bluuebunny/crossref_metadata_2025_split huggingface dataset:
126 Objective Functional Outcome Measures Expose Relevant Ceiling Effects Inherent to Subjective Patient-Reported Outcome Measures in Patients Undergoing Surgery for Lumbar Degenerative Disorders
Authors: Maldaner Nicolai , Zeitlberger Anna , Ziga Michal , Bozinov Oliver , Regli Luca , Stienen Martin N. 
Published: March 2023

INTRODUCTION:
Patient-reported outcome measures (PROMs) may be subject to relevant floor and ceiling effects which may induce substantial bias to the outcome assessment after spine surgery.

METHODS:
In a prospective study, 50 patients were assessed preoperatively, 6-weeks and 3-months postoperatively for objective functional impairment using the smartphone-based 6-minute walking test (6WT) as well as a set of widely used PROMs. Paired sample t-tests were used to establish significant difference between the changes in raw 6-minute walking distance (6WD) and PROMs at baseline, 6-weeks and 3-months follow-up. Floor and ceiling effect were considered present if >15% achieved the worst and best status. Pearson correlation coefficients were used to define the relationship between 6WT and PROMs at 6-weeks and 3-months.

RESULTS:
The mean 6WD improved from 377 m preoperative to 490 m and 517 m at 6-weeks and 3-months follow-up (p < 0,05). While all PROMs improved from pre- to six-week postoperative, no significant improvement was observed beyond the 6-weeks follow up in the Core Outcome Measure Index (COMI), the Zurich Claudication Questionnaire (ZCQ) Symptoms Severity Scale, the ZCQ Physical Performance Scale, VAS Back and Leg pain. A ceiling effect was observed for the COMI, the ZCQ Symptoms Severity Scale, the ZCQ Physical Performance Scale, VAS back and VAS leg pain in 2%, 4%, 24%, 20% and 16% of patient at the 6-weeks follow up. Correlation between the 6WD and PROMs significantly increased from the 6-weeks to 12-weeks follow up.

CONCLUSIONS:
PROMs reach their best possible score in a relevant number of patients early after surgery for DLD while objective functional outcome continues to improve beyond the 6-weeks follow-up. Objective measures of function may expose relevant ceiling effects observed by PROMs and describe the continued recovery of patient.
127 Modeling Traumatic Brain Injury Using Human Cerebral Organoids
Authors: Tallat Ahmed Mohamed , Beltrán Susana , Bobo Justin , Kodavali Chowdari , Edwards Lincoln , LeDuc Philip , Zinn Pascal O. 
Published: March 2023

INTRODUCTION:
Traumatic brain injury (TBI) is a leading cause of morbidity and mortality worldwide. The ability to model pathophysiological processes through 3D cultures systems may enable new treatments while eliminating the need for animal and human testing. Advances in 3D cell culture systems have resulted in the generation of human cerebral organoids, which to a great extent recapitulate key neural cytoarchitectural features. We currently have no in-vitro human TBI model.

METHODS:
We generated cerebral organoids from human embryonic stem cells. After maturation, the organoids were subjected to a custom-designed Mechanical Excitation Testbed (MET) that delivered compressed the organoid with controlled strain rates and strain for a given number of pulses. We investigated the repercussions of organoid compression by assessing the neuronal function, calcium signaling, and morphological changes, electrophysiology, real-time calcium imaging, and immunohistochemistry. Molecular and gene ontology analysis was also performed using RNA-seq and Ingenuity Pathway Analysis/Gene Set Enrichment.

RESULTS:
Our results demonstrated significant real-time calcium signaling upregulation and altered neuronal activity consistent with TBI severity. Moreover, RNA-seq data demonstrate unsupervised clustering of gene activity of moderate and severe TBI. Furthermore, gene enrichment analysis identified 3 key genes ENO1, CARD9, and FOXP3 which are associated with neuronal development, regulation of cellular apoptosis & IL-17 mediated inflammation pathway, and immunoregulation of T-cells respectively. Finally, TBI response pathways were identified involving stromal elasticity, and extracellular matrix, consistent with TBI.

CONCLUSIONS:
This in-vitro brain organoid TBI model shows strong phenotypic and genetic similarities with TBI patients. Furthermore, This novel TBI model could provide a basis for a high-throughput personalized patient-less model that could be used to study TBIs and test potential therapeutic modalities.
129 Genetically Engineered Exosomes Derived From Mesenchymal Stromal Cells Promote Functional and Structural Recovery in Rats After Traumatic Brain Injury
Authors: Mahmood Asim , Zhang Yanlu , Zhang Yi , Chopp Michael , Xiong Ye 
Published: March 2023

INTRODUCTION:
Previous studies have demonstrated that multi-potent mesenchymal stromal cell (MSC)-derived exosomes improve functional recovery after experimental traumatic brain injury (TBI). Our present research focuses on augmenting the beneficial effects of exosomes by transfecting them with microRNAs.

METHODS:
Adult male rats were injured with controlled cortical impact. Animals received a single intravenous injection of MiR-17-92 cluster-enriched exosomes (100 µg/rat) or control exosomes (100 µg/rat) or Vehicle (phosphate-buffered solution) one day after injury. A battery of neurological functional tests was performed after TBI. Spatial learning and memory were measured using the Morris water maze test. All animals were sacrificed five weeks after injury. Their brains were processed for histopathological and immunohistochemical analysis of cell loss, angiogenesis, neurogenesis, and neuroinflammation.

RESULTS:
Compared with control, both Exo-17-92 and Exo-empty treatments significantly improved sensorimotor and cognitive function, reduced neuroinflammation and hippocampal neuronal cell loss, and promoted angiogenesis and neurogenesis (p < 0.05). Moreover, Exo-17-92 treatment exhibited a significantly more robust effect in improving functional recovery and in reducing cell loss, and enhancing angiogenesis and neurogenesis compared to Exo-empty treatment (p<0.05).

CONCLUSIONS:
Exosomes enriched with miR-17-92 cluster have a significantly better effect on improving functional recovery after TBI compared with Exo-empty treatment, likely by enhancing endogenous angiogenesis and neurogenesis. Engineering specific miRNA in exosomes may provide a novel therapeutic strategy for the management of TBI.
132 A Novel Mechanism of Periventricular Strain Observed in Post-Mortem Human Brains for Mild Traumatic Brain Injury
Authors: Poon Katherine , Post Andrew , Brien Susan , Rovt Jennifer , Dutrisac Scott , Cusimano Michael , Jalali Alireza , Goodwin Shannon , Petel Oren , Karton Clara , Hoshizaki Thomas 
Published: March 2023

INTRODUCTION:
Mild traumatic brain injury (mTBI) can result in a myriad of long-term functional deficits reflecting diffuse axonal disruption. While microstructural anomalies in the periventricular regions of the brain have been identified through immunohistochemical analyses, diffusion tensor imaging and animal models, and contribute to a range of symptoms observed in mTBI, the mechanism of injury is not fully described.

METHODS:
Post-mortem human brains without space-occupying lesions and significant atrophy were included in this study. Using MRI and anatomical surface landmark localisation, cortical and subcortical markers were implanted along a sagittal plane in anterior, posterior and inferior periventricular regions as well as in the frontal, parietal, occipital and cerebellar lobes. A high-speed, high-resolution, two-dimensional imaging system was employed to measure brain displacement from direct low-velocity frontal impacts. Impact kinematics of the skull were measured using a DTS 6DX SLICE sensor array. Marker displacement in the anterior, inferior and posterior periventricular regions were calculated and individual frame position time-histories for markers' centre of gravity were recorded.

RESULTS:
Upon impact, the frontal horns of the lateral ventricles were observed to immediately collapse, followed by posterior fluid motion and occipital horn dilation not previously described in the literature. Substantial deformation was recorded in the periventricular areas, resulting in a significantly higher magnitude of strain relative to more superficial subcortical and cortical structures. In comparison, the posterior periventricular region of the brain recorded the highest magnitude of strain.

CONCLUSIONS:
This study describes the generation of unique high magnitude strain in the periventricular regions from ventricular fluid flow upon low-velocity frontal head impacts. While the clinical significance of the ventricular deformation remains to be elucidated, this represents an important association between the mechanism of injury and diffuse symptomatology observed in mTBI.
135 Real-World Data of Microvascular Decompression in Trigeminal Neuralgia: Analysis of 26 Tertiary Care Centers of the European Continent
Authors: Sommer Björn , Shiban Ehab , Schatlo Bawarjan , Rohde Veit , Thomé Claudius , Brito Silva Barbosa Marcos Daniel , Jödicke Andreas , Gandía González Maria Luisa , Blasco Guillermo , Demetriades Andreas K. , Sure Ulrich , Vanaclocha Vincente , Mastronardi Luciano , Ringel Florian , Gonzalez-Lopez; Peter Vajkoczy Pablo , Ruiz-Juretschke Fernando , Stummer Walter , Sames Martin , Fedirko Volodymyr , Bijlenga Philippe A. , Seifert Volker , Meyer Bernhard , Lehmberg Jens 
Published: March 2023

INTRODUCTION:
Patients with classic trigeminal neuralgia (TN) usually receive first-line treatment with carbamazapine. The known effect of wearing-off is hold against the result of expert single-center series of microvascular decompression (MVD) as a successful treatment option. However, real-world data regarding MVD is lacking.

METHODS:
A multicenter retrospective data analysis was performed in 26 European hospitals. Inclusion criteria were a) age >18 to 85 years, b) patients with classical TN, c) patients who underwent microvascular decompression (MVD) and d) minimum follow-up of 12 months. Primary outcome is pain-freedom at last follow up. Secondary outcome parameters were duration of symptoms prior to MVD, neurovascular conflict in MRI, time to pain recurrence, complications, and a tailored questionnaire.

RESULTS:
1140 patients from 26 European institutions were analysed. Of those, 591 (346 female, 245 male, age (mean±SD) 60.1 ± 13.4 years) fulfilled the inclusion criteria. Mean duration of symptoms prior to surgery was 73.3 ± 67.0 months (6.1 ± 5.6 years). 73.3% of patients had a visible neurovascular conflict in MRI. After a follow-up 49.9 ± 36.8 months, 68.7% of patients were pain free or had occasional pain (BNI score 1 and 2). There was no correlation between symptom duration and time to pain recurrence. Involvement of SCA (61%) was associated with a high probability of pain freedom (p<0.01). Complications occurred in 31.6% of all cases, with hypoesthesia of the facial nerve being the most common event. Three out of four patients (74%) were satisfied with the treatment, and 72% would choose MVD as the preferred treatment option again.

CONCLUSIONS:
Microvascular decompression for trigeminal neuralgia is an effective treatment modality with excellent pain control. Two-third of patients were satisfied with the treatment.
140 Diffuse Midline Glioma Harbors Alterations That are Attenuated by MEK Inhibitors and 5-Aminolevulinic Acid-Photodynamic Therapy
Authors: Price Gabrielle , Anastasiadou Maria , Bouras Alexandros , Hadjipanayis Constantinos G. 
Published: March 2023

INTRODUCTION:
Diffuse midline glioma (DMG) is the leading cause of brain cancer-related mortality in children. There is a desperate need for therapeutic models that abrogate tumor cell invasion processes since standard radiation therapy is associated with transitory benefit and therapeutic resistance. 5-aminolevulinic acid-photodynamic therapy (5-ALA-PDT) is a photo-therapy that preferentially ablates tumor cells when 5-ALA is delivered with 635 nm light by metabolizing to protoporphyrin IX (5-ALA metabolite). The RAS/MEK signaling pathway has been implicated in tumorigenesis and been shown to synergize with 5-ALA-PDT in various carcinoma models.

METHODS:
Five DMG lines were treated with 5-ALA-PDT and MEKi trametinib to evaluate effects on proliferation, invasion, live cell dynamics, and cell death in vitro. Apoptotic effects and changes in the tumor microenvironment were evaluated in vivo using a patient-derived xenograft model

RESULTS:
Functional screens demonstrate sensitivity to 5-ALA-PDT and trametinib (5-ALA-PDT IC50 = 0.25-0.41 µM; trametinib IC50 = 0.03 µM-0.03 mM). An increase in cleaved-caspase3 (p = 0.0006) and reactive oxygen species concentration (p < 0.0001) was characteristic in DMG cell lines post-treatment. Immunofluorescence stainings showed a decrease in PDGFRa (p = 0.007) and increase in Hsp70 (p < 0.0001) expression. Trametinib and 5-ALA-PDT dampened cell invasion (invasive/total cells: 1.30, 0.20, 0.26, 0.05 for control, trametinib, 5-ALA-PDT, and combination, respectively). For in vivo studies, there were changes in cleaved-caspase3 (>4-fold difference) and glioma-associated neovascularization in tumor bearing mice.

CONCLUSIONS:
This study proposes a promising, novel combinatorial strategy involving the use of 5-ALA-PDT and MEKi for DMG treatment and can be implemented for other CNS tumors.
142 Pediatric Epilepsy Outcomes After Laser Ablation: An Institutional Cohort Analysis
Authors: Li Daphne , Barros Guinle Maria Isabel , Johnstone Thomas , Kaur Harsheen , Porter Brenda , Grant Gerald A. 
Published: March 2023

INTRODUCTION:
Laser interstitial thermotherapy (LiTT) is a minimally invasive technique for targeting epileptogenic foci but there is limited data on outcomes in pediatric epilepsy.

METHODS:
A retrospective review of consecutive pediatric epilepsy patients at Stanford who underwent invasive stereoelectroencephalography between May 2017 to August 2021 and LiTT ablation of epileptogenic foci. Patient demographic, medication usage, seizure, prior surgical interventions, procedural details, and pre- and post-operative seizure history were analyzed.

RESULTS:
Thirty-five patients (24 male, 11 female) identified with average seizure onset 2.8 ± 2.8 years (range 0.25-12)) and average age 9.3 ± 5 years at the time of LiTT (range 2.4-17.9). Etiologies include 21 lesional patients (16 tuberous sclerosis, 4 focal cortical dysplasia, 1 gliosis), and 14 non-lesional (5 insular, 2 frontal, 5 temporal lobe, 2 had multiple foci). Eighteen patients had prior interventions including open resections n = 13 (singular n = 11, multiple n = 2), LiTT (n = 4) or a combination (n = 1), of which LiTT targeted a nearby area in 5. The median number of lasers placed in each procedure was 3 (range 1-5). Complications occurred in 13 cases (37%): 1 venous hemorrhage requiring evacuation intraoperatively, 1 aseptic meningitis, 2 immediate post-operative seizures, and 9 neurologic deficits (6 improving with therapy, 3 stable). Average post-operative length of stay is 2.11 ± 2.11 days (median 1, range: 1-9). Postoperatively, 18 patients (51.43%) were seizure free and median Engel score was 1 (Engel 1 n = 18, Engel 2 n = 6, Engel 3 n = 4, and Engel 4, n = 7) at last follow-up (average follow-up: 13.040 ± 11.37 months; range: 0.43-47.83). 15 (42.86%) patients were reported to experience neurocognitive or behavioral improvement, but this was not found to correlate with lower engel score (p = 0.777).

CONCLUSIONS:
LiTT is a safe and effective method of treatment for pediatric patients with medically refractory epilepsy of various etiologies.
147 The Impact of Tming of Primary Nerve Surgery on Shoulder Recovery in Neonatal Brachial Plexus Palsy
Authors: Muhlestein Whitney , Smith Brandon W. , Chang Kate , Jun-San Yang Lynda 
Published: March 2023

INTRODUCTION:
Neonatal brachial plexus palsy (NBPP) almost universally impacts shoulder abduction, forward flexion, and external rotation. While nerve reconstruction options are available for restoration of these movement, the outcomes for nerve surgery for shoulder have lagged behind those at other joints. Operative timing is a potentially modifiable variable but remains controversial.

METHODS:
We interrogated a prospective database of all patients with NBPP who underwent primary nerve surgery at a single tertiary referral center between 2005-2020. The cohort was divided into those who underwent surgery ≤6 months old, 6-9 months old, and >9 months old. AROM for shoulder abduction, forward flexion, and external rotation was plotted over time for each group and a logistic regression and 95% confidence interval fit to each plot to visualize both absolute and rate of recovery of AROM for each group.

RESULTS:
99 children with 2196 AROM measurements were included in the analysis with average follow-up of 46 months. 26 underwent surgery ≤6 months old, 47 between 6-9 months, and 26 >9 months old. Those who underwent surgery ≤9 months old had more rapid and better overall recovery of shoulder abduction and forward flexion than those who had surgery >9 months. Timing of operation did not clearly impact recovery of external rotation. Patients who presented to a multidisciplinary clinic earlier were more likely to have earlier operations.

CONCLUSIONS:
Surgery prior to 9 months old may improve long-term recovery of shoulder AROM in NBPP. Early referral should be encouraged to optimize timing of operative intervention.
157 Identifying Spatial Transcriptomics Signaling Networks in Human Glioblastoma Using Graph-Based Machine Learning
Authors: Miyagishima Danielle F. , Kuchroo Manik , Steach Holly , Phan Duy , Godavarthi Abhinav , Takeo Yutaka , Barak Tanyeri , Youlten Scott , Gorur Ketu Mishra , Moliterno Jennifer Alissa , Erson-Omay Zeynep , McGuone Declan , Krishnaswamy Smita , Gunel Murat 
Published: March 2023

INTRODUCTION:
The median survival for glioblastoma multiforme (GBM) has only improved by 4.6 months in more than 100 years, underlying the need for innovative methods for understanding this devastating tumor. Spatial transcriptomics is a new method of whole-transcriptome assessment which allows for simultaneous visualization of mRNA expression in situ with histopathology.

METHODS:
We applied spARC to 25,517 Unique Molecular Identifiers from 10 surgically resected human IDH-mutant astrocytic gliomas (Grade II (n = 3) and Grade III (n = 3)) and GBMs (n = 4). spARC uses manifold learning, graph filters, data diffusion and diffusion filtration to enable discovery of gene-gene relationships, spatial co-localization of genes, and receptor-ligand interactions applicable across a variety of spatial transcriptomic methods. A Neuropathologist annotated whole-slide images blind to our computational analysis and we used in-situ hybridization and immunohistochemistry to demonstrate that spaRC imputation recovery of gene expression is superior to raw expression.

RESULTS:
We demonstrate that spARC can identify spatially restricted tumor niches of dense tumor, leading edge, infiltration/high tumor burden, hemoglobin, and vasculature with high specificity. These clusters can be identified with genes including CD44, VIM, LDHA (dense tumor); SNAP25, UCHL1, OLMF1 (leading edge); OLIG2, MBP, PDGFRA (Infiltrating/High Tumor Burden). In our assessment of ligand-receptor interactions we found that GBM samples were enriched for SPP1-CD44 signaling. We validated this using GBM TCGA data stratifying patients based on expression of SPP1 and CD44 genes and found that high expression conferred lower survival at 12 months.

CONCLUSIONS:
Spatial transcriptomics paired with graph-based machine learning methods applied to human GBMs is a powerful technique able to uncover signaling networks relevant to patient survival and may aid in developing new therapeutic strategies.
159 Neuroplastic Changes Across Multiple Brain Resections in Glioma Patients: Identification of Patterns that Predict Beneficial Repeat Resection
Authors: Valdes Pablo Andres , Ng Sam , Herbet Guillaume , Duffau Hugues 
Published: March 2023

INTRODUCTION:
The brain displays degrees of functional reorganization, i.e., neuroplasticity, that enable interventions that were previously thought to be impossible (e.g., resection of “Broca’s area”). Studies have described the static, single-point in time neuroplastic potential in diffuse low-grade gliomas (DLGG) following one surgery.

METHODS:
We studied n=103 patients with a DLGG that underwent multiple brain resections achieved up to critical neural networks identified under awake mapping by means of direct cortical and subcortical electrostimulation. We used normalized postoperative images to generate probability overlap, atlas-based cortical and subcortical parcellation, and functional compensation maps for both surgeries. We performed statistical analysis correcting for multiple comparisons across all cortical parcels and tracts to determine differences at the cortical and subcortical levels between surgeries.

RESULTS:
We show for the first time the dynamics of neuroplastic changes occurring in DLGG that undergo multiple awake resections. We created residual and resection cavity overlap probability maps; cortical parcel damage and subcortical tract disconnection maps and the difference between surgeries; and functional compensation maps and subcortical volumes. We discovered the following four main patterns that constrain how and to what degree this dynamic reorganization occurs between surgeries: cortical vs subcortical, superficial vs deep, unimodal vs multimodal, and left vs right. We found greater plasticity at the cortical level, superficial terminations of white matter tracts, multimodal networks, and left ventral and right dorsal networks.

CONCLUSIONS:
These newly discovered patterns of reorganization provide a unifying model to understand the dynamics of neuroplasticity in DLGG patients undergoing multiple resections. These dynamics with its patterns that constrain mechanisms of neuroplasticity, can help guide neurosurgeons to predict which patients are likely to benefit from a repeat resection.