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OBJECTIVE Food and Drug Administration (FDA) approval for vagus nerve stimulator (VNS) implantation is limited to patients older than 4 years of age with medically refractory partial-onset seizures. In younger children with severe generalized epilepsy, however, VNS implantation remains off-label. In this study, the authors followed up on their previously reported cohort to review the longer-term safety and efficacy of VNS placement in children younger than 6 years with generalized medically refractory epilepsy (MRE), providing the largest cohort with > 2 years of follow-up to date in this age group. METHODS This was a retrospective observational cohort study of patients younger than 6 years of age with generalized MRE who underwent VNS implantation at a single institution between 2010 and 2020. Inclusion criteria encompassed failure of more than two antiepileptic drugs alone or in combination, neurologist referral for vagus nerve stimulation, informed consent with knowledge of the off-label status in young children, and > 1 year of follow-up. Outcome measures included seizure reduction rate ≥ 50% and postoperative morbidity defined nominally. Statistical analysis was conducted with Stata/SE. RESULTS Forty-five patients were included: 11 patients younger than 4 years of age and 34 between 4 and 6 years of age. There were no intraoperative complications. Perioperative complications within 1 year occurred in 11% (n = 5) of the patients and included two wound infections, a mild cough, hyperactivity, hoarseness, and 1 patient with persistent surgical site pain. A seizure reduction ≥ 50% was observed in 36.4% (n = 4) of the patients younger than 4 years of age at the 6-month and 1-, 2-, and 5-year follow-ups. In the 4- to 6-year-old cohort, this was observed in 32.4% (n = 11) of the patients at 6 months, 41.2% (n = 14) at 1 year, 38.2% (n = 13) at 2 years, and 41.2% (n = 14) at 5 years. CONCLUSIONS VNS implantation for patients younger than 4 years of age with generalized onset MRE has not been approved by the FDA. This retrospective study establishes feasibility, illustrates an acceptable safety profile in children younger than 6 years, and demonstrates efficacy comparable to that reported in older patients.

Neurosurgery (NS) is among the most selective specialties in the United States. As the United States Medical Licensing Examination (USMLE) Step 1 transitions to a binary pass/fail score, residency programs face unclear challenges in screening and evaluating applicants. The aim of this study is to provide insights into the perceived impact of changes to the USMLE Step 1 grading in the applicant selection process.We created a survey using questions regarding NS program demographics, the perceived predictive abilities of Step 1 and Step 2 clinical knowledge (CK), and several factors that programs consider when assessing applicants. We queried program directors (PDs), program coordinators (PCs), and assistant PDs at 117 NS residency programs. Respondents were asked to rank these factors in order of importance for selection at their respective training program. We used descriptive statistics and a Wilcoxon matched-pairs signed-rank test to evaluate the effects of these changes using STATA 17.A total of 35 (30%) residency programs responded with 26 (74%) completing the factor ranking questions. 86% (95% confidence interval, 71.5%-94.3%) disagreed that the changes will better prepare students clinically. USMLE Step 2 CK scores, class rank, and away rotations saw significant increases in priority in the absence of a graded Step 1, whereas letters of recommendation and surrogates for research productivity saw notable, but not significant, changes after adjusting for multiple testing.Reporting binary Step 1 grades marks a significant shift in assessing applicants for NS residency by emphasizing Step 2 CK, class rank, and research productivity.

ImportanceEndovascular thrombectomy (ET) has previously been reserved for patients with small to medium acute ischemic strokes. Three recent randomized control trials (RCTs) have demonstrated functional benefit and risk profiles for ET in large volume ischemic strokes.ObjectiveThe primary objective of the meta-analysis was to determine the combined benefit of ET in adult patients with large volume acute ischemic strokes and to better determine the risk of adverse events following ET.Data SourcesWe systematically searched MEDLINE, EMBASE, SCOPUS, the Cochrane Central Register of Controlled, and Google Scholar for all RCTs published in English language between January 1, 2010, to February 19, 2023.Study SelectionWe included only RCTs specifically comparing ET to medical therapy in patients with acute ischemic stroke with large volume infarctions as defined by Alberta Stroke Program Early Computed Tomography Score (ASPECTS) 3-5 or calculated infarct volume of > 50-70mL. Two independent reviewers screened potential studies for full text review and metaanalysis inclusion with conflicts being resolved by consensus or third reviewer.Data Extraction and SynthesisData was extracted based on pre-specified variables on study methods and design, participant characteristics, analysis approach, as well as efficacy and safety outcomes. Results were combined using a restricted maximum-likelihood estimation random-effects model. Studies were assessed for potential bias and quality of evidence.Main Outcome(s) and Measure(s)The prespecified primary outcome was an overall ordinal shift across the range of modified Rankin scale scores toward a better outcome at 90 days following either ET or medical management for patients with large volume ischemic strokes.ResultsA total of 3044 studies were screened, and 29 underwent full text review. 3 RCTs (1011 patients) were included in the analysis. The pooled random effects model for the primary outcome of mRS improvement favored ET over medical management, generalized odds ratio 1.55 [95% CI 1.25 – 1.91, T2= 0.01, I2= 42.84%]. There was a trend toward increased risk of symptomatic ICH in the ET group, relative risk 1.85 [95% CI 0.94 – 3.63, T2= 0.00, I2= 0.00%].Conclusions and RelevanceIn patients with large volume ischemic strokes, ET has a clear functional benefit and does not confer increased risk of significant complications compared to medical management alone.

Background Brain tumors are the most common solid tumors and the leading cause of cancer-related deaths in children. Incidence in the US has been on the rise for the last 2 decades. While therapeutic advances in diagnosis and treatment have improved survival and quality of life in many children, prognosis remains poor and current treatments have significant long-term sequelae. Summary There is a substantial need for the development of new therapeutic approaches, and since the introduction of immunotherapy by immune checkpoint inhibitors there has been an exponential increase in clinical trials to adopt these and other immunotherapy approaches in children with brain tumors. In this review, we summarize the current immunotherapy landscape for various pediatric brain tumor types including choroid plexus tumors, embryonal tumors (medulloblastoma, AT/RT, PNETs), ependymoma, germ cell tumors, gliomas, glioneuronal and neuronal tumors, and mesenchymal tumors. We discuss the latest clinical trials and noteworthy preclinical studies to treat these pediatric brain tumors using immune checkpoint inhibitors, cellular therapies (CAR-T, NK, T cell), oncolytic virotherapy, radioimmunotherapy, tumor vaccines, immunomodulators, and other targeted therapies. Key Messages The current landscape for immunotherapy in pediatric brain tumors is still emerging, but results in certain tumors have been promising. In the age of targeted therapy, genetic tumor profiling, and many ongoing clinical trials, immunotherapy will likely become an increasingly effective tool in the neuro-oncologist armamentarium.

Several instruments and outcomes measures have been reported in pediatric patients undergoing epilepsy surgery. The objective of this systematic review is to summarize, evaluate, and quantify outcome metrics for the surgical treatment of pediatric epilepsy that address seizure frequency, neuropsychological, and health-related quality of life (HRQL). We performed a systematic review according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to identify publications between 2010 and June 2021 from PubMed, Embase, and the Cochrane Database of Systematic Reviews that report clinical outcomes in pediatric epilepsy surgery. Eighty-one articles were included for review. Overall, rates of postoperative seizure frequency were the most common metric reported (n = 78 studies, 96%). Among the seizure frequency metrics, the Engel Epilepsy Surgery Outcome Scale (n = 48 studies, 59%) was most commonly reported. Neuropsychological outcomes, performed in 32 studies (40%) were assessed using 36 different named metrics. HRQL outcomes were performed in 16 studies (20%) using 13 different metrics. Forty-six studies (57%) reported postoperative changes in antiepileptic drug (AED) regimen, and time-to-event analysis was performed in 15 (19%) studies. Only 13 outcomes metrics (1/5 seizure frequency, 6/13 HRQL, 6/36 neuropsychological) have been validated for use in pediatric patients with epilepsy and only 13 have been assessed through reliability studies (4/5 seizure frequency, 6/13 HRQL, and 3/36 neuropsychological). Of the 81 included studies, 17 (21%) used at least one validated metric. Outcome variable metrics in pediatric epilepsy surgery are highly variable. Although nearly all studies report seizure frequency, there is considerable variation in reporting. HRQL and neuropsychological outcomes are less frequently and much more heterogeneously reported. Reliable and validated outcomes metrics should be used to increase standardization and accuracy of reporting outcomes in pediatric patients undergoing epilepsy surgery.

OBJECTIVE The optimal surgical management of Chiari malformation type I (CM-I) remains controversial and heterogeneous. The authors sought to investigate patient-specific, technical, and perioperative features that may affect the incidence of CSF-related complications including pseudomeningocele and CSF leak at their institution. METHODS The authors performed a single-center, retrospective review of all adult patients with CM-I who underwent posterior fossa decompression. Patient demographics, operative details, and perioperative factors were collected via electronic medical record review. The authors performed Fisher’s exact test and independent Student t-tests for categorical and continuous variables, respectively. Univariate regression analysis was performed to determine odds ratios. A multivariable regression analysis was performed for those factors with p < 0.10 or large effect sizes (OR ≥ 2.0 or ≤ 0.50) by univariate analysis. The STROBE guidelines for observational studies were followed. RESULTS A total of 59 adult patients were included. Most patients were female (78.0%), and the mean body mass index was 32.2 (± 9.0). Almost one-third (30.5%) of patients had a syrinx on preoperative imaging. All patients underwent expansile duraplasty, of which 47 (79.7%) were from autologous pericranium. Arachnoid opening for fourth ventricular inspection was performed in 26 (44.1%) cases. CSF-related complications were identified in 18 (30.5%) of cases. Thirteen (22.0%) patients required readmission and 11 (18.6%) required intervention such as wound revision (n = 5), wound revision with CSF diversion (n = 4), CSF diversion alone (n = 1), or blood patch (n = 1). Three (5.1%) patients required permanent CSF diversion. Male sex (OR 3.495), diabetes mellitus (OR 0.249), tobacco use (OR 2.53), body mass index more than 30 (OR 2.45), preoperative syrinx (OR 1.733), autologous duraplasty (OR 0.331), and postoperative steroids (OR 2.825) were included in the multivariable analysis. No factors achieved significance by univariate or multivariable analysis (all p > 0.05). CONCLUSIONS The authors report a single-center, retrospective experience of posterior fossa decompression for 59 adults with CM-I. No perioperative or technical features were found to affect the CSF-related complication rate. More standardized practices within centers are necessary to better delineate the true risk factors and potential protective factors against CSF-related complications.

OBJECTIVEDespite significant recent efforts applied toward the development of efficacious therapies for glioblastoma (GBM) through exploration of GBM’s genome and transcriptome, curative therapeutic strategies remain highly elusive. As such, novel and effective therapeutics are urgently required. In this study, the authors sought to explore the kinomic landscape of GBM from a previously underutilized approach (i.e., spatial heterogeneity), followed by validation of Bruton’s tyrosine kinase (BTK) targeting according to this stepwise kinomic-based novel approach.METHODSTwelve GBM tumor samples were obtained and characterized histopathologically from 2 patients with GBM. PamStation peptide-array analysis of these tissues was performed to measure the kinomic activity of each sample. The Ivy GBM database was then utilized to determine the intratumoral spatial localization of BTK activity by investigating the expression of BTK-related transcription factors (TFs) within tumors. Genetic inhibition of BTK family members through lentiviral short hairpin RNA (shRNA) knockdown was performed to determine their function in the core-like and edge-like GBM neurosphere models. Finally, the small-molecule inhibitor of BTK, ONO/GS-4059, which is currently under clinical investigation in nonbrain cancers, was applied for pharmacological inhibition of regionally specified newly established GBM edge and core neurosphere models.RESULTSKinomic investigation identified two major subclusters of GBM tissues from both patients exhibiting distinct profiles of kinase activity. Comparatively, in these spatially defined subgroups, BTK was the centric kinase differentially expressed. According to the Ivy GBM database, BTK-related TFs were highly expressed in the tumor core, but not in edge counterparts. Short hairpin RNA–mediated gene silencing of BTK in previously established edge- and core-like GBM neurospheres demonstrated increased apoptotic activity with predominance of the sub-G1 phase of core-like neurospheres compared to edge-like neurospheres. Lastly, pharmacological inhibition of BTK by ONO/GS-4059 resulted in growth inhibition of regionally derived GBM core cells and, to a lesser extent, their edge counterparts.CONCLUSIONSThis study identifies significant heterogeneity in kinase activity both within and across distinct GBM tumors. The study findings indicate that BTK activity is elevated in the classically therapy-resistant GBM tumor core. Given these findings, targeting GBM’s resistant core through BTK may potentially provide therapeutic benefit for patients with GBM.

Glioblastoma (GBM), the most common primary malignant brain tumor in adults, is associated with significant morbidity and mortality despite maximal safe resection followed by chemo- and radiotherapy. GBMs contain self-renewing, tumorigenic glioma stem cells that contribute to tumor initiation, heterogeneity, therapeutic resistance, and recurrence. Intratumoral heterogeneity (ITH) of GBMs is also a major contributing factor to poor clinical outcomes associated with these high-grade glial tumors. Herein, the authors summarize recent discoveries and advances in the molecular and phenotypic characterization of GBMs with particular focus on ITH. In so doing, they attempt to highlight recent advances in molecular signatures/properties and metabolic alterations in an effort to clarify translational implications that may ultimately improve clinical outcomes.

With a motto of "Be Worthy to Serve the Suffering," Alpha Omega Alpha Honor Medical Society (AΩA) supports the importance, inclusion, and development of a culturally and ethnically diverse medical profession with equitable access for all. The underrepresentation of minorities in medical schools and medicine continues to be a challenge for the medical profession, medical education, and AΩA. AΩA has worked, and continues to work, to ensure the development of diverse leaders, fostering within them the objectivity and equity to be inclusive servant leaders who understand and embrace diversity in all its forms.Inclusion of talented individuals from different backgrounds benefits patient care, population health, education, and scientific discovery. AΩA values an inclusive, diverse, fair, and equitable work and learning environment for all and supports the medical profession in its work to achieve a welcoming, inclusive environment in teaching, learning, caring for patients, and collaboration.The diversity of medical schools is changing and will continue to change. AΩA is committed to continuing to work with its members, medical school deans, and AΩA chapters to assure that AΩA elections are unbiased and based on the values of AΩA and the profession of medicine in service to patients and the profession.Progress toward diversity, inclusion, and equity is more than simply checking off a box or responding to criticism-it is about being and developing diverse excellent physicians. AΩA and all those in the medical profession must continue to guide medicine to be unbiased, open, accepting, inclusive, and culturally aware in order to "Be Worthy to Serve the Suffering."

BACKGROUND Gliomas are the most common primary brain tumor in adults in the US with an annual age-adjusted incidence rate (AAA-IR) of 4.67 to 5.73 per 100,000 persons. There are several sources of carcinogenic contaminants in northeast Alabama and western Georgia with the Coosa River serving as the region’s primary water source. We aimed to examine the incidence rate of glioma, as well as tumor characteristics and overall survival, in northeast Alabama compared to the rest of the state. METHODS This is a retrospective cohort study using the UAB Neuro-Oncology clinic database including adult patients ( ≥ 20 years at diagnosis) with histologically confirmed diagnosis of glioma (ICD10: 71.9) residing in the state of Alabama at the time of diagnosis between January 2015 and December 2019. We calculated AAA-IR among residents in counties intersected by the Coosa River in northeast Alabama (exposed group) compared to the rest of the state (non-exposed group). The electronic medical records of the participants were reviewed for patient demographics, insurance status, tumor grade and molecular markers, as well as the vital status. The overall survival was graphically examined using Kaplan-Meier. RESULTS A total of 660 patients were included in this study (528 non-exposed, and 132 exposed). The AAA-IR of glioma in the exposed group was 4.76 per 100,000 persons vs 3.14 per 100,000 persons in the non-exposed group with a 50 % higher incidence rate of glioma in the exposed group (RR = 1.50; 95% CI, 1.22-1.89). There was no statistically significant difference between the two groups with respect to age at diagnosis, sex, race, surgery type, tumor grade, IDH status, or overall survival. CONCLUSIONS Our findings indicate a higher incidence of glioma in northeast Alabama. Future geospatial and population-based epidemiological investigations are needed to identify possible regional environmental risk factors and examine temporal sequence.

Background Spontaneous isolated carotid artery (CA) or vertebral artery (VA) dissection in the absence of coarctation has rarely been reported in the literature. We report the case of a 20-year-old woman with Turner syndrome (TS) who developed an acute left middle cerebral artery territory ischemic stroke from a spontaneous left internal carotid artery (ICA) dissection. We also conducted a systematic review of the literature to identify prior studies establishing an association or other case reports of isolated CA or VA dissection in TS. We queried 5 databases: MEDLINE (PubMed), Scopus, Embase, Cochrane Central, and CINAHL EBSCO. We used a standardized search clause across databases. Inclusion and exclusion criteria were applied to articles retrieved. Studies were excluded based on title alone, abstract, or after vetting the data presented in the paper. Case Description Three case reports of patients with TS presenting with spontaneous intracranial and/or extracranial dissection of the ICA or VA were identified and included in this review. Conclusions We present a case of bilateral spontaneous dissection of the ICA in a patient with TS. Only 3 reported cases of spontaneous extra- or intracranial dissection of the CA or VA were identified via a systematic review of the literature. Arterial dissection of the CA or VA, especially in absence of aortic coarctation, in individuals affected with TS suggest the possibility of systemic vasculopathy. More research is needed to establish a better understanding of the phenotypic effects of TS in macro- and microvascular structures.

OBJECTIVEDespite an aggressive multimodal therapeutic regimen, glioblastoma (GBM) continues to portend a grave prognosis, which is driven in part by tumor heterogeneity at both the molecular and cellular levels. Accordingly, herein the authors sought to identify metabolic differences between GBM tumor core cells and edge cells and, in so doing, elucidate novel actionable therapeutic targets centered on tumor metabolism.METHODSComprehensive metabolic analyses were performed on 20 high-grade glioma (HGG) tissues and 30 glioma-initiating cell (GIC) sphere culture models. The results of the metabolic analyses were combined with the Ivy GBM data set. Differences in tumor metabolism between GBM tumor tissue derived from within the contrast-enhancing region (i.e., tumor core) and that from the peritumoral brain lesions (i.e., tumor edge) were sought and explored. Such changes were ultimately confirmed at the protein level via immunohistochemistry.RESULTSMetabolic heterogeneity in both HGG tumor tissues and GBM sphere culture models was identified, and analyses suggested that tyrosine metabolism may serve as a possible therapeutic target in GBM, particularly in the tumor core. Furthermore, activation of the enzyme tyrosine aminotransferase (TAT) within the tyrosine metabolic pathway influenced the noted therapeutic resistance of the GBM core.CONCLUSIONSSelective inhibition of the tyrosine metabolism pathway may prove highly beneficial as an adjuvant to multimodal GBM therapies.

Background Antimicrobial resistance is a global public health problem, particularly in low- and middle-income countries (LMICs), where antibiotics are often obtained without a prescription. H. pylori antimicrobial resistance patterns are informative for patient care and gastric cancer prevention programs, have been shown to correlate with general antimicrobial consumption, and may guide antimicrobial stewardship programs in LMICs. We report H. pylori resistance and antimicrobial utilization patterns for western Honduras, representative of rural Central America. Methods In the context of the western Honduras gastric cancer epidemiology initiative, gastric biopsies from 189 patients were studied for culture and resistance patterns. Antimicrobial utilization was investigated for common H. pylori treatment regimens from regional public (7 antimicrobials) and national private (4 antimicrobials) data, analyzed in accordance with WHO anatomical therapeutic chemical defined daily doses (DDD) method and expressed as DDD/1000 inhabitants per day (DID) and per year (DIY). Results H. pylori was successfully cultured from 116 patients (56% males, mean age: 54), and nearly all strains were cagA+ and vacAs1m1+ positive (99% and 90.4%, respectively). Unexpectedly, high resistance was noted for levofloxacin (20.9%) and amoxicillin (10.7%), while metronidazole (67.9%) and clarithromycin (11.2%) were similar to data from Latin America. Significant associations with age, gender, or histology were not noted, with the exception of levofloxacin (28%, P = 0.01) in those with histology limited to non-atrophic gastritis. Total antimicrobial usage in western Honduras of amoxicillin (17.3 DID) and the quinolones had the highest relative utilizations compared with other representative nations. Conclusions We observed significant H. pylori resistance to amoxicillin and levofloxacin in the context of high community antimicrobial utilization. This has implications in Central America for H. pylori treatment guidelines as well as antimicrobial stewardship programs.

Protein SUMOylation is a dynamic post-translational modification which is involved in a diverse set of physiologic processes throughout the cell. Of note, SUMOylation also plays a role in the pathobiology of a myriad of cancers, one of which is glioblastoma (GBM). Accordingly, herein, we review core aspects of SUMOylation as it relates to GBM and in so doing highlight putative methods/modalities capable of therapeutically engaging the pathway for treatment of this deadly neoplasm.

The objective of this study was to determine the clinical factors that are predictors for intraoperative transfusion in orthopaedic trauma patients. A retrospective chart review of patients admitted to a level I trauma center with isolated fractures was conducted. Variables such as gender, height, weight, body mass index, American Society of Anesthesiologists (ASA) classification, and medical comorbidities were assessed to determine likelihood of blood transfusion. A total of 1819 patients with isolated fractures were identified. ASA class was strongly associated with patients receiving intraoperative blood transfusion. For example, compared with patients with an ASA class I, patients with an ASA class IV were 14.71 times more likely to receive transfusion. Patients' ASA class is correlated with the need for intraoperative blood transfusion in patients undergoing orthopaedic surgery for isolated fractures. Institutional or departmental maximum surgical blood order schedule algorithms could use patients' preoperative ASA class to determine whether blood transfusion will be necessary during procedures.

Neural tube defects (NTDs) are one of the greatest causes of childhood mortality and disability-adjusted life years worldwide. Global prevalence at birth is approximately 18.6 per 10,000 live births, with more than 300,000 infants with NTDs born every year. Substantial strides have been made in understanding the genetics, pathophysiology, and surgical treatment of NTDs, yet the natural history remains one of high morbidity and profound impairment of quality of life. Direct and indirect costs of care are enormous, which ensures profound inequities and disparities in the burden of disease in countries of low and moderate resources. All indices of disease burden are higher for NTDs in developing countries. The great tragedy is that the majority of NTDs can be prevented with folate fortification of commercially produced food. Unequivocal evidence of the effectiveness of folate to reduce the incidence of NTDs has existed for more than 25 years. Yet, the most comprehensive surveys of effectiveness of implementation strategies show that more than 100 countries fail to fortify, and consequently only 13% of folate-preventable spina bifida is actually prevented. Neurosurgeons harbor a disproportionate, central, and fundamental role in the management of NTDs and enjoy high standing in society. No organized group in medicine can speak as authoritatively or convincingly. As a result, neurosurgeons and organized neurosurgery harbor disproportionate potential to advocate for more comprehensive folate fortification, and thereby prevent the most common and severe birth defect to impact the human nervous system. Assertive, proactive, informed advocacy for folate fortification should be a central and integral part of the neurosurgical approach to NTDs. Only by making the prevention of dysraphism a priority can we best address the inequities often observed worldwide.

In an era of concern over the rising cost of health care, cost-effectiveness of auxiliary services merits careful evaluation. We compared costs and benefits of Helicopter Emergency Medical Service (HEMS) with Ground Emergency Medical Service (GEMS) in patients with an isolated ankle fracture. A medical record review was conducted for patients with an isolated ankle fracture who had been transported to a level 1 trauma center by either HEMS or GEMS from January 1, 2000 to December 31, 2010. We abstracted demographic data, fracture grade, complications, and transportation mode. Transportation costs were obtained by examining medical center financial records. A total of 303 patients was included in the analysis. Of 87 (28.71%) HEMS patients, 53 (60.92%) had sustained closed injuries and 34 (39.08%) had open injuries. Of the 216 (71.29%) GEMS patients, 156 (72.22%) had closed injuries and 60 (27.78%) had open injuries. No significant difference was seen between the groups regarding the percentage of patients with open fractures or the grade of the open fracture (p = .07). No significant difference in the rate of complications was found between the 2 groups (p = 18). The mean baseline cost to transport a patient via HEMS was $10,220 + a $108/mile surcharge, whereas the mean transport cost using GEMS was $976 per patient + $16/mile. Because the HEMS mode of emergency transport did not significantly improve patient outcomes, health systems should reconsider the use of HEMS for patients with isolated ankle fractures.