Browsing by Author "Grant, Gerald A"
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Item Open Access A prospective neurosurgical registry evaluating the clinical care of traumatic brain injury patients presenting to Mulago National Referral Hospital in Uganda.(PloS one, 2017-01) Kuo, Benjamin J; Vaca, Silvia D; Vissoci, Joao Ricardo Nickenig; Staton, Catherine A; Xu, Linda; Muhumuza, Michael; Ssenyonjo, Hussein; Mukasa, John; Kiryabwire, Joel; Nanjula, Lydia; Muhumuza, Christine; Rice, Henry E; Grant, Gerald A; Haglund, Michael MBackground
Traumatic Brain Injury (TBI) is disproportionally concentrated in low- and middle-income countries (LMICs), with the odds of dying from TBI in Uganda more than 4 times higher than in high income countries (HICs). The objectives of this study are to describe the processes of care and determine risk factors predictive of poor outcomes for TBI patients presenting to Mulago National Referral Hospital (MNRH), Kampala, Uganda.Methods
We used a prospective neurosurgical registry based on Research Electronic Data Capture (REDCap) to systematically collect variables spanning 8 categories. Univariate and multivariate analysis were conducted to determine significant predictors of mortality.Results
563 TBI patients were enrolled from 1 June- 30 November 2016. 102 patients (18%) received surgery, 29 patients (5.1%) intended for surgery failed to receive it, and 251 patients (45%) received non-operative management. Overall mortality was 9.6%, which ranged from 4.7% for mild and moderate TBI to 55% for severe TBI patients with GCS 3-5. Within each TBI severity category, mortality differed by management pathway. Variables predictive of mortality were TBI severity, more than one intracranial bleed, failure to receive surgery, high dependency unit admission, ventilator support outside of surgery, and hospital arrival delayed by more than 4 hours.Conclusions
The overall mortality rate of 9.6% in Uganda for TBI is high, and likely underestimates the true TBI mortality. Furthermore, the wide-ranging mortality (3-82%), high ICU fatality, and negative impact of care delays suggest shortcomings with the current triaging practices. Lack of surgical intervention when needed was highly predictive of mortality in TBI patients. Further research into the determinants of surgical interventions, quality of step-up care, and prolonged care delays are needed to better understand the complex interplay of variables that affect patient outcome. These insights guide the development of future interventions and resource allocation to improve patient outcomes.Item Open Access An epigenome-wide association study of posttraumatic stress disorder in US veterans implicates several new DNA methylation loci.(Clinical epigenetics, 2020-03) Logue, Mark W; Miller, Mark W; Wolf, Erika J; Huber, Bertrand Russ; Morrison, Filomene G; Zhou, Zhenwei; Zheng, Yuanchao; Smith, Alicia K; Daskalakis, Nikolaos P; Ratanatharathorn, Andrew; Uddin, Monica; Nievergelt, Caroline M; Ashley-Koch, Allison E; Baker, Dewleen G; Beckham, Jean C; Garrett, Melanie E; Boks, Marco P; Geuze, Elbert; Grant, Gerald A; Hauser, Michael A; Kessler, Ronald C; Kimbrel, Nathan A; Maihofer, Adam X; Marx, Christine E; Qin, Xue-Jun; Risbrough, Victoria B; Rutten, Bart PF; Stein, Murray B; Ursano, Robert J; Vermetten, Eric; Vinkers, Christiaan H; Ware, Erin B; Stone, Annjanette; Schichman, Steven A; McGlinchey, Regina E; Milberg, William P; Hayes, Jasmeet P; Verfaellie, Mieke; Traumatic Stress Brain Study GroupBackground
Previous studies using candidate gene and genome-wide approaches have identified epigenetic changes in DNA methylation (DNAm) associated with posttraumatic stress disorder (PTSD).Methods
In this study, we performed an EWAS of PTSD in a cohort of Veterans (n = 378 lifetime PTSD cases and 135 controls) from the Translational Research Center for TBI and Stress Disorders (TRACTS) cohort assessed using the Illumina EPIC Methylation BeadChip which assesses DNAm at more than 850,000 sites throughout the genome. Our model included covariates for ancestry, cell heterogeneity, sex, age, and a smoking score based on DNAm at 39 smoking-associated CpGs. We also examined in EPIC-based DNAm data generated from pre-frontal cortex (PFC) tissue from the National PTSD Brain Bank (n = 72).Results
The analysis of blood samples yielded one genome-wide significant association with PTSD at cg19534438 in the gene G0S2 (p = 1.19 × 10-7, padj = 0.048). This association was replicated in an independent PGC-PTSD-EWAS consortium meta-analysis of military cohorts (p = 0.0024). We also observed association with the smoking-related locus cg05575921 in AHRR despite inclusion of a methylation-based smoking score covariate (p = 9.16 × 10-6), which replicates a previously observed PGC-PTSD-EWAS association (Smith et al. 2019), and yields evidence consistent with a smoking-independent effect. The top 100 EWAS loci were then examined in the PFC data. One of the blood-based PTSD loci, cg04130728 in CHST11, which was in the top 10 loci in blood, but which was not genome-wide significant, was significantly associated with PTSD in brain tissue (in blood p = 1.19 × 10-5, padj = 0.60, in brain, p = 0.00032 with the same direction of effect). Gene set enrichment analysis of the top 500 EWAS loci yielded several significant overlapping GO terms involved in pathogen response, including "Response to lipopolysaccharide" (p = 6.97 × 10-6, padj = 0.042).Conclusions
The cross replication observed in independent cohorts is evidence that DNA methylation in peripheral tissue can yield consistent and replicable PTSD associations, and our results also suggest that that some PTSD associations observed in peripheral tissue may mirror associations in the brain.Item Open Access Athlete Enjoyment of Prior Education Moderates change in Concussion-Reporting Intention after Interactive Education.(Inquiry : a journal of medical care organization, provision and financing, 2021-01) Daneshvar, Daniel H; Baugh, Christine M; Yutsis, Maya; Pea, Roy D; Goldman, Shelley; Grant, Gerald A; Cantu, Robert C; Sanders, Lee M; Chen, Christine L; Lama, Roberto D; Zafonte, Ross D; Sorcar, PiyaUndiagnosed concussions increase risk of additional injuries and can prolong recovery. Because of the difficulties recognizing concussive symptoms, concussion education must specifically target improving athlete concussion reporting. Many concussion education programs are designed without significant input from athletes, resulting in a less enjoyable athlete experience, with potential implications on program efficacy. Athlete enjoyment of previous concussion education programs moderates the improvement in concussion-reporting intention after experiencing the research version of CrashCourse (CC) concussion education. Prospective cohort study. Level of evidence: Level IV. Quantitative assessment utilizing ANOVA with moderation analysis of 173 male high school football players, aged 13 to 17, who completed baseline assessments of concussion knowledge, concussion reporting, and attitudes about prior educational interventions. Athletes were subsequently shown CC, before a follow-up assessment was administered assessing the same domains. At baseline, only 58.5% of athletes reported that they enjoyed their previous concussion education. After CC, athletes were significantly more likely to endorse that they would report a suspected concussion (from 69.3% of athletes to 85.6%; P < .01). Enjoyment of previous concussion education moderated concussion-reporting intention after CC (P = .02), with CC having a greater effect on concussion-reporting intention in athletes with low enjoyment of previous concussion education (b = 0.21, P = .02), than on individuals with high enjoyment of previous concussion education (P = .99). Enjoyment of CC did not have a moderating effect on concussion-reporting intention. Athletes who previously did not enjoy concussion education exhibited greater gains in concussion-reporting intention than athletes who enjoyed previous education. Given the potential risks associated with undiagnosed concussions, concussion education has sought to improve concussion reporting. Because most athletes participate in concussion education programs due to league or state mandates, improving concussion-reporting intention in these low-enjoyment athletes is of particular relevance to improving concussion-reporting intention broadly.Item Open Access Clinical Features, Neuropathology, and Surgical Outcome in Patients With Refractory Epilepsy and Brain Somatic Variants in the SLC35A2 Gene.(Neurology, 2023-01) Barba, Carmen; Blumcke, Ingmar; Winawer, Melodie R; Hartlieb, Till; Kang, Hoon-Chul; Grisotto, Laura; Chipaux, Mathilde; Bien, Christian G; Heřmanovská, Barbora; Porter, Brenda E; Lidov, Hart GW; Cetica, Valentina; Woermann, Friedrich G; Lopez-Rivera, Javier A; Canoll, Peter D; Mader, Irina; D'Incerti, Ludovico; Baldassari, Sara; Yang, Edward; Gaballa, Ahmed; Vogel, Hannes; Straka, Barbora; Macconi, Letizia; Polster, Tilman; Grant, Gerald A; Krsková, Lenka; Shin, Hui Jin; Ko, Ara; Crino, Peter B; Krsek, Pavel; Lee, Jeong Ho; Lal, Dennis; Baulac, Stéphanie; Poduri, Annapurna; Guerrini, Renzo; SLC35A2 Study GroupBackground and objectives
The SLC35A2 gene, located at chromosome Xp11.23, encodes for a uridine diphosphate-galactose transporter. We describe clinical, genetic, neuroimaging, EEG, and histopathologic findings and assess possible predictors of postoperative seizure and cognitive outcome in 47 patients with refractory epilepsy and brain somatic SLC35A2 gene variants.Methods
This is a retrospective multicenter study where we performed a descriptive analysis and classical hypothesis testing. We included the variables of interest significantly associated with the outcomes in the generalized linear models.Results
Two main phenotypes were associated with brain somatic SLC35A2 variants: (1) early epileptic encephalopathy (EE, 39 patients) with epileptic spasms as the predominant seizure type and moderate to severe intellectual disability and (2) drug-resistant focal epilepsy (DR-FE, 8 patients) associated with normal/borderline cognitive function and specific neuropsychological deficits. Brain MRI was abnormal in all patients with EE and in 50% of those with DR-FE. Histopathology review identified mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy in 44/47 patients and was inconclusive in 3. The 47 patients harbored 42 distinct mosaic SLC35A2 variants, including 14 (33.3%) missense, 13 (30.9%) frameshift, 10 (23.8%) nonsense, 4 (9.5%) in-frame deletions/duplications, and 1 (2.4%) splicing variant. Variant allele frequencies (VAFs) ranged from 1.4% to 52.6% (mean VAF: 17.3 ± 13.5). At last follow-up (35.5 ± 21.5 months), 30 patients (63.8%) were in Engel Class I, of which 26 (55.3%) were in Class IA. Cognitive performances remained unchanged in most patients after surgery. Regression analyses showed that the probability of achieving both Engel Class IA and Class I outcomes, adjusted by age at seizure onset, was lower when the duration of epilepsy increased and higher when postoperative EEG was normal or improved. Lower brain VAF was associated with improved postoperative cognitive outcome in the analysis of associations, but this finding was not confirmed in regression analyses.Discussion
Brain somatic SLC35A2 gene variants are associated with 2 main clinical phenotypes, EE and DR-FE, and a histopathologic diagnosis of MOGHE. Additional studies will be needed to delineate any possible correlation between specific genetic variants, mutational load in the epileptogenic tissue, and surgical outcomes.Item Open Access Cortical stimulation mapping for localization of visual and auditory language in pediatric epilepsy patients.(Journal of neurosurgery. Pediatrics, 2019-11-08) Muh, Carrie R; Chou, Naomi D; Rahimpour, Shervin; Komisarow, Jordan M; Spears, Tracy G; Fuchs, Herbert E; Serafini, Sandra; Grant, Gerald AOBJECTIVE:To determine resection margins near eloquent tissue, electrical cortical stimulation (ECS) mapping is often used with visual naming tasks. In recent years, auditory naming tasks have been found to provide a more comprehensive map. Differences in modality-specific language sites have been found in adult patients, but there is a paucity of research on ECS language studies in pediatric patients. The goals of this study were to evaluate word-finding distinctions between visual and auditory modalities and identify which cortical subregions most often contain critical language function in a pediatric population. METHODS:Twenty-one pediatric patients with epilepsy or temporal lobe pathology underwent ECS mapping using visual (n = 21) and auditory (n = 14) tasks. Fisher's exact test was used to determine whether the frequency of errors in the stimulated trials was greater than the patient's baseline error rate for each tested modality and subregion. RESULTS:While the medial superior temporal gyrus was a common language site for both visual and auditory language (43.8% and 46.2% of patients, respectively), other subregions showed significant differences between modalities, and there was significant variability between patients. Visual language was more likely to be located in the anterior temporal lobe than was auditory language. The pediatric patients exhibited fewer parietal language sites and a larger range of sites overall than did adult patients in previously published studies. CONCLUSIONS:There was no single area critical for language in more than 50% of patients tested in either modality for which more than 1 patient was tested (n > 1), affirming that language function is plastic in the setting of dominant-hemisphere pathology. The high rates of language function throughout the left frontal, temporal, and anterior parietal regions with few areas of overlap between modalities suggest that ECS mapping with both visual and auditory testing is necessary to obtain a comprehensive language map prior to epileptic focus or tumor resection.Item Open Access Early Effects of COVID-19 Pandemic on Neurosurgical Training in the United States: A Case Volume Analysis of 8 Programs.(World neurosurgery, 2021-01) Aljuboori, Zaid S; Young, Christopher C; Srinivasan, Visish M; Kellogg, Ryan T; Quon, Jennifer L; Alshareef, Mohammed A; Chen, Stephanie H; Ivan, Michael; Grant, Gerald A; McEvoy, Sean D; Davanzo, Justin R; Majid, Sonia; Durfy, Sharon; Levitt, Michael R; Sieg, Emily P; Ellenbogen, Richard G; Nauta, Haring JObjective
To determine the impact of the 2019 novel coronavirus disease (COVID-19) pandemic on operative case volume in 8 U.S. neurosurgical residency training programs in early 2020 and to survey these programs regarding training activities during this period.Methods
A retrospective review was conducted of monthly operative case volumes and types for 8 residency programs for 2019 and January through April 2020. Cases were grouped as elective cranial, elective spine, and nonelective emergent cases. Programs were surveyed regarding residents' perceptions of the impact of COVID-19 on surgical training, didactics, and research participation. Data were analyzed for individual programs and pooled across programs.Results
Across programs, the 2019 monthly mean ± SD case volume was 211 ± 82; 2020 mean ± SD case volumes for January, February, March, and April were 228 ± 93, 214 ± 84, 180 ± 73, and 107 ± 45. Compared with 2019, March and April 2020 mean cases declined 15% (P = 0.003) and 49% (P = 0.002), respectively. COVID-19 affected surgical case volume for all programs; 75% reported didactics negatively affected, and 90% reported COVID-19 resulted in increased research time. Several neurosurgery residents required COVID-19 testing; however, to our knowledge, only 1 resident from the participating programs tested positive.Conclusions
This study documents a significant reduction in operative volume in 8 neurosurgery residency training programs in early 2020. During this time, neurosurgery residents engaged in online didactics and research-related activities, reporting increased research productivity. Residency programs should collect data to determine the educational impact of the COVID-19 pandemic on residents' operative case volumes, identify deficiencies, and develop plans to mitigate any effects.Item Open Access Expanding eligibility for intracranial electroencephalography using Dexmedetomidine Hydrochloride in children with behavioral dyscontrol.(Epilepsy & behavior : E&B, 2023-11) Johnstone, Thomas; Isabel Barros Guinle, Maria; Grant, Gerald A; Porter, Brenda EIntroduction
Invasive intracranial electroencephalography (IEEG) is advantageous for identifying epileptogenic foci in pediatric patients with medically intractable epilepsy. Patients with behavioral challenges due to autism, intellectual disabilities, and hyperactivity have greater difficulty tolerating prolonged IEEG recording and risk injuring themselves or others. There is a need for therapies that increase the safety of IEEG but do not interfere with IEEG recording or prolong hospitalization. Dexmedetomidine Hydrochloride's (DH) use has been reported to improve safety in patients with behavioral challenges during routine surface EEG recording but has not been characterized during IEEG. Here we evaluated DH administration in pediatric patients undergoing IEEG to assess its safety and impact on the IEEG recordings.Methods
A retrospective review identified all pediatric patients undergoing IEEG between January 2016 and September 2022. Patient demographics, DH administration, DH dose, hospital duration, and IEEG seizure data were analyzed. The number of seizures recorded for each patient was divided by the days each patient was monitored with IEEG. The total number of seizures, as well as seizures per day, were compared between DH and non-DH patients via summary statistics, multivariable linear regression, and univariate analysis. Other data were compared across groups with univariate statistics.Results
Eighty-four pediatric patients met the inclusion criteria. Eighteen (21.4 %) received DH treatment during their IEEG recording. There were no statistical differences between the DH and non-DH groups' demographic data, length of hospital stays, or seizure burden. Non-DH patients had a median age of 12.0 years (interquartile range: 7.25-15.00), while DH-receiving patients had a median age of 8.0 years old (interquartile range: 3.00-13.50) (p = 0.07). The non-DH cohort was 57.6 % male, and the DH cohort was 50.0 % male (p = 0.76). The median length of IEEG recordings was 5.0 days (interquartile range: 4.00-6.25) for DH patients versus 6.0 days (interquartile range: 4.00-8.00) for non-DH patients (p = 0.25). Median total seizures recorded in the non-DH group was 8.0 (interquartile range: 5.00-13.25) versus 15.0 in the DH group (interquartile range: 5.00-22.25) (p = 0.33). Median total seizures per day of IEEG monitoring were comparable across groups: 1.50 (interquartile range: 0.65-3.17) for non-DH patients compared to 2.83 (interquartile range: 0.89-4.35) (p = 0.25) for those who received DH. Lastly, non-DH patients were hospitalized for a median of 8.0 days (interquartile range: 6.00-11.25), while DH patients had a median length of stay of 7.00 days (interquartile range: 5.00-8.25) (p = 0.27). No adverse events were reported because of DH administration.Conclusions
Administration of DH was not associated with adverse events. Additionally, the frequency of seizures captured on the IEEG, as well as the duration of hospitalization, were not significantly different between patients receiving and not receiving DH during IEEG. Incorporating DH into the management of patients with behavioral dyscontrol and intractable epilepsy may expand the use of IEEG to patients who previously could not tolerate it, improve safety, and preserve epileptic activity during the recording period.Item Open Access Factors for Differential Outcome Across Cancers in Clinical Molecule-Targeted Fluorescence Imaging.(Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 2022-11) Zhou, Quan; van den Berg, Nynke S; Kang, Wenying; Pei, Jacqueline; Nishio, Naoki; van Keulen, Stan; Engelen, Myrthe A; Lee, Yu-Jin; Hom, Marisa; Vega Leonel, Johana CM; Hart, Zachary; Vogel, Hannes; Cayrol, Romain; Martin, Brock A; Roesner, Mark; Shields, Glenn; Lui, Natalie; Gephart, Melanie Hayden; Raymundo, Roan C; Yi, Grace; Granucci, Monica; Grant, Gerald A; Li, Gordon; Rosenthal, Eben LClinical imaging performance using a fluorescent antibody was compared across 3 cancers to elucidate physical and biologic factors contributing to differential translation of epidermal growth factor receptor (EGFR) expression to macroscopic fluorescence in tumors. Methods: Thirty-one patients with high-grade glioma (HGG, n = 5), head-and-neck squamous cell carcinoma (HNSCC, n = 23), or lung adenocarcinoma (LAC, n = 3) were systemically infused with 50 mg of panitumumab-IRDye800 1-3 d before surgery. Intraoperative open-field fluorescent images of the surgical field were acquired, with imaging device settings and operating room lighting conditions being tested on tissue-mimicking phantoms. Fluorescence contrast and margin size were measured on resected specimen surfaces. Antibody distribution and EGFR immunoreactivity were characterized in macroscopic and microscopic histologic structures. The integrity of the blood-brain barrier was examined via tight junction protein (Claudin-5) expression with immunohistochemistry. Stepwise multivariate linear regression of biologic variables was performed to identify independent predictors of panitumumab-IRDye800 concentration in tissue. Results: Optimally acquired at the lowest gain for tumor detection with ambient light, intraoperative fluorescence imaging enhanced tissue-size dependent tumor contrast by 5.2-fold, 3.4-fold, and 1.4-fold in HGG, HNSCC, and LAC, respectively. Tissue surface fluorescence target-to-background ratio correlated with margin size and identified 78%-97% of at-risk resection margins ex vivo. In 4-μm-thick tissue sections, fluorescence detected tumor with 0.85-0.89 areas under the receiver-operating-characteristic curves. Preferential breakdown of blood-brain barrier in HGG improved tumor specificity of intratumoral antibody distribution relative to that of EGFR (96% vs. 80%) despite its reduced concentration (3.9 ng/mg of tissue) compared with HNSCC (8.1 ng/mg) and LAC (6.3 ng/mg). Cellular EGFR expression, tumor cell density, plasma antibody concentration, and delivery barrier were independently associated with local intratumoral panitumumab-IRDye800 concentration, with 0.62 goodness of fit of prediction. Conclusion: In multicancer clinical imaging of a receptor-ligand-based molecular probe, plasma antibody concentration, delivery barrier, and intratumoral EGFR expression driven by cellular biomarker expression and tumor cell density led to heterogeneous intratumoral antibody accumulation and spatial distribution whereas tumor size, resection margin, and intraoperative imaging settings substantially influenced macroscopic tumor contrast.Item Open Access First-in-human intraoperative near-infrared fluorescence imaging of glioblastoma using cetuximab-IRDye800.(Journal of neuro-oncology, 2018-08) Miller, Sarah E; Tummers, Willemieke S; Teraphongphom, Nutte; van den Berg, Nynke S; Hasan, Alifia; Ertsey, Robert D; Nagpal, Seema; Recht, Lawrence D; Plowey, Edward D; Vogel, Hannes; Harsh, Griffith R; Grant, Gerald A; Li, Gordon H; Rosenthal, Eben LIntroduction
Maximizing extent of surgical resection with the least morbidity remains critical for survival in glioblastoma patients, and we hypothesize that it can be improved by enhancements in intraoperative tumor detection. In a clinical study, we determined if therapeutic antibodies could be repurposed for intraoperative imaging during resection.Methods
Fluorescently labeled cetuximab-IRDye800 was systemically administered to three patients 2 days prior to surgery. Near-infrared fluorescence imaging of tumor and histologically negative peri-tumoral tissue was performed intraoperatively and ex vivo. Fluorescence was measured as mean fluorescence intensity (MFI), and tumor-to-background ratios (TBRs) were calculated by comparing MFIs of tumor and histologically uninvolved tissue.Results
The mean TBR was significantly higher in tumor tissue of contrast-enhancing (CE) tumors on preoperative imaging (4.0 ± 0.5) compared to non-CE tumors (1.2 ± 0.3; p = 0.02). The TBR was higher at a 100 mg dose than at 50 mg (4.3 vs. 3.6). The smallest detectable tumor volume in a closed-field setting was 70 mg with 50 mg of dye and 10 mg with 100 mg. On sections of paraffin embedded tissues, fluorescence positively correlated with histological evidence of tumor. Sensitivity and specificity of tumor fluorescence for viable tumor detection was calculated and fluorescence was found to be highly sensitive (73.0% for 50 mg dose, 98.2% for 100 mg dose) and specific (66.3% for 50 mg dose, 69.8% for 100 mg dose) for viable tumor tissue in CE tumors while normal peri-tumoral tissue showed minimal fluorescence.Conclusion
This first-in-human study demonstrates the feasibility and safety of antibody based imaging for CE glioblastomas.Item Open Access Gene Expression Analysis in Three Posttraumatic Stress Disorder Cohorts Implicates Inflammation and Innate Immunity Pathways and Uncovers Shared Genetic Risk With Major Depressive Disorder.(Frontiers in neuroscience, 2021-01) Garrett, Melanie E; Qin, Xue Jun; Mehta, Divya; Dennis, Michelle F; Marx, Christine E; Grant, Gerald A; VA Mid-Atlantic MIRECC Workgroup; PTSD Initiative; Injury and Traumatic Stress (INTRuST) Clinical Consortium; Psychiatric Genomics Consortium PTSD Group; Stein, Murray B; Kimbrel, Nathan A; Beckham, Jean C; Hauser, Michael A; Ashley-Koch, Allison EPosttraumatic stress disorder (PTSD) is a complex psychiatric disorder that can develop following exposure to traumatic events. The Psychiatric Genomics Consortium PTSD group (PGC-PTSD) has collected over 20,000 multi-ethnic PTSD cases and controls and has identified both genetic and epigenetic factors associated with PTSD risk. To further investigate biological correlates of PTSD risk, we examined three PGC-PTSD cohorts comprising 977 subjects to identify differentially expressed genes among PTSD cases and controls. Whole blood gene expression was quantified with the HumanHT-12 v4 Expression BeadChip for 726 OEF/OIF veterans from the Veterans Affairs (VA) Mental Illness Research Education and Clinical Center (MIRECC), 155 samples from the Injury and Traumatic Stress (INTRuST) Clinical Consortium, and 96 Australian Vietnam War veterans. Differential gene expression analysis was performed in each cohort separately followed by meta-analysis. In the largest cohort, we performed co-expression analysis to identify modules of genes that are associated with PTSD and MDD. We then conducted expression quantitative trait loci (eQTL) analysis and assessed the presence of eQTL interactions involving PTSD and major depressive disorder (MDD). Finally, we utilized PTSD and MDD GWAS summary statistics to identify regions that colocalize with eQTLs. Although not surpassing correction for multiple testing, the most differentially expressed genes in meta-analysis were interleukin-1 beta (IL1B), a pro-inflammatory cytokine previously associated with PTSD, and integrin-linked kinase (ILK), which is highly expressed in brain and can rescue dysregulated hippocampal neurogenesis and memory deficits. Pathway analysis revealed enrichment of toll-like receptor (TLR) and interleukin-1 receptor genes, which are integral to cellular innate immune response. Co-expression analysis identified four modules of genes associated with PTSD, two of which are also associated with MDD, demonstrating common biological pathways underlying the two conditions. Lastly, we identified four genes (UBA7, HLA-F, HSPA1B, and RERE) with high probability of a shared causal eQTL variant with PTSD and/or MDD GWAS variants, thereby providing a potential mechanism by which the GWAS variant contributes to disease risk. In summary, we provide additional evidence for genes and pathways previously reported and identified plausible novel candidates for PTSD. These data provide further insight into genetic factors and pathways involved in PTSD, as well as potential regions of pleiotropy between PTSD and MDD.Item Open Access Intracranial Artery Morphology in Pediatric Moya Moya Disease and Moya Moya Syndrome.(Neurosurgery, 2022-11) Yedavalli, Vivek S; Quon, Jennifer L; Tong, Elizabeth; van Staalduinen, Eric K; Mouches, Pauline; Kim, Lily H; Steinberg, Gary K; Grant, Gerald A; Yeom, Kristen W; Forkert, Nils DBackground
Moya Moya disease (MMD) and Moya Moya syndrome (MMS) are cerebrovascular disorders, which affect the internal carotid arteries (ICAs). Diagnosis and surveillance of MMD/MMS in children mostly rely on qualitative evaluation of vascular imaging, especially MR angiography (MRA).Objective
To quantitatively characterize arterial differences in pediatric patients with MMD/MMS compared with normal controls.Methods
MRA data sets from 17 presurgery MMD/MMS (10M/7F, mean age = 10.0 years) patients were retrospectively collected and compared with MRA data sets of 98 children with normal vessel morphology (49 male patients; mean age = 10.6 years). Using a level set segmentation method with anisotropic energy weights, the cerebral arteries were automatically extracted and used to compute the radius of the ICA, middle cerebral artery (MCA), anterior cerebral artery (ACA), posterior cerebral artery (PCA), and basilar artery (BA). Moreover, the density and the average radius of all arteries in the MCA, ACA, and PCA flow territories were quantified.Results
Statistical analysis revealed significant differences comparing children with MMD/MMS and those with normal vasculature ( P < .001), whereas post hoc analyses identified significantly smaller radii of the ICA, MCA-M1, MCA-M2, and ACA ( P < .001) in the MMD/MMS group. No significant differences were found for the radii of the PCA and BA or any artery density and average artery radius measurement in the flow territories ( P > .05).Conclusion
His study describes the results of an automatic approach for quantitative characterization of the cerebrovascular system in patients with MMD/MMS with promising preliminary results for quantitative surveillance in pediatric MMD/MMS management.Item Open Access Machine-learning-based head impact subtyping based on the spectral densities of the measurable head kinematics(Journal of Sport and Health Science, 2023-03) Zhan, Xianghao; Li, Yiheng; Liu, Yuzhe; Cecchi, Nicholas J; Raymond, Samuel J; Zhou, Zhou; Vahid Alizadeh, Hossein; Ruan, Jesse; Barbat, Saeed; Tiernan, Stephen; Gevaert, Olivier; Zeineh, Michael M; Grant, Gerald A; Camarillo, David BItem Open Access Management of Severe Traumatic Brain Injury in Pediatric Patients.(Frontiers in toxicology, 2022-01) Lui, Austin; Kumar, Kevin K; Grant, Gerald AThe optimal management of severe traumatic brain injury (TBI) in the pediatric population has not been well studied. There are a limited number of research articles studying the management of TBI in children. Given the prevalence of severe TBI in the pediatric population, it is crucial to develop a reference TBI management plan for this vulnerable population. In this review, we seek to delineate the differences between severe TBI management in adults and children. Additionally, we also discuss the known molecular pathogenesis of TBI. A better understanding of the pathophysiology of TBI will inform clinical management and development of therapeutics. Finally, we propose a clinical algorithm for the management and treatment of severe TBI in children using published data.Item Open Access Molecular Identity Changes of Tumor-Associated Macrophages and Microglia After Magnetic Resonance Imaging–Guided Focused Ultrasound–Induced Blood–Brain Barrier Opening in a Mouse Glioblastoma Model(Ultrasound in Medicine and Biology, 2023-01-01) Zhang, Yanrong; Wang, Jing; Ghobadi, Sara Natasha; Zhou, Haiyan; Huang, Ai; Gerosa, Marco; Hou, Qingyi; Keunen, Olivier; Golebiewska, Anna; Habte, Frezghi G; Grant, Gerald A; Paulmurugan, Ramasamy; Lee, Kevin S; Wintermark, MaxAn orthotopically allografted mouse GL26 glioma model (Ccr2RFP/wt–Cx3cr1GFP/wt) was used to evaluate the effect of transient, focal opening of the blood–brain barrier (BBB) on the composition of tumor-associated macrophages and microglia (TAMs). BBB opening was induced by magnetic resonance imaging (MRI)–guided focused ultrasound (MRgFUS) combined with microbubbles. CX3CR1-GFP cells and CCR2-RFP cells in brain tumors were quantified in microscopic images. Tumors in animals treated with a single session of MRgFUS did not exhibit significant changes in cell numbers when compared with tumors in animals not receiving FUS. However, tumors that received two or three sessions of MRgFUS had significantly increased amounts of both CX3CR1-GFP and CCR2-RFP cells. The effect of MRgFUS on immune cell composition was also characterized and quantified using flow cytometry. Glioma implantation resulted in increased amounts of lymphocytes, monocytes and neutrophils in the brain parenchyma. Tumors administered MRgFUS exhibited increased numbers of monocytes and monocyte-derived TAMs. In addition, MRgFUS-treated tumors exhibited more CD80+ cells in monocytes and microglia. In summary, transient, focal opening of the BBB using MRgFUS combined with microbubbles can activate the homing and differentiation of monocytes and induce a shift toward a more pro-inflammatory status of the immune environment in glioblastoma.Item Open Access Molecular imaging of a fluorescent antibody against epidermal growth factor receptor detects high-grade glioma.(Scientific reports, 2021-03) Zhou, Quan; Vega Leonel, Johana CM; Santoso, Michelle Rai; Wilson, Christy; van den Berg, Nynke S; Chan, Carmel T; Aryal, Muna; Vogel, Hannes; Cayrol, Romain; Mandella, Michael J; Schonig, Frank; Lu, Guolan; Gambhir, Sanjiv S; Moseley, Michael E; Rosenthal, Eben L; Grant, Gerald AThe prognosis for high-grade glioma (HGG) remains dismal and the extent of resection correlates with overall survival and progression free disease. Epidermal growth factor receptor (EGFR) is a biomarker heterogeneously expressed in HGG. We assessed the feasibility of detecting HGG using near-infrared fluorescent antibody targeting EGFR. Mice bearing orthotopic HGG xenografts with modest EGFR expression were imaged in vivo after systemic panitumumab-IRDye800 injection to assess its tumor-specific uptake macroscopically over 14 days, and microscopically ex vivo. EGFR immunohistochemical staining of 59 tumor specimens from 35 HGG patients was scored by pathologists and expression levels were compared to that of mouse xenografts. Intratumoral distribution of panitumumab-IRDye800 correlated with near-infrared fluorescence and EGFR expression. Fluorescence distinguished tumor cells with 90% specificity and 82.5% sensitivity. Target-to-background ratios peaked at 14 h post panitumumab-IRDye800 infusion, reaching 19.5 in vivo and 7.6 ex vivo, respectively. Equivalent or higher EGFR protein expression compared to the mouse xenografts was present in 77.1% HGG patients. Age, combined with IDH-wildtype cerebral tumor, was predictive of greater EGFR protein expression in human tumors. Tumor specific uptake of panitumumab-IRDye800 provided remarkable contrast and a flexible imaging window for fluorescence-guided identification of HGGs despite modest EGFR expression.Item Open Access Multidisciplinary Stroke Pathway for Children Supported With Ventricular Assist Devices(ASAIO Journal, 2023-04) Lee, Sarah; Ryan, Kathleen R; Murray, Jenna; Chen, Sharon; Grant, Gerald A; Wilkins, Sarah; Yarlagadda, Vamsi V; Wintermark, Max; Dodd, Robert; Rosenthal, David; Teuteburg, Jeffrey; Navaratnam, Manchula; Lee, Joanne; Jordan, Lori C; Almond, Christopher SItem Open Access Neurosurgical Randomized Trials in Low- and Middle-Income Countries.(Neurosurgery, 2020-09) Griswold, Dylan P; Khan, Ahsan A; Chao, Tiffany E; Clark, David J; Budohoski, Karol; Devi, B Indira; Azad, Tej D; Grant, Gerald A; Trivedi, Rikin A; Rubiano, Andres M; Johnson, Walter D; Park, Kee B; Broekman, Marike; Servadei, Franco; Hutchinson, Peter J; Kolias, Angelos GBackground
The setting of a randomized trial can determine whether its findings are generalizable and can therefore apply to different settings. The contribution of low- and middle-income countries (LMICs) to neurosurgical randomized trials has not been systematically described before.Objective
To perform a systematic analysis of design characteristics and methodology, funding source, and interventions studied between trials led by and/or conducted in high-income countries (HICs) vs LMICs.Methods
From January 2003 to July 2016, English-language trials with >5 patients assessing any one neurosurgical procedure against another procedure, nonsurgical treatment, or no treatment were retrieved from MEDLINE, Scopus, and Cochrane Library. Income classification for each country was assessed using the World Bank Atlas method.Results
A total of 73.3% of the 397 studies that met inclusion criteria were led by HICs, whereas 26.7% were led by LMICs. Of the 106 LMIC-led studies, 71 were led by China. If China is excluded, only 8.8% were led by LMICs. HIC-led trials enrolled a median of 92 patients vs a median of 65 patients in LMIC-led trials. HIC-led trials enrolled from 7.6 sites vs 1.8 sites in LMIC-led studies. Over half of LMIC-led trials were institutionally funded (54.7%). The majority of both HIC- and LMIC-led trials evaluated spinal neurosurgery, 68% and 71.7%, respectively.Conclusion
We have established that there is a substantial disparity between HICs and LMICs in the number of published neurosurgical trials. A concerted effort to invest in research capacity building in LMICs is an essential step towards ensuring context- and resource-specific high-quality evidence is generated.Item Open Access Padded Helmet Shell Covers in American Football: A Comprehensive Laboratory Evaluation with Preliminary On-Field Findings.(Annals of biomedical engineering, 2023-03) Cecchi, Nicholas J; Callan, Ashlyn A; Watson, Landon P; Liu, Yuzhe; Zhan, Xianghao; Vegesna, Ramanand V; Pang, Collin; Le Flao, Enora; Grant, Gerald A; Zeineh, Michael M; Camarillo, David BProtective headgear effects measured in the laboratory may not always translate to the field. In this study, we evaluated the impact attenuation capabilities of a commercially available padded helmet shell cover in the laboratory and on the field. In the laboratory, we evaluated the padded helmet shell cover's efficacy in attenuating impact magnitude across six impact locations and three impact velocities when equipped to three different helmet models. In a preliminary on-field investigation, we used instrumented mouthguards to monitor head impact magnitude in collegiate linebackers during practice sessions while not wearing the padded helmet shell covers (i.e., bare helmets) for one season and whilst wearing the padded helmet shell covers for another season. The addition of the padded helmet shell cover was effective in attenuating the magnitude of angular head accelerations and two brain injury risk metrics (DAMAGE, HARM) across most laboratory impact conditions, but did not significantly attenuate linear head accelerations for all helmets. Overall, HARM values were reduced in laboratory impact tests by an average of 25% at 3.5 m/s (range: 9.7 to 39.6%), 18% at 5.5 m/s (range: - 5.5 to 40.5%), and 10% at 7.4 m/s (range: - 6.0 to 31.0%). However, on the field, no significant differences in any measure of head impact magnitude were observed between the bare helmet impacts and padded helmet impacts. Further laboratory tests were conducted to evaluate the ability of the padded helmet shell cover to maintain its performance after exposure to repeated, successive impacts and across a range of temperatures. This research provides a detailed assessment of padded helmet shell covers and supports the continuation of in vivo helmet research to validate laboratory testing results.Item Open Access Piecewise Multivariate Linearity Between Kinematic Features and Cumulative Strain Damage Measure (CSDM) Across Different Types of Head Impacts.(Annals of biomedical engineering, 2022-11) Zhan, Xianghao; Li, Yiheng; Liu, Yuzhe; Cecchi, Nicholas J; Gevaert, Olivier; Zeineh, Michael M; Grant, Gerald A; Camarillo, David BIn a previous study, we found that the relationship between brain strain and kinematic features cannot be described by a generalized linear model across different types of head impacts. In this study, we investigate if such a linear relationship exists when partitioning head impacts using a data-driven approach. We applied the K-means clustering method to partition 3161 impacts from various sources including simulation, college football, mixed martial arts, and car crashes. We found piecewise multivariate linearity between the cumulative strain damage (CSDM; assessed at the threshold of 0.15) and head kinematic features. Compared with the linear regression models without partition and the partition according to the types of head impacts, K-means-based data-driven partition showed significantly higher CSDM regression accuracy, which suggested the presence of piecewise multivariate linearity across types of head impacts. Additionally, we compared the piecewise linearity with the partitions based on individual features used in clustering. We found that the partition with maximum angular acceleration magnitude at 4706 rad/s2 led to the highest piecewise linearity. This study may contribute to an improved method for the rapid prediction of CSDM in the future.Item Open Access Repeated autologous umbilical cord blood infusions are feasible and had no acute safety issues in young babies with congenital hydrocephalus.(Pediatric research, 2015-12) Sun, Jessica M; Grant, Gerald A; McLaughlin, Colleen; Allison, June; Fitzgerald, Anne; Waters-Pick, Barbara; Kurtzberg, JoanneBackground
Babies with congenital hydrocephalus often experience developmental disabilities due to brain injury associated with prolonged increased pressure on the developing brain parenchyma. Umbilical cord blood (CB) infusion has favorable effects in animal models of brain hypoxia and stroke and is being investigated in clinical trials of brain injury in both children and adults. We sought to establish the safety and feasibility of repeated intravenous infusions of autologous CB in young babies with congenital hydrocephalus.Methods
Infants with severe congenital hydrocephalus and an available qualified autologous CB unit traveled to Duke for evaluation and CB infusion. When possible, the CB unit was utilized for multiple infusions. Patient and CB data were obtained at the time of infusion and analyzed retrospectively.Results
From October 2006 to August 2014, 76 patients with congenital hydrocephalus received 143 autologous CB infusions. Most babies received repeated doses, for a total of two (n = 45), three (n = 18), or four (n = 4) infusions. There were no infusion-related adverse events. As expected, all babies experienced developmental delays.Conclusion
Cryopreserved CB products may be effectively manipulated to provide multiple CB doses. Repeated intravenous infusion of autologous CB is safe and feasible in young babies with congenital hydrocephalus.