bluuebunny/crossref_metadata_2025_split huggingface dataset:
196 Multi-omic Convergence of Human Craniosynostosis Genes Within a Developmental Bone-Dura-Brain Nexus
Authors: Kiziltug Emre , Allington Garrett , Kawaguchi Riki , Panchagnula Shreyas , Geschwind Daniel , Kahle Kristopher 
Published: March 2022

INTRODUCTION:
Craniosynostosis (CS) is the premature fusion of the calvarial sutures and has long been considered mostly an aesthetic disorder, despite many affected children experiencing neurocognitive deficiencies and seizures. The two types of CS, syndromic and non-syndromic, present with significant genetic clinical heterogeneity, suggesting a complex interplay of genetic and environmental causes. Given the neurodevelopmental symptoms observed in CS patients, we hypothesized the genes involved in the pathophysiology of CS may play a key role in the functional development of the brain.

METHODS:
We applied a multimodal integrative genomic approach to examine the functional relationships as well as the spatiotemporal and cellular interactions of all currently known craniosynostosis-associated genes (CSGs) and also explored whether they are linked to other neurodevelopmental disorders (NDD). To this end, we constructed gene co-expression modules using a bulk-RNA expression dataset with 27 human brains encompassing 16 human brain regions across fetal development into early childhood. We further used scRNA-seq datasets derived from embryonic mouse meninges, calvarial sutures and developmental human brain to identify cell-types enriched with CSGs.

RESULTS:
The set of co-expression modules significantly enriched with CSGs were highly expressed during mid-gestation and in primary motor, somatosensory and prefrontal cortices, and the ganglionic eminence. Moreover, some of these modules were also significantly enriched with autism-spectrum disorder (ASD) and NDD genes. The most significant modules were associated with histone-3 lysine-4 methylation, neural crest differentiation, endochondral ossification and reactive astrogliosis. The mouse meninges scRNAseq analysis showed enrichment in pial and dural fibroblasts. The whole-brain scRNA-seq analysis showed CSGs were enriched in medial ganglionic eminence (MGE)-derived cortical interneurons, astrocytes and oligodendrocyte precursors during mid-fetal brain development.

CONCLUSION:
CSGs may contribute to pathogenesis through epigenetic dysregulation, disrupted neural crest differentiation facilitated by neuroglial cells and MGE interneuron migration very early during development. These processes are in confluence with premature suture fusion mediated by dural and pial fibroblasts.
204 Anatomical Modeling of Two-Trajectory Laser Amygdalohippocampotomy
Authors: Liu David D. , Lauro Peter , Leary Owen P. , Zheng Bryan , Phillips Ronald , Roth Julie , Blum Andrew , Segar David J. , Asaad Wael 
Published: March 2022

INTRODUCTION:
Laser interstitial thermal therapy (LITT) for mesial temporal lobe epilepsy (mTLE) is typically performed with one laser trajectory to target the medial temporal lobe (MTL). MTL structures such as piriform and entorhinal cortex are epileptogenic, but due to their relative geometry, are difficult to target with one trajectory while simultaneously maintaining adequate ablation of the amygdala and hippocampus.

METHODS:
Magnetic resonance imaging (MRI) from the Human Connectome Project (HCP) was used to create subject-specific target structures consisting of hippocampus, amygdala, and piriform/entorhinal/perirhinal cortex. An algorithm searched for safe potential trajectories along the hippocampal axis (catheter one) and along the amygdala-piriform axis (catheter two) and compared this to a single trajectory optimized over all structures. The proportion of each structure ablated at various burn radii was evaluated. A cohort of 11 consecutive patients with mTLE received two laser LITT.

RESULTS:
The two-laser trajectory approach was superior at nearly all burn radii for all hippocampal subfields and amygdala nuclei (p < 0.05). Two-laser trajectories achieved full ablation of MTL cortical structures at physiologically realistic burn radii, while one-laser trajectories could not. 5 patients with at least 1 year follow-up (mean = 21.8 months) experienced Engel class I outcomes; 6 patients with less than 1 year follow-up (mean = 6.6 months) are on track for Engel I outcomes.

CONCLUSION:
Large-scale artificial intelligence search through high-quality HCP imaging data reveals the theoretical advantage of two-laser LITT over one-laser LITT.
347 Cancer-associated Fibroblasts Affect GBM Progression
Authors: Kim Timothy Y. , Srivastava Siddhartha , Medikonda Ravi , Pant Ayush , Patel Kisha K. , Rodriguez Fausto , Lim Michael 
Published: March 2022

INTRODUCTION:
Glioblastoma is an extremely aggressive form of brain cancer and despite the many advances made in therapeutic options, outcome and quality of life remains poor. Fibroblasts have been demonstrated to play a role in various systemic cancers by remodeling and reprogramming the tumor microenvironment immunologically and metabolically. Recently, cancer-associated fibroblasts (CAFs) have been identified in glioblastoma (GBM) patients and there is reason to believe that CAFs may have a protumoral effect in GBM progression.

METHODS:
Nine patients with resected GBM tumor samples were identified by pathology reports and embedded in paraffin, sectioned, and then stained with antibodies for alpha-SMA and GFAP. Ten 40x high-power fields per slide were visualized by a Zeiss Axio Observer microscope and counted by two independent researchers and verified by a board-certified neuropathologist. For in vivo work, 6-week C57BL/6J wild-type female mice were intracranially implanted with either Gl261-luciferase (Gl261-luc) tagged cells alone or in combination with NIH3T3 embryonic fibroblasts. Tumor burden was assessed on post-implantation day 7 via bioluminescent IVIS imaging.

RESULTS:
We found that fibroblasts were consistently present in human glioblastoma samples albeit in minute quantities of <1%. We then discovered on IVIS that Gl261 cells mixed with NIH3T3 fibroblasts produced larger tumors on day 7 post-implantation. Implantation of these exogenous fibroblasts significantly worsened survival although this effect was not dose-dependent.

CONCLUSION:
Fibroblasts are present in glioblastoma patient samples. Despite their scarcity, they may still have the ability to affect the tumor microenvironment. Exogenous intracranial implantation of fibroblasts led to increased proliferation of gl261-luc tumor cells. As expected, these larger tumors had a negative effect on mouse survival and suggest that fibroblasts may be a potential avenue of glioblastoma therapy that needs further exploration.
354 Improving Perioperative Communication Using a Mobile Application
Authors: Hubbard Zachary , Kalhorn Stephen 
Published: March 2022

INTRODUCTION:
Introduction of perioperative measures, such as the pre-operative time out, has shown to improve communication and outcomes across various surgical subspecialties. We utilized a standardized preoperative workflow using a technological platform in an effort to reduce operative inefficiency and improve preparedness.

METHODS:
Data was collected prospectively from neurosurgical cases before (July – October 2020) and after (October – January 2021) implantation of a mobile app designed to improve perioperative workflow and communication. All faculty and residents operating at the MUSC University Hospital during the intervention period were invited to use the mobile application. We used a double-blinded design to assess surgical team performance over the data collection period. The circulating/scrub nurses/technicians completed surveys detailing impression of resident preparedness, operative teamwork, last minute requests, near misses, and patient safety reports. Analysis of the cases in the intervention period was based on participating neurosurgical attendings, regardless of whether the cases were assigned, briefed, and/or debriefed on the application.

RESULTS:
112 cases were performed over the duration of the study period. Perception of resident preparation (0-5 score) was 4.13 before and 4.66 after implementation of the app (P<0.05). Resident familiarity (0-5 score) was 4.23 before and 4.58 after (P<0.05). Adverse events occurred in 11 pre-app cases and 4 in post app cases (P=0.77). Patient safety intelligence reports occurred in 0 cases before and after implementation. Impression of case efficiency averaged 4.48 (0-5) before use of the app and 4.61 after (P<0.05).

CONCLUSION:
Use of the mobile app significantly increased perceived resident preparedness, familiarity of the case plan, and teamwork. There were fewer adverse events after use of the app, however this did not reach statistical significance. There was no change in patient safety intelligence events following implementation of the app.
360 CyberKnife Radiosurgery Versus Radiofrequency Thermocoagulation in Patients with Trigeminal Neuralgia With or Without Multiple Sclerosis: A Single-Center Comparison
Authors: Loebel Franziska , Senger Carolin , Acker Gueliz , Conti Alfredo , Vajkoczy Peter , Budach Volker , Dengler Nora 
Published: March 2022

INTRODUCTION:
Treatment of refractory trigeminal neuralgia (TN), especially in patients with Multiple Sclerosis (MS), remains challenging. Single-fraction Cyberknife radiosurgery (CK) and retrogasserian thermocoagulation (TC) are possible therapeutic options. Comparative studies regarding treatment efficacy and outcome in patients with refractory TN treated with CK or TC, with additional consideration to MS, are scarce.

METHODS:
Clinical and radiographic data of patients with TN treated with single-fraction CK or TC at a single academic institution were analyzed. Pain level was evaluated using the Barrow Neurological Institute (BNIp) pain scale pre-intervention and 3, 6, 12 months and last follow-up (LFU) post-interventionally. Subgroup analysis was performed in patients with MS.

RESULTS:
113 patients were treated with 161 treatments. Median age of the cohort was 61.1 (31.1–98.4) years. There were no significant differences between the cohorts regarding age, side, branch distribution and pre-procedural BNIp. Median follow-up time was 44.3 (3.0–135.9) months. After CK, improved outcome was reported in 59.1%, 57.9%, 66.7%, and 67.3% at 3, 6, 12 months and LFU, while after TC, improved outcome was reported in 85.0%, 77.4%, 70.8% and 55.9%. Patients were more likely to benefit initially and at 3 months follow-up from a TC procedure (p<.0001), but improved outcome at LFU was more pronounced in the CK cohort (p=.077). Repeated treatments were significantly more common in the TC cohort (p=.02). MS was the most frequent neurological co-morbidity. Exclusive analysis of the MS subgroup revealed similar results regarding pain improvement at 3-months follow-up (TC: 95.5% vs. CK: 54.0%; p<.001) and at LFU, (TC: 72% vs. 86.0%; p=.009). Incidence of new-onset hypesthesia was not significantly different in both cohorts (p=.550).

CONCLUSION:
Both therapies present safe and efficient treatment strategies for patients with refractory TN. Initial BNIp improvement was significantly better in patients treated with TC, while longterm effects were more pronounced in the CK cohort. This was also true for patients with MS.
363 Efficacy of Flexible Intrathecal Morphine Delivery in the Treatment of Chronic Pain
Authors: Jalal Muhammad , Jalaluddin Muhammad 
Published: March 2022

INTRODUCTION:
The use of intrathecal morphine via a morphine drug delivery system has been shown as a promising alternative to the treatment of chronic pain. These programmable devices can deliver morphine via simple or flexible programs. Simple programs release morphine continuously at the same rate over a 24-hour period, whereas flexible programs are optimized to release different dosages at different times.

METHODS:
Patients were enrolled at St. James Mercy Hospital, University of Rochester, New York from February 2016 to February 2020. An out-patient intrathecal morphine trial was performed by injecting a single dose of 0.1-0.3 mg of preservative free morphine in the lumbar intrathecal space. Following at least 60% reduction in pain compared to baseline, a permanent intrathecal catheter and morphine pump were implanted. The drug delivery system was programmed to deliver morphine doses in a simple continuous or flexible mode. Follow up visits occurred between 12 and 60 months, and the efficacy of the flexible dosing was assessed.

RESULTS:
58 patients enrolled (34 female, 24 male, median age 59), 46 patients were on flexible dose morphine and 12 were on simple dose morphine. Statistical analysis found a significant difference in pain reduction between the two groups (p < 0.01). The flexible sample had a mean reduction in pain of 8.72 and the simple sample had a mean reduction in pain of 8.17 out of 10 points on the 0-10 pain scale. There were no infections or complications present in the study.

CONCLUSION:
While both flexible and simple program intrathecal morphine drug delivery system proved effective in reducing chronic pain, flexible programs were significantly more effective. A future multi-center study with a larger sample size is desired.
369 Toward a Complete Mechanism of Action in Epidural Spinal Cord Stimulation - Including Threshold Accommodation
Authors: Arle Jeffrey E. 
Published: March 2022

INTRODUCTION:
Multiple waveform variations have been introduced for treating neuropathic pain with epidural spinal cord stimulation. These include higher frequencies (eg up to 10kHz) and different cadences of bursting signals. Prior understanding of mechansims of action for reducing pain have relied upon the reduction in WDR cell firing through retrograde stimulation of the largest Ab axons in the dorsal columns. However, prior models did not include details about diameter dependent threshold changes in the dorsal column axons. We sought to include this critical detail toward determining a deeper understand of how all of the waveform variations, including non-paresthetic stimuli, might also acheive pain relief.

METHODS:
Prior FEM and axonal models were used to achieve this analysis with additional adjustments of adding empirically-derived threshold accomodation to the axon membrane properties. These were calibrated based on axon diameter. Software was programmed in COMSOL and Mathematica, as well as proprietary programs using C++, Java, and JavaScript.

RESULTS:
Tonic stimulation above 100-300Hz and with increasing PW show accomodation changes and threshold inversions. Also, however, Burst and HF waveforms also showed threshold inversions and led to non-paresthetic activity within dorsal column fibers. Amplitudes were found to achive this phenomenon within typically-used clinical ranges.

CONCLUSION:
By accounting for known threshold accommodation, related to axon diameters within the dorsal coulmns, a clear mechnism of action could be ascribed to all known waveforms being used clinically. The results show that there would likely not be paresthesia experienced at clinically relevant amplitudes for many of these waveforms and a coherent complete mechanism of action for achieving pain relief is derived from this approach.
376 Hemoglobin Disrupts Microglial Function in the Developing Brain
Authors: Pandya Chirayukumar , Trout Amanda , Miller Brandon 
Published: March 2022

INTRODUCTION:
Intraventricular hemorrhage of prematurity (IVH) interrupts normal white matter development. During normal brain development, microglia play an important role in myelination by producing insulin-like growth factor 1 (IGF-1) which is necessary for oligodendrocyte progenitor cells (OPCs) to mature into myelinating oligodendrocytes. IGF-1 is produced by a subpopulation of microglia that express the antigen CD11c, and these microglia are enriched during early brain development.

METHODS:
A cell culture system of isolated microglia was used for in vitro studies. A rat model of neonatal IVH was used for in vivo studies. Magnetic bead sorting was used to isolate CD11c+ microglia. Real-time PCR was used to quantify IGF-1 expression. ELISA was used to measure IGF-1 and cytokine production. Immunohistochemistry was used to quantify white matter and label OPCs, microglia, and CD11c.

RESULTS:
Hemoglobin induced a greater degree of TNFa production compared to an equivalent dose of whole blood. in vitro, hemoglobin reduced the percentage of microglia that expressed CD11c, and reduced the IGF-1production measured by ELISA. In an animal model of neonatal IVH, where hemoglobin injection reduces white matter development but not OPC survival, CD11c+ cells decreased their IGF-1 production as measured by real-time PCR.

CONCLUSION:
Hemoglobin is a potent pro-inflammatory stimulus for microglia in the developing brain. Hemoglobin induces classically proinflammatory microglial activation, with production of cytokines and reduction of IGF-1 production. CD11c+ microglia, the cells that provide the IGF-1 critical for myelination, reduce IGF-1 production in vivo when exposed to hemoglobin. This loss of microglial IGF-1 may be the reason OPCs fail to mature and myelinate effectively. Replacing IGF-1 maybe a therapeutic strategy for neonatal IVH.
378 Sacral Dimpling and GI/GU Symptoms in KBG Patients May Indicate Comorbid Tethered Cord Syndrome (TCS)
Authors: Pugacheva Alisa , Klinge Petra Margarete 
Published: March 2022

INTRODUCTION:
KBG is an autosomal dominant disorder characterized by costovertebral bony anomalies, scoliosis, and intellectual disability, and neurological disability. Tethered Cord Syndrome (TCS) is tissue tethering of the spinal cord due to a persistent embryological filum terminale causing subsequent bladder and bowel incontinence, scoliosis, and neurological signs and symptoms in the lower extremities. Tethered cord syndrome in genetic constellations, given the congenital nature, warrants further epidemiological studies.

METHODS:
Beyond the Diagnosis (https://www.beyondthediagnosis.org/), a local nonprofit organization in Rhode Island distributed an optional survey to members of their Facebook page in August 2020. Patients themselves or a family member chose to complete the optional survey about current symptoms and provided their age, sex, and consent to the responses being used in further research. Responses were anonymized and analyzed in Excel. Symptom prevalences across the responses and correlations between specific symptoms were calculated to explore whether a subset of symptoms among the patient sample was comorbid.

RESULTS:
83 KBG patients answered the survey (dTCS, n = 10, sTCS, n = 73, average age = 9.71). The most prevalent symptoms were sacral dimple (60%), severe constipation (60%), and poor coordination (50%) among dTCS patients, and sacral dimple (65.75%), gait changes/leg weakness (58.90%), and severe constipation (43.84%) among sTCS patients. Objective signs of TCS were combined into GI/GU, neurocutaneous, and orthopedic sign clusters. Pearson matrix analysis showed a correlation (R = 0.339) between GI/GU and orthopedic signs, especially between bladder/bowel changes and orthopedic signs (R = 0.468).

CONCLUSION:
Surveyed sTCS patients had a high prevalence of TCS symptoms such as sacral dimples and GI/GU issues. Upon symptom clustering, there was a notable correlation between bladder/bowel changes and orthopedic signs.
407 Residual and Recurrent Spinal Cord Cavernous Malformations: Outcomes and Technical Notes for Optimal Resection
Authors: Srinivasan Visish M. , Karahalios Katherine , Shlobin Nathan A. , Koester Stefan , Nguyen Candice , Rumalla Kavelin , Rahmani Redi , Catapano Joshua , Labib Mohamed , Mitha Alim P. , Lawton Michael T. 
Published: March 2022

INTRODUCTION:
Intramedullary spinal cord cavernous malformations (SCCMs) account for a small proportion (5%) of CMs overall and of spinal vascular malformations. However, they are well reported in the literature, with over 700 cases as of 2020. To date, the occurrence of recurrent or residual SCCMs has not been assessed or discussed, nor have the technical nuances of resection related to this issue.

METHODS:
An institutional database of vascular malformations was queried for all surgically managed cases of intramedullary cavernous malformations. Demographic, radiologic, intraoperative findings, and surgical outcomes data were obtained and retrospectively analyzed. A systematic review was performed using three databases (PubMed, Ovid MEDLINE, and Scopus) to analyze all cases of spinal cavernous malformations in the literature, to augment a prior review.

RESULTS:
146 cases of SCCM surgeries were identified in the database, including 17 recurrent lesions. Recurrences occurred at various time points, from as few as 3 to 264 months following initial resection. At the postoperative exam, 10 patients had better outcome scores than preoperative scores, 1 of which was status post resection of a recurrent lesion. A total of 21 patients had worse outcome scores, 4 of which were status post resection of recurrent lesion.

CONCLUSION:
Intramedullary spinal cord cavernous malformations are rare findings but may cause significant symptoms. Resection of these lesions is technically challenging, akin to the resection of brainstem cavernous malformations. Care should be taken to avoid leaving residual lesion, as this can leave the patient vulnerable to future hemorrhagic events and neurological morbidity. Satisfactory results are still achievable even with secondary or tertiary resections.
409 Impact of COVID-19 on the Hospitalization, Treatment, and Outcomes of Intracerebral Hemorrhage and Subarachnoid Hemorrhage in the United States
Authors: Ravindra Vijay , Grandhi Ramesh , de Havenon Adam 
Published: March 2022

INTRODUCTION:
The novel coronavirus severe acute respiratory syndrome-CoV-2 (SARS-CoV-2) led to a global pandemic of patients with COVID-19, The clinical outcomes of patients with intracranial hemorrhage with COVID-19 are not fully known, with only small cohorts of patients with intracranial hemorrhage and comorbid COVID-19 published to date.

METHODS:
We performed a retrospective analysis using the Vizient Clinical Data Base and separately compared cohorts of patients with COVID-19 admitted April 1–October 31, 2020—patients with intracerebral hemorrhage (ICH) and those with subarachnoid hemorrhage (SAH)—with control patients with ICH or SAH who did not have COVID-19 admitted at the same hospitals in 2019. The primary outcome was in-hospital death. Favorable discharge and length of hospital and intensive-care stay were secondary outcomes.

RESULTS:
There were 559 ICH-COVID patients and 23,378 ICH controls from 194 hospitals. In the ICH-COVID cohort versus controls, there was a significantly higher proportion of Hispanic patients (24.5% vs. 8.9%), Black patients (23.3% vs. 20.9%), nonsmokers (11.5% vs. 3.2%), obesity (31.3% vs. 13.5%), and diabetes (43.4% vs. 28.5%), and patients had a longer hospital stay (21.6 vs. 10.5 days), a longer intensive-care stay (16.5 vs. 6.0 days), and a higher in-hospital death rate (46.5% vs. 18.0%). Patients with ICH-COVID had an adjusted odds ratio (aOR) of 2.43 [1.96-3.00] for the outcome of death and an aOR of 0.55 [0.44-0.68] for favorable discharge. There were 212 SAH-COVID patients and 5,029 controls from 119 hospitals. The hospital (26.9 vs. 13.4 days) and intensive-care (21.9 vs. 9.6 days) length of stays and in-hospital death rate (42.9% vs. 14.8%) were higher in the SAH-COVID cohort compared with controls. Patients with SAH-COVID had an aOR of 1.81 [1.26-2.59] for death and an aOR of 0.54 [0.37-0.78] for favorable discharge.

CONCLUSION:
Patients with spontaneous ICH or SAH and comorbid COVID infection were more likely to be a racial or ethnic minority, diabetic, and obese and had higher rates of death and longer hospital length of stay.