bluuebunny/crossref_metadata_2025_split huggingface dataset:
459 Association Between Vitamin D Deficiency and Surgical Site Infection Following Elective Lumbar Fusions
Authors: Planchard Ryan F. , Alomari Safwan , Azad Tej D. , Feghali James , Sciubba Daniel M. , Witham Timothy F. , Theodore Nicholas , Bydon Ali 
Published: March 2022

INTRODUCTION:
Vitamin D deficiency has been associated with higher rates of SSI following a variety of surgical procedures. However, this association has been under-investigated for spinal procedures.

METHODS:
Patients who underwent lumbar fusions between 2011-2014 were reviewed from the HCUP-NIS database. Propensity score matching was utilized to minimize the effect of confounding variables between the 2 groups (normal vitamin D vs vitamin D deficiency).

RESULTS:
A total of 238,875 cases of lumbar fusions met inclusion criteria for analysis. These included posterior/transforaminal lateral interbody fusions (PLIF/TLIF), Anterior lumbar interbody fusion (ALIF) and lateral lumbar interbody fusion (LLIF). 22,454 (9.4%) patients carried the diagnosis of vitamin D deficiency and were significantly more likely to be non-white (26.5% vs. 19.9%) and obese (21.1% vs. 15.4%) as compared to patients without deficiency. Other patient characteristics, socioeconomic factors, and hospital setting were comparable between two groups. SSI rates were compared between matched cohorts (18,350 patients in each). In patients without vitamin D deficiency, there were 202 (1.1%) cases of SSI recorded, while there were 1266 (6.9%) cases of SSI recorded in patients with vitamin D deficiency (P<0.001). Patients with vitamin D deficiency had higher incidence of thromboembolic events (2.6% vs. 0.3%), length of hospital stay (5.7 vs. 3.4 days) as well as increased hospital charges (87,812$ vs. 79,650), (P <0.05).

CONCLUSION:
Optimizing preoperative vitamin D level could be potentially a cost-effective strategy to reduce the rate of SSI, thromboembolic events and prolonged hospital stay in patients undergoing lumbar fusion. Further cost-effectiveness analyses are encouraged to make definitive claims regarding pre-operative vitamin D screening/supplementation in these patients.
465 Analysis of Female Authorship Trends in Neurosurgery Over a 10-year period: 2010–2020
Authors: Shah Darsh , Kohli Vikraant , Shah Aayush , Surapaneni Akhil , Tyler-Kabara Elizabeth C. , Kuo John S. 
Published: March 2022

INTRODUCTION:
While women had greater representation in medicine in recent years, neurosurgery continues to rank towards the bottom when it comes to the proportion of women occupying a residency position in the US. Many have inferred a gender gap in the authorship of neurosurgical literature. To our knowledge, no study has analyzed changes in the representation of women among first and principal (last) authors in neurosurgery over a consecutive period.

METHODS:
Using the PUBMED search engine, all articles published from January 1st, 2010, to December 31st, 2020 in 10 prominent general and subspecialty neurosurgery journals were examined. Author gender was inferred using a verified online gender determination tool.

RESULTS:
Among the 49,023 neurosurgery articles analyzed from 2010 to 2020, 8,845 were published by a female first author, while 40,178 were published by a male first author (18.0% vs. 82.0%). Moreover, among articles with at least two authors, 5,542 were published by a female principal author, while 39,682 were published by a male principal author (12.3% vs. 87.7%). The top three publishers in terms of the proportion of female authorship (first or last author) were all subspecialty journals. Over this 10-year period, the proportion of female first authorship increased at a greater rate than female principal authorship. The rate of increase in female first authorship was greater among general neurosurgery literature compared to subspeciality neurosurgery literature. Using binomial logistic regression, articles with a female principal author were 1.72 times more likely to have a female first author than those with a male last author.

CONCLUSION:
In the past decade, woman representation in original neurosurgery literature has varied by time, subspecialty, and principal authorship gender. A gradual rise in woman authorship highlights incremental progress in gender diversity and the need for expanded efforts to achieve equity in neurosurgery research.
470 Blood-based Brain and Global Biomarker Changes Following Combined Hypoxemia and Hemorrhagic Shock in a Rat Model of Penetrating Ballistic-Like Brain Injury
Authors: Pierre Kevin , Li Xue , Yang Zhihui , Nugyen Lynn , Johnson Gabrielle , Venetucci Juliana , Torres Isabel , Lucke-Wold Brandon , Shi Yuan , Boutte Angela , Shear Deborah , Leung Lai Yee , Wang Kevin 
Published: March 2022

INTRODUCTION:
Penetrating traumatic brain injury (pTBI) often occurs with systemic insults like hemorrhagic (HS) and hypoxemic (HX) shock.

METHODS:
30 rats were randomly assigned to sham, PBBI, HS+HX, and PBBI+HS+HX groups. PBBI and sham groups underwent craniotomy with and without probe insertion and balloon expansion, respectively. HX and HS was then simulated by blood withdrawal and FiO2 reduction. Biomarker serum concentrations were determined at one (D1) and two (D2) days post-injury with ELISA methods.

RESULTS:
Axonal injury-linked biomarkers pNF-H and NF-L serum levels in PBBI groups were higher than those in sham and HX + HS groups at D1 and D2 post-injury. The same was true for PBBI + HX + HS compared to sham (D2 only for pNF-H) and HX + HS groups. However, pNF-H and NF-L levels in PBBI + HX + HS were not different than their PBBI counterparts. At D1, αII-spectrin levels in the HX + HS and PBBI + HS + HX groups were higher than the sham groups. αII-spectrin levels in the HX + HS group were higher than the PBBI group. This suggests HX + HS as the common insult driving αII-spectrin elevations.

CONCLUSION:
pNF-H and NF-L may serve as specific serum biomarkers of penetrating TBI in the presence or absence of systemic insults. αII-spectrin may be a sensitive acute biomarker in detecting systemic insults occurring alone or with pTBI.
478 Long-term Outcomes of Patients with Complications from Multi-modal Monitoring in Severe Traumatic Brain Injury
Authors: Pease Matthew , Nwachuku Enyinna , Goldschmidt Ezequiel , Jacobs Rachel , Elmer Jonathan , Okonkwo David O. 
Published: March 2022

INTRODUCTION:
Insertion of an external ventricular drain or intracranial pressure monitor is one of the most commonly performed neurosurgical procedures. Multi-modal invasive neuromonitoring (IN) is a mainstay of modern management of severe traumatic brain injury (TBI). Complication rates of IN placement are widely reported, but their effects on long-term outcomes following severe TBI are less studied.

METHODS:
We evaluated 599 patients with a severe TBI from November 2002 through December 2018 for IN-associated hemorrhage and infection. Trained neuropsychologists assessed outcomes at 3, 6, 12, and 24 months using the Glasgow Outcome Scale (GOS). We compared GOS between patients with and without IN-associated complications.

RESULTS:
IN-associated hemorrhage occurred in 62 patients out of 535 with post-placement CT scans (12%). Craniotomy was associated with increased risk for hemorrhage after monitor placement (53% vs 28%, p<0.001). Clinical outcomes did not differ in patients with IN-associated hemorrhage compared to those without. IN-associated infection occurred in 34 (7%) of 519 patients with post-IN placement cerebrospinal fluid cultures. Infection was associated with worse outcomes at 3 months (p=0.03), where the proportion of patients with favorable outcomes (p = 0.02) was decreased despite similar mortality (p = 0.24). Patients with an IN-related infection recovered by 6 months, at which point there were no differences in total GOS score or rates of favorable outcomes then or at later time points (p > 0.26). Patients with IN-associated infection trended towards improved outcomes over time with no patients with a GOS 3 or higher at 3 months falling below GOS 3 at a later point. IN-associated infection was associated with increased length of stay (p=0.01), but did not affect rates of shunting (p=0.99).

CONCLUSION:
Complications of IN in severe TBI are associated with delayed recovery but not long-term outcomes.
487 The Human Anti-Ganglioside GM1 Autoantibody Response Following Traumatic and Surgical Central Nervous System Insults
Authors: Roukerd Maryam R. , Schneider Lonnie , Hawryluk Gregory W. J. , Faulkner Jenna , Reichert Ethan , Flis Alexandra , Abou-Al-Shaar Hussam , Rubiano Andres M. 
Published: March 2022

INTRODUCTION:
The immune response to central nervous system (CNS) injuries has long been considered a significant contributor to secondary injury following neurotrauma however the autoimmune response to the normal immune-privileged CNS has been insufficiently considered. It has been identified as a possible pathomechanism underlying delayed dementias known to occur after TBI and SCI however the CNS-directed autoantibody response following CNS injury remains poorly understood and the autoimmune response following intra-axial brain surgery is unknown.

METHODS:
Nine serum samples were collected serially from 17 acute severe TBI, 22 acute SCI, and 24 intra-axial brain tumor resection patients for 30 days; 25 healthy subjects served as a control group. An ELISA assay quantitated IgG and IgM autoantibodies to ganglioside GM-1. The maximum autoantibody titers and their correlation with putative predictors such as age, gender, clinical and radiological measurements were investigated.

RESULTS:
Anti-GM1 IgG autoantibody titers were increased following SCI, TBI, and brain tumor resection as compared with baseline values and control patients. By contrast, anti-GM1 IgM autoantibody titers did not significantly change following insult nor show promise as a biomarker. The maximum IgG titers measured in the first 30 days were significantly increased in TBI patients (p<0.01), in SCI patients (p<0.01), and in brain tumor resection patients (p<0.05). The highest IgG titers (or peaks) were most commonly seen at day 14 post-insult in TBI and SCI patients while brain tumor patients did not demonstrate acute increases consistent with a peak. Higher GM1 IgG autoantibodies were associated with more severe insults. The Rotterdam score strongly correlated with increased IgG titers in TBI patients (p<0.05). Age and gender did not correlate with GM1 autoantibody titers in any of the types of insult we studied.

CONCLUSION:
These findings suggest that patients with diverse CNS insults are at risk for CNS-directed autoimmune responses and in particular those with more severe insults. These findings highlight the need to better understand the CNS-directed autoimmune response to insult, its clinical relevance and potential as a therapeutic target.
488 Superiority of Craniotomy Over Supportive Care for Octogenarians and Nonagenarians in Operable Acute Traumatic Subdural Hematoma
Authors: Duehr James , Puccio Ava , Deng Hansen , Hamilton D. Kojo , Okonkwo David O. , Nwachuku Enyinna L. 
Published: March 2022

INTRODUCTION:
The neurosurgical evacuation acute subdural hematoma in elderly trauma patients is controversial. We analyzed impact of craniotomy for acute subdural hematoma on survival in patients greater than eighty years of age.

METHODS:
Study population included patients aged 80 years and older who presented with acute traumatic SDHs between September 1, 2015 and January 1, 2020, and had radiographic findings indicating operative eligibility (i.e. midline shift >5mm and/or overall thickness >10mm). 104 patients met inclusion criteria. 35 received craniotomy and 69 were treated with supportive measures due to family/patient wishes or surgeon’s professional decision. Comparative statistics and a Poisson regression adjusted for the influence of covariates were used.

RESULTS:
Of 35 craniotomy patients, 21 (60.00%) were deceased at 2 years of follow-up, compared to 48 (69.57%) deceased out of 69 control patients. No significant demographic differences existed between the two groups, other than age (craniotomy patients were younger; median age 84 vs 86; p < 0.001). In outcomes, the craniotomy cohort survived longer and in higher proportions (p = 0.028; Gehan-Breslow-Wilcoxon test). When adjusting for covariates, this effect became more pronounced: surgical patients died at 41.1% the rate of non-surgical ones. Of all the covariates, only initial GCS had a significant impact on the protective effect of craniotomy. In a logarithmic relationship, each point higher on initial GCS was associated with less benefit from surgery.

CONCLUSION:
The results presented here indicate a surgical benefit for this elderly cohort, consistent with prior findings of benefit in the setting of severe traumatic aSDH. Patients with worse neurologic impairment, i.e. low GCS, had the greatest survival benefit for surgical intervention.
495 5-ALA PDT and Targeting MEK/ERK Signaling Elicits Synergistic Antitumor Effects in Diffuse Midline Glioma
Authors: Price Gabrielle , Rivera Daniel , Bouras Alexandros , Hadjipanayis Constantinos G. 
Published: March 2022

INTRODUCTION:
Diffuse midline gliomas are highly invasive, unresectable tumors in children. To date, there is no effective treatment for DMG. Concurrent radiotherapy (RT) and systemic therapies, the standard of care, has only been successful in providing limited disease control. The major obstacle to therapy is the selectively permeable blood brain barrier (BBB) that limits systemic drug delivery. Given the unmet need for penetrant and minimally invasive DMG treatments, photodynamic therapy (PDT), with the precursor photosensitizing agent 5-aminolevulinic acid (5-ALA), is an oncologic treatment that holds promise. 5-ALA PDT of tumors occurs by targeting tumor cells that accumulate the 5-ALA metabolite, protoporphyrin IX (PPIX), with 635 nm light to create deadly reactive oxygen species (ROS).

METHODS:
Growth delay assays were conducted for each individual treatment modality or in combination. FDA-approved MEK/ERK inhibitors were administered to mice with aggressive heterotopic allograft DMGs through intraperitoneal injection. Ex vivo immunofluorescence staining was performed on those mice that received 5-ALA PDT treatment.

RESULTS:
We demonstrated that sub-micromolar levels of 5-ALA PDT and nanomolar levels of MEK inhibitor successfully decrease cell proliferation and induce apoptosis in DMG cell lines. Cell viability assays revealed that drug response differs based on the histone mutation (H3.1 or H3.3) of the line. Mechanisms of decreased cell survival involves the generation of reactive oxygen species that induces programmed cell death. Through the use of a DMG genetically engineered mouse model, we also found 5-ALA PDT to induce apoptosis in vivo.

CONCLUSION:
The synergistic effects of MEK inhibition and 5-ALA PDT in vitro and apoptotic effects of 5-ALA PDT in vivo, highlights the potential therapeutic efficacy of this treatment modality.
498 Assessing Knowledge Silos in the Craniosynostosis Literature
Authors: Motiwala Mustafa , Kumar Rahul , Amro Amro , Himel Sean , Motiwala Ahmed , Kazmi Shehroz , Klimo Paul 
Published: March 2022

INTRODUCTION:
The surgical treatment of craniosynostosis has traditionally been a multidisciplinary effort, involving pediatric neurosurgeons and plastic surgeons. Advances in treating this condition may result from collaboration between these two specialties, yet there exists a certain risk of sequestering clinical knowledge between the two which may limit continued progress in this regard.

METHODS:
During September 2020, the Scopus database was queried to identify journal articles related to craniosynostosis. Bibliometric measures were collected for each article, and a database was constructed to assess knowledge sharing between neurosurgeons and plastic surgeons.

RESULTS:
5335 articles were identified. 720 (13.5%) were published in a neurosurgery journal with 499 (9.4%) published by neurosurgeons and 665 (12.5%) by neurosurgeons and plastic surgeons collaborating together. As expected, neurosurgeons published primarily (319, 63.9%) in neurosurgical journals, whereas plastic surgeons published most in plastic surgery journals (990, 65.7%). Collaborations were mostly published in plastic surgery journals (326, 49%). After normalizing for years in press, neurosurgeons were observed to be cited significantly less than plastic surgeons (p <0.0001), and articles published in neurosurgery journals were cited at a lower rate than those published in plastic surgery journals. The differential association of terms used in plastic surgery versus neurosurgery article abstracts illustrates the potential sites of knowledge silo formation in the craniosynostosis literature.

CONCLUSION:
This study demonstrates that a distinct sequestering of knowledge exists between neurosurgeons and plastic surgeons publishing on the topic. Publications by plastic surgeons are more highly cited than by neurosurgeons. While there are certainly specialty-based topics within craniosynostosis, we recommend continued collaboration on all research fronts to avoid sequestration of knowledge and progress.
502 Spy1 as a Novel Cell Cycle Target Against Medulloblastoma
Authors: Habashy Philip , Jassar Samer , Lubanska Dorota , Soliman Mohamed , Porter Lisa 
Published: March 2022

INTRODUCTION:
The current treatment strategies for medulloblastoma (MB) are highly aggressive, cytotoxic, and ultimately unsuccessful. One recent therapeutic approach is the use of synthetic cyclin-dependent kinase inhibitors (CKIs). Speedy (Spy1) is a cyclin-like protein that primes its complexes with CDKs insensitive to natural CKIs and promotes uncontrolled cell proliferation by overriding the safety cell cycle checkpoints. Spy1 has been implicated in the expansion of stem-like populations of therapy-resistant tumour initiating cells (TICs) in neural systems.

METHODS:
We established an in vitro neurosphere platform as well as in vivo high-throughput Zebrafish (ZF) xenograft model using ONS-76 and DAOY MB cell lines derived from three patients. Fluorescent Activated Cell Sorting (FACS) was used to enrich for specific CD133+/- or CD15 +/- populations of MB. Spy1 levels were manipulated using lentivirus to obtain overexpression or knockdown of Spy1 protein levels in the derived TICs as well as heterogenous cell populations.

RESULTS:
We found that downregulation of Spy1 levels in the employed cell lines resulted in a decrease in neurospheres formation efficiency as well as significantly lower tumour burden in Zebrafish when compared to control (p<0.001). Spy1 overexpression in CD133 or CD15 negative MB populations resulted in the upregulation of Msi1 mRNA levels. Finally, in vivo treatment of ZF xenografts with R-roscovitine, a synthetic CKI, demonstrated declined migration of Spy1 KD MB cells in comparison to control cells (p<0.05).

CONCLUSION:
This study shows that Spy1 plays a role in the regulation of stemness and aggressive characteristics of TICs in medulloblastoma. The assessed effect on CKI treatment efficacy on the tumours in vivo demonstrated that downregulation of Spy1 may sensitize, at least a subset of MB, to therapy. This work may contribute toward optimizing the design of CKIs and their use in combination therapy for patients with MB.
508 Syngeneic Pair-wise Transcriptomic/Epigenomic Analysis of Sporadic Cushing’s Adenomas and Adjacent Gland Reveals Novel Tumorigenic Pathways
Authors: Asuzu David , Alvarez Reinier , Fletcher Patrick , Mandal Debjani , Chittiboina Prashant 
Published: March 2022

INTRODUCTION:
Sporadic pituitary adenomas are found in more than 10% of the general population and are mutationally bland. The normal human pituitary transcriptome is unknown, precluding syngeneic studies on Cushing's disease (CD) pathogenesis.

METHODS:
We surgically annotated adenomas and adjacent normal glands and performed single cell RNAseq (scRNAseq; 10X Genomics Chromium 3’) on 28,724 cells from 6 patients (3 CD and 3 non-CD). We performed bulk RNAseq (Illumina Nextseq) in 7 patients (5 CD and 2 non-CD) and DNA methylation analysis (Illumina Infinium MethylEPIC 850k) in 6 patients (3 CD and 3 non-CD). Transcriptomic/epigenomic data were analyzed using R packages and custom Python pipelines for pairwise differential expression analyses.

RESULTS:
We mapped the post-natal human pituitary gland at single cell resolution and identified canonical resident pituitary cell classes. Corticotrophs were abundant within CD adenomas but rare in the surrounding normal gland, with downregulated POMC expression consistent with repression in the hypercortisolemic state. CD corticotrophs overexpressed signature genes PCSK1, PPP1R17, EGLN, RSPO3 and PMAIP1 compared to surrounding tissues. This gene signature was specific for core adenomas and correlated with anatomic demarcation at the time of surgery. We confirmed overexpression of PCSK1, PPP1R17, RSPO3 and PMAIP1 by independent RNAseq. We identified hypomethylation at the promoters of PMAIP1, PPP1R17 and RSPO3 but not PCSK1 or EGLN1 in CD adenomas.

CONCLUSION:
We mapped the transcriptome of the adult human pituitary gland, identified novel signature genes for CD and highlighted DNA methylation as an epigenetic mechanism of transcriptional activation in a number of Cushing’s adenoma signature genes. We provide novel, targetable mechanistic pathways for therapeutic intervention in Cushing’s disease.
513 Surveilling Cerebrospinal Fluid Protein Biomarkers in Brain Metastasis
Authors: Cheok Stephanie , Arnal-Estape Anna , Wei Wei , Nguyen Don , Chiang Veronica 
Published: March 2022

INTRODUCTION:
Cerebrospinal fluid (CSF) is in constant and direct contact with the brain parenchyma, vessels and meninges. The distribution and relative isolation of CSF makes it valuable in the evaluation of central nervous system pathologies. CSF protein profiling has been widely studied in neuro-degenerative and inflammatory diseases. This analysis may also be relevant in patients with brain metastases.

METHODS:
Patients were enrolled between May 2017 and March 2020 under an IRB protocol. CSF and plasma were processed and stored at -80°C. Concentrations of 142 soluble proteins were quantified by Luminex (Eve Technologies).

RESULTS:
Seventy-four patients were included in this study. Of the 60 patients with brain metastases, most had lung cancer (N=29), melanoma (N=10) and breast cancer (N=7). Non-malignant samples included normal pressure hydrocephalus (NPH, N=5), CSF leak (N=9) and radiation necrosis (N=9). Of the 142 soluble proteins profiled, 44 were significantly elevated in patients with LMD compared to intraparenchymal disease. None were more elevated in intraparenchymal disease. This finding was not replicated in the plasma. The CSF profile of patients with LMD and NPH were highly similar.

CONCLUSION:
Soluble CSF proteins are detectable in patients with brain metastases and concentrations differ based on extent of intracranial disease. This difference was not seen in plasma. These findings suggest that patients with LMD have a protein signature, different from those with intraparenchymal brain metastases only, which can help augment current diagnostic standards and reflect the tumor microenvironment. The similarity of LMD and NPH CSF proposes a similar pathogenesis and warrants further exploration. Further analysis of clinical data including survival and treatment response may assist in the management of patients with brain metastases.