OBJECTIVEMaximal safe resection of gliomas near motor pathways is facilitated by intraoperative mapping. The authors and other groups have described the use of bipolar or monopolar direct stimulation to identify functional tissue, as well as transcranial or transcortical motor evoked potentials (MEPs) to monitor motor pathways. Here, the authors describe their initial experience using all 3 modalities to identify, monitor, and preserve cortical and subcortical motor systems during glioma surgery.METHODSIntraoperative mapping data were extracted from a prospective registry of glioma resections near motor pathways. Additional demographic, clinical, pathological, and imaging data were extracted from the electronic medical record. All patients with new or worsened postoperative motor deficits were followed for at least 6 months.RESULTSBetween January 2018 and August 2019, 59 operations were performed in 58 patients. Overall, patients in 6 cases (10.2%) had new or worse immediate postoperative deficits. Patients with temporary deficits all had at least Medical Research Council grade 4/5 power. Only 2 patients (3.4%) had permanently worsened deficits after 6 months, both of which were associated with diffusion restriction consistent with ischemia within the corticospinal tract. One patient’s deficit improved to 4/5 and the other to 4/5 proximally and 3/5 distally in the lower limb, allowing ambulation following rehabilitation. Subcortical motor pathways were identified in 51 cases (86.4%) with monopolar high-frequency stimulation, but only in 6 patients using bipolar stimulation. Transcranial or cortical MEPs were diminished in only 6 cases, 3 of which had new or worsened deficits, with 1 permanent deficit. Insula location (p = 0.001) and reduction in MEPs (p = 0.01) were the only univariate predictors of new or worsened postoperative deficits. Insula location was the only predictor of permanent deficits (p = 0.046). The median extent of resection was 98.0%.CONCLUSIONSAsleep triple motor mapping is safe and resulted in a low rate of deficits without compromising the extent of resection.

Background Mild-traumatic brain injury (mTBI) and concussions cause significant morbidity. To date, synthesis of specific health care disparities and gaps in care for rural mTBI/concussion patients remains needed. Methods A comprehensive literature search was performed using PubMed database for English articles with keywords "rural" and ("concussion" or "mild traumatic brain injury") from 1991 to 2019. Eighteen articles focusing on rural epidemiology (n = 5), management/cost (n = 5), military (n = 2), and concussion prevention/return to play (n = 6) were included. Results mTBI/concussion incidence was higher in rural compared with urban areas. Compared with urban patients, rural patients were at increased risk for vehicular injuries, lifetime number of concussions, admissions for observation without neuroimaging, and injury-related costs. Rural patients were less likely to utilize ambulatory and mental health services following mTBI/concussion. Rural secondary schools had decreased access to certified personnel for concussion evaluation, and decreased use of standardized assessment instruments/neurocognitive testing. While school coaches were aware of return-to-play laws, mTBI/concussion education rates for athletes and parents were suboptimal in both settings. Rural veterans were at increased risk for postconcussive symptoms and posttraumatic stress. Telemedicine in rural/low-resource areas is an emerging tool for rapid evaluation, triage, and follow-up. Conclusions Rural patients are at unique risk for mTBI/concussions and health care costs. Barriers to care include lower socioeconomic status, longer distances to regional medical center, and decreased availability of neuroimaging and consultants. Due to socioeconomic and distance barriers, rural schools are less able to recruit personnel certified for concussion evaluation. Telemedicine is an emerging tool for remote triage and evaluation. AbstractKeywords ► concussion ► epidemiology ► health disparity ► mild-traumatic brain injury ► rural ► prevention ► return to play

Background and Objectives: The annual global incidence of traumatic brain injury (TBI) is over 10 million. An estimated 29% of TBI patients with negative computed tomography (CT−) have positive magnetic resonance imaging (MRI+) findings. Judicious use of serum biomarkers with MRI may aid in diagnosis of CT-occult TBI. The current manuscript aimed to evaluate the diagnostic, therapeutic and risk-stratification utility of known biomarkers and intracranial MRI pathology. Materials and Methods: The PubMed database was queried with keywords (plasma OR serum) AND (biomarker OR marker OR protein) AND (brain injury/trauma OR head injury/trauma OR concussion) AND (magnetic resonance imaging/MRI) (title/abstract) in English. Seventeen articles on TBI biomarkers and MRI were included: S100 calcium-binding protein B (S100B; N = 6), glial fibrillary acidic protein (GFAP; N = 3), GFAP/ubiquitin carboxyl-terminal hydrolase-L1 (UCH-L1; N = 2), Tau (N = 2), neurofilament-light (NF-L; N = 2), alpha-synuclein (N = 1), and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor peptide (AMPAR; N = 1). Results: Acute GFAP distinguished CT−/MRI+ from CT−/MRI− (AUC = 0.777, 0.852 at 9–16 h). GFAP discriminated CT−/diffuse axonal injury (DAI+) from controls (AUC = 0.903). Tau correlated directly with number of head strikes and inversely with white matter fractional anisotropy (FA), and a cutoff > 1.5 pg/mL discriminated between DAI+ and DAI− (sensitivity = 74%/specificity = 69%). NF-L had 100% discrimination of DAI in severe TBI and correlated with FA. Low alpha-synuclein was associated with poorer functional connectivity. AMPAR cutoff > 0.4 ng/mL had a sensitivity of 91% and a specificity of 92% for concussion and was associated with minor MRI findings. Low/undetectable S100B had a high negative predictive value for CT/MRI pathology. UCH-L1 showed no notable correlations with MRI. Conclusions: An acute circulating biomarker capable of discriminating intracranial MRI abnormalities is critical to establishing diagnosis for CT-occult TBI and can triage patients who may benefit from outpatient MRI, surveillance and/or follow up with TBI specialists. GFAP has shown diagnostic potential for MRI findings such as DAI and awaits further validation. Tau shows promise in detecting DAI and disrupted functional connectivity. Candidate biomarkers should be evaluated within the context of analytical performance of the assays used, as well as the post-injury timeframe for blood collection relative to MRI abnormalities.

Introduction: Traumatic brain injury (TBI) remains a primary cause of pediatric morbidity. The improved characterization of healthcare disparities for pediatric TBI in United States (U.S.) rural communities is needed to advance care. Methods: The PubMed database was queried using keywords ((“brain/head trauma” OR “brain/head injury”) AND “rural/underserved” AND “pediatric/child”). All qualifying articles focusing on rural pediatric TBI, including the subtopics epidemiology (N = 3), intervention/healthcare cost (N = 6), and prevention (N = 1), were reviewed. Results: Rural pediatric TBIs were more likely to have increased trauma and head injury severity, with higher-velocity mechanisms (e.g., motor vehicle collisions). Rural patients were at risk of delays in care due to protracted transport times, inclement weather, and mis-triage to non-trauma centers. They were also more likely than urban patients to be unnecessarily transferred to another hospital, incurring greater costs. In general, rural centers had decreased access to mental health and/or specialist care, while the average healthcare costs were greater. Prevention efforts, such as mandating bicycle helmet use through education by the police department, showed improved compliance in children aged 5–12 years. Conclusions: U.S. rural pediatric patients are at higher risk of dangerous injury mechanisms, trauma severity, and TBI severity compared to urban. The barriers to care include protracted transport times, transfer to less-resourced centers, increased healthcare costs, missing data, and decreased access to mental health and/or specialty care during hospitalization and follow-up. Preventative efforts can be successful and will require an improved multidisciplinary awareness and education.

OBJECTIVE Epileptic seizures are a common and potentially devastating complication of metastatic brain tumors. Although tumor-related seizures have been described in previous case series, most studies have focused on primary brain tumors and have not differentiated between different types of cerebral metastases. The authors analyzed a large surgical cohort of patients with brain metastases to examine risk factors associated with preoperative and postoperative seizures and to better understand the seizure risk factors of metastatic brain tumors. METHODS Patients who underwent resection of a brain metastasis at the University of California, San Francisco (UCSF), were retrospectively reviewed. Patients included in the study were ≥ 18 years of age, required resection of a brain metastasis, and were treated at UCSF. Primary cancers included melanoma, non–small cell lung adenocarcinoma, breast adenocarcinoma, colorectal adenocarcinoma, esophageal adenocarcinoma, gastric adenocarcinoma, renal cell carcinoma, urothelial carcinoma, ovarian carcinoma, cervical squamous cell carcinoma, and endometrial adenocarcinoma. Patients were evaluated for primary cancer type and seizure occurrence, as well as need for use of antiepileptic drugs preoperatively, at time of discharge, and at 6 months postoperatively. Additionally, Engel classification scores were assigned to those patients who initially presented with seizures preoperatively. Univariate and multivariate regression analyses were used to assess the association of tumor type with preoperative seizures. RESULTS Data were retrospectively analyzed for 348 consecutive patients who underwent surgical treatment of brain metastases between 1998 and 2019. The cohort had a mean age of 60 years at the time of surgery and was 59% female. The mean and median follow-up durations after the date of surgery for the cohort were 22 months and 10.8 months, respectively. In univariate analysis, frontal lobe location (p = 0.05), melanoma (p = 0.02), KRAS mutation in lung carcinoma (p = 0.04), intratumoral hemorrhage (p = 0.04), and prior radiotherapy (p = 0.04) were associated with seizure presentation. Postoperative checkpoint inhibitor use (p = 0.002), prior radiotherapy (p = 0.05), older age (p = 0.002), distant CNS progression (p = 0.004), and parietal lobe tumor location (p = 0.002) were associated with seizures at 6 months postoperatively. The final multivariate model confirmed the independent effects of tumor location in the frontal lobe and presence of intratumoral hemorrhage as predictors of preoperative seizures, and checkpoint inhibitor use and parietal lobe location were identified as significant predictors of seizures at 6 months postoperatively. CONCLUSIONS Within this surgical cohort of patients with brain metastases, seizures were seen in almost a quarter of patients preoperatively. Frontal lobe metastases and hemorrhagic tumors were associated with higher risk of preoperative seizures, whereas checkpoint inhibitor use and parietal lobe tumors appeared to be associated with seizures at 6 months postoperatively. Future research should focus on the effect of metastatic lesion–targeting therapeutic interventions on seizure control in these patients.

BackgroundOpen Payments is a United States federal program mandating reporting of medical industry payments to physicians, increasing transparency of physician conflicts of interest (COI). Study objectives were to assess industry payments to physician-editors, and to compare their financial COI rate to all physicians within the specialty.Methods and findingsWe performed a retrospective analysis of prospectively collected data, reviewing Open Payments from August 1, 2013 to December 31, 2016. We reviewed general payments (“… not made in connection with a research agreement”) and research funding to “top tier” physician-editors of highly-cited medical journals. We compared payments to physician-editors and physicians-by-specialty. In 35 journals, 333 (74.5%) of 447 “top tier” US-based editors met inclusion criteria. Of these, 212 (63.7%) received industry-associated payments in the study period. In an average year, 141 (42.3%) of physician-editors received any direct payments to themselves including general payments and research payments, 66 (19.8%) received direct payments >$5,000 (National Institutes of Health threshold for a Significant Financial Interest) and 51 (15.3%) received >$10,000. Mean annual general payments to physician-editors was $55,157 (median 3,512, standard deviation 561,885, range 10–10,981,153). Median general payments to physician-editors were mostly higher compared to all physicians within their specialty. Mean annual direct research payment to the physician-editor was $14,558 (median 4,000, range 15–174,440). Mean annual indirect research funding to the physician-editor’s institution (highly valued by academic leaders such as departmental chairs and deans) was $175,282 (median 49,107, range 0.18–5,000,000). The main study limitation was difficulty identifying physician-editors primarily responsible for making manuscript decisions.ConclusionsA substantial minority of physician-editors receive payments from industry within any given year, sometimes quite large. Most editors received payment of some kind during the four-year study period. Given the extent of editors’ influences on the medical literature, more robust and accessible editor financial COI declarations are recommended.

Toxoplasma gondii is an obligate intracellular parasite with worldwide distribution. Felines are the definitive hosts supporting the complete life cycle of T. gondii. However, other warm-blooded animals such as rodents and humans can also be infected. Infection of such secondary hosts results in long-term infection characterized by the presence of tissue cysts in the brain and other organs. While it is known that T. gondii infection in rodents is associated with behavioral changes, the mechanisms behind these changes remain unclear. Alterations of the host intestinal microflora are recognized as a prominent role player in shaping host behavior and cognition. It has been shown that acute T. gondii infection of mice results in microflora changes as a result of gastrointestinal inflammation in inbred mouse models. The long-term effects of chronic T. gondii infection on microbial communities, however, are unknown. In this study, after we verified using our model in terms of measuring microflora changes during an acute episode of toxoplasmosis, we assessed the microbiome changes that occur during a long-term infection; then we further investigated these changes in a follow-up study of chronic infection. These analyses were performed by constructing and sequencing 16S rRNA amplicon DNA libraries from small intestine fecal specimens. We found that acute infection with the GT1 strain of T. gondii caused an enrichment of Bacteroidetes compared with controls in CD1 mice. Strikingly, this enrichment upheld throughout long-term chronic infection. The potential biological consequences of this alteration in rodents and humans should be subjected to further exploration.

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