihal , Warman Pranav , Najjuma Josephine , Punchak Maria , Sexton Daniel , Dunn Timothy , Kolls Brad , Haglund Michael M. , Fuller Anthony , Kitya David 
Published: March 2024

INTRODUCTION:
Pediatric traumatic brain injury (pTBI) is the leading cause of death and disability among children globally. However, few studies have explored pTBI in low- and middle-income countries (LMICs) compared to high-income countries (HICs).

METHODS:
Patient records were extracted from the Duke University Hospital subset of the National Trauma Data Bank (NTDB, n = 866) and a dataset at the Mbarara Regional Referral Hospital in Uganda (MRRH, n = 571). Descriptive statistics were performed to compare across settings. Logistic regression was used to quantify the odds of mortality in each setting given ICU utilization, admission GCS, and other factors.

RESULTS:
In-hospital mortality was higher in the LMIC versus the HIC (9.4% vs 2.9%, p < 0.001), while ICU utilization was lower in the LMIC (9.0% vs 33.4%, p < 0.001). Rates of surgical management did not differ significantly (15.8% vs 17.0%). More patients presented with moderate (27.8% vs 4.3%) and severe TBI (16.5% vs 11.8%) in the LMIC (p < 0.001). No deaths were reported among patients presenting with moderate or mild TBI in the HIC setting, whereas LMIC pTBI patients died in every TBI severity category. Over 50% of LMIC ICU patients died, versus 8.1% of HIC ICU patients. In a multivariate regression model of mortality, ICU placement was associated with mortality (OR: 6.7, 95% CI: 2.1-20.9), an association not seen in the HIC setting.

CONCLUSIONS:
Pediatric TBI mortality is greater in the LMIC vs the HIC setting. The LMIC setting also had a high prevalence of moderate/severe TBI and low ICU availability and effectiveness. Future work should involve the implementation and evaluation of interventions to assess these gaps in the LMIC setting.
282 Does Axial Cervical Pain Improve With Surgical Fusion? A Meta-analysis
Authors: Harrop James S. , Gonzalez Ozuna Glenn Arturo , Qasba Reyan , Porto Guilherme Bastos , Wainwright John , Thalheimer Sara , Schorsch Merrie , Vaccaro Alexander , Ghogawala Zoher 
Published: March 2024

INTRODUCTION:
Isolated axial neck pain is a prevalent condition that causes significant morbidity and productivity loss.

METHODS:
This study searched for RCTs and cohort studies in English language databases with a minimum 6-month follow-up, limited to patients with axial neck pain/cervical radiculopathy and pre/post-operative NDI and VAS scores. Literature reviews, meta-analyses, systematic reviews, surveys, and case studies were excluded. Two patient groups were analyzed: the arm pain predominant (pAP) cohort and the neck pain predominant (pNP) cohort. A 30% reduction in PROMs scores from baseline represented the Minimal Clinically Important Difference (MCID).

RESULTS:
Five studies with 5,221 patients met the inclusion criteria. Patients with pAP had a slightly greater reduction in PROMs scores than those with pNP. NDI reduction was 41.34 % (16.3/39.42) in pNP patients (p < 0.0001) and 45.12% (15.86/35.15) in pAP patients (p < 0.0001). Surgical improvement was comparable between the two groups (16.3 vs. 15.86 points, p = 0.3193) .Patients with pNP had a greater reduction in neck pain (53.4%; 3.60/6.74, p < 0.0001) compared to pAP (50.30%; 2.46/4.89, p < 0.0001), with a significant difference in VAS scores (3.6 vs. 2.46, p < 0.0134). Patients with pNP had 43.6% (1.96/4.5) improvement in arm pain (p < 0.0001), while pAP patients had 66.12% (4.43/6.7) improvement (p < 0.0001), with significantly higher VAS scores for arm pain in pAP patients (4.43 vs. 1.96 points, p < 0.0051).

CONCLUSIONS:
Surgical intervention is increasingly supported for primary axial neck pain, with studies demonstrating greater improvements in neck pain than arm pain, exceeding MCID and reaching SCB. However, given the multifaceted nature of the condition, further research is needed to determine optimal patients and pathologies for surgery.
284 CT-Based Assessment of Prone Versus Lateral Pedicle Screw Placement Accuracy: A Retrospective Single-surgeon Study
Authors: Brown Nolan James , Musmar Basel , Pennington Zach , Kuo Cathleen , Chakravarti Sachiv , Diaz-Aguilar Luis Daniel , Mehkri Yusuf , Singh Rohin , Pham Martin H. 
Published: March 2024

INTRODUCTION:
Lateral lumbar interbody fusion (LLIF) including the anterior-to-psoas oblique lumbar interbody fusion (OLIF) has conventionally relied on pedicle screw placement (PSP) for construct stabilization. Single-position surgery with lumbar interbody fusion (LIF) in the lateral decubitus position with concomitant PSP has been associated with increased operative efficiency. What remains unclear is the accuracy of PSP with robotic guidance when compared to the more familiar prone patient positioning.

METHODS:
We identified all consecutive patients treated with interbody fusion and PSP in the prone or lateral position by a single surgeon between January 2019 and October 2022. All pedicle screws placed were analyzed using CT imaging to determine appropriate positioning according to the Gertzbein-Robbins Classification Grading System. Multivariate logistic regression models were constructed to identify risk factors for the occurrence of a radiographically significant breach.

RESULTS:
89 consecutive patients were included (n = 690 screws), of whom 46 were treated in the prone position (n = 477 screws) and 43 in the lateral decubitus position (n = 213 screws). There were fewer breaches in the prone (n = 13; 2.7%) versus lateral decubitus group (n = 15; 7.0%; p = 0.012). Nine (1.9%) radiographically significant breaches occurred in the prone group compared to 10 (4.7%) in the lateral decubitus group (p = 0.019), for a prone vs. lateral decubitus pedicle screw accuracy rate of 98.1% vs. 95.3%. There were no significant differences in BMI between prone vs. lateral decubitus cohorts (30.1 vs. 29.6) or breached patients vs. non-breached patients (31.2 vs. 29.5). In multivariate models, prone position was the only significant protective factor for screw accuracy; we did not identify any other significant risk factors for screw breach.

CONCLUSIONS:
The present data suggest pedicle screws placed with robotic assistance have higher placement accuracy in the prone position.
298 Differential Gene Expression Underlying Glioma Related Epilepsy
Authors: Mortazavi Armin , Nieblas-Bedolla Edwin , Khan Anas , Carney Ryan , Johnson Kory , Zaghloul Kareem A. 
Published: March 2024

INTRODUCTION:
Seizures are a common sequalae for patients suffering from gliomas. There are several factors, such as molecular characteristics, known to influence the initiation of seizures that may ultimately drive tumor growth. However, different levels of gene expression associated with seizures for gliomas remain unclear. Here, we review current literature and analyze RNA sequencing of gliomas to further probe these differences.

METHODS:
Utilizing total RNA sequencing obtained from The Cancer Genome Atlas - Lower Grade Glioma to identify and characterize differential expression in patients that do and do not experience seizures. Utilizing QIAGEN Ingenuity Pathways Analysis (IPA), we identified canonical and functional pathways to further characterize differential expression.

RESULTS:
From 289 patients with gliomas, 83 (28.7%) had available information regarding seizures and other variables of interest. Of these, 50 (60.2%) were allocated to the seizure group and the remaining 33 (39.8%) to the non-seizure group. There were no statistically significant differences in age (p = 0.4661), sex (p = -0.1338), race/ethnicity (p = 0.7331), molecular subtype (0.8656), tumor grade (p = 0.2260), or anatomical location. When comparing the level of RNA expression from these tumors between the seizure and non-seizure groups, we identified 52 genes that were significantly differentially regulated. Critical canonical pathways were identified, most significantly RHOGDI and Semaphorin Neuronal Repulsive signaling.Finally, in the functional analysis, tumors that promoted seizures had gene sets that were significantly increased involving neuronal differentiation and synaptogenesis.

CONCLUSIONS:
In the setting of gliomas, differences in tumor gene expression exist between individuals with seizures and without seizures despite similarities in patient demographics and other tumor characteristics. There was significant difference in gene expression that were most associated with neuron development and synaptogenesis, ultimately suggesting a mechanistic role of a tumor-neuron synapse in seizure initiation and potentially tumor growth.
304 NF2 Loss-of-Function and Hypoxia Together Drive Radioresistance in Grade 2 Meningiomas
Authors: Pugazenthi Sangami , Patel Bhuvic , English Collin , Mahlokozera Tatenda , Lu Hsiang-Chih , Yang Alicia , Roberts Kaleigh , Mao Diane , Sinha Namita , Dahiya Sonika , Petti Allegra , Klish Tiemo , Harmanci Akdes , Patel Akash J. , Kim Albert H. 
Published: March 2024

INTRODUCTION:
Grade 2 meningiomas (G2Ms) are associated with an aggressive natural history characterized by recurrence and resistance to radiation therapy. Histopathological necrosis is associated with worse progression-free survival (PFS) following radiation therapy in G2Ms. We seek to understand the molecular pathophysiology of radiation resistance and to identify molecular biomarkers and therapeutic targets for radioresistant G2M.

METHODS:
We performed genetic sequencing and histopathological analysis of 121 G2Ms. Using the IOMM-Lee meningioma cell line, we investigated the role of tumor hypoxia and genes of interest in radio-resistance through lentivirally targeted gene knockdown and clonogenic survival assays following exposure to ionizing radiation. Transcriptional profiling of cells in in vitro and in 38 patient G2Ms was performed using RNA sequencing.

RESULTS:
NF2 loss of function mutations were significantly associated with tumor necrosis in G2Ms (p = 0.0026). Patients with NF2mutation and spontaneous necrosis had worse post-radiation PFS compared to NF2 wildtype patients without necrosis (p = 0.035). In the setting of hypoxia, NF2 knockdown significantly increased radio-resistance in vitro (p < 0.001). Gene set enrichment analysis on in vivo and in vitro data and functional assays revealed downregulation of apoptosis and upregulation of cell proliferation in NF2-deficient and necrotic group compared to control. Integration of differentially expressed genes in both NF2-deficient cells in vitro and human necrotic tumors identified shared upregulation of HES1, XDH, NOG, IGFBP3, ALOXE3, THSB1, and TRIML2, suggesting these genes may represent targets for radio-sensitization or biomarkers of radio-resistance.

CONCLUSIONS:
NF2 loss-of-function in the setting of hypoxia confers radiation resistance through a transcriptional program that promotes proliferation and DNA repair. Targeting molecular pathways identified by transcriptional profiling may improve local control in patients with radioresistant G2M.