The effect of age on baseline neurocognitive performance.

OBJECTIVE: Evaluate the independent effect of age on baseline neurocognitive performance. STUDY DESIGN: Baseline ImPACT scores from tests taken by 7454 athletes aged 12-22 from 2009 to 2019 were split into three age cohorts: 12-14 years (3244), 15-17 years (3732), and 18-22 years (477). Linear regression analyses were used to evaluate the effect of age on ImPACT composite scores while controlling for demographic differences, medication-use, and symptom burden. Significance values have been set at p < 0.05. RESULTS: Linear regression analyses demonstrated that increased age does not significantly affect symptom score (ß = 0.06, p = 0.54) but does improve impulse control (ß = -0.45, p < 0.0001), verbal memory (ß = 0.23, p = 0.03), visualmotor (ß = 0.77, p < 0.0001), and reaction time (ß = -0.008, p < 0.0001) scores.  However, age did not have an effect on visual memory scores (ß = -0.25, p = 0.07). CONCLUSIONS: Age was shown to be an independent modifier of impulse control, verbal memory, visual motor, and reaction time scores but not visual memory or symptom scores.  This underscores the previous literature showing developmental differences as age increases among the adolescent athlete population.  This data also indicates the need for repeat neurocognitive baseline testing every other year as baseline scoring is likely to change as athletes become older.

UK Medical Cannabis Registry: a case series analyzing clinical outcomes of medical cannabis therapy for generalized anxiety disorder patients.

This study aims to analyze changes in health-related quality of life (HRQoL) and safety in patients with generalized anxiety disorder (GAD) prescribed a homogenous selection of cannabis-based medicinal products (CBMPs). Patients prescribed Adven CBMPs (Curaleaf International, UK) for GAD were identified from the UK Medical Cannabis Registry. Primary outcomes were changes in patient-reported outcome measures (PROMs) from baseline up to 12 months, including GAD-7, Single-Item Sleep Quality Scale (SQS), and EQ-5D-5L. Adverse events were recorded using CTCAE version 4.0. A total of 120 patients were identified for inclusion, of which 38 (31.67%), 52 (43.33%), and 30 (25.00%) were prescribed oils, dried flower, and both formulations of CBMP. Associated improvements in GAD-7, SQS, and EQ-5D-5L at 1, 3, 6, and 12 months were observed compared to baseline (P < 0.010). There were 24 (20.00%) patients who reported 442 (368.33%) adverse events, most of which were mild (n = 184, 41.63%) and moderate (n = 197, 44.57%). This study reports an association between initiation of a homogeneous CBMP therapy and improvements in anxiety severity and HRQoL in individuals with GAD. Moreover, therapy was well-tolerated at 12 months follow-up. Further investigation through randomized controlled trials will ultimately be required to determine causation.

Somatic mutation as an explanation for epigenetic aging.

DNA methylation marks have recently been used to build models known as "epigenetic clocks" which predict calendar age. As methylation of cytosine promotes C-to-T mutations, we hypothesized that the methylation changes observed with age should reflect the accrual of somatic mutations, and the two should yield analogous aging estimates. In analysis of multimodal data from 9,331 human individuals, we find that CpG mutations indeed coincide with changes in methylation, not only at the mutated site but also with pervasive remodeling of the methylome out to ±10 kilobases. This one-to-many mapping enables mutation-based predictions of age that agree with epigenetic clocks, including which individuals are aging faster or slower than expected. Moreover, genomic loci where mutations accumulate with age also tend to have methylation patterns that are especially predictive of age. These results suggest a close coupling between the accumulation of sporadic somatic mutations and the widespread changes in methylation observed over the course of life.

Baseline ImPACT Composite Scores in Student-Athletes With Attention-Deficit/Hyperactivity Disorder.

BACKGROUND: Athletes who are diagnosed with attention-deficit/hyperactivity disorder (ADHD) are at increased risk of concussion compared to other athletes. Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) is a widely used concussion tool, but it relies on pre-injury baseline testing that can be affected by psychiatric conditions. This research aims to determine if there are differences in pre-injury testing composite scores in student-athletes with ADHD compared to those without ADHD diagnosis. METHODS: We obtained 11,563 pre-season ImPACT assessments of 7,454 student-athletes (ages: 12-22) from 2009 to 2019. After exclusions, there were 6,920 control and 276 ADHD subjects. Multivariable linear regression analyses compared the independent effect of ADHD on the six ImPACT composite score metrics with Bonferroni correction for multiple comparisons with a = 0.008. RESULTS: Univariate analyses indicated ADHD is associated with more symptoms as measured by the Post-Concussion Symptom Scale (PCSS) (ß = 2.67, 95% CI: 1.47-3.87, p < .0001) and worse Impulse Control scores (ß = 0.93, 95% CI: 0.33-1.53, p = .002). In multivariate analysis, this association was the same for symptom score (ß = 2.48, 95% CI: 1.22-3.74, p < .0001), but Impulse Control was not significantly different after multiple comparison adjustment (ß = 0.87, 95% CI: 0.22-1.15, p = .009). CONCLUSIONS: The ADHD subjects reported worse symptoms at baseline and had worse Impulse Control in univariate analysis, but not multivariate analysis. These results can further guide clinicians in concussion diagnosis and test interpretations for student-athletes with ADHD, considering the symptom burden at baseline.

Bibliometric Analysis of International Medical Graduates and Professorship Promotion in Neurosurgery.

BACKGROUND: International medical graduates (IMGs) comprise ∼25% of physicians in the United States. Differences in promotion rates from assistant to associate to full professorship based on medical school location have been understudied. We aim to stratify odds of professional advancement by 3 categories: IMG with U.S. residency, IMG with international residency, and U.S. medical with U.S. residency training. METHODS: We created and queried a database after exclusions of 1334 neurosurgeons including multiple demographic factors: academic productivity and promotion rates. Stratified logistic regression modeled odds of promotion including the variables: decades out of training, Scopus h-index, gender, and training location. Odds ratios (ORs) and 95% confidence intervals (CIs) for each variable were calculated. RESULTS: Significant predictors of increased associate versus assistant professorship included decades out of training (OR = 2.519 [95% CI: 2.07-3.093], P < 0.0001) and Scopus h-index (OR = 1.085 [95% CI: 1.064-1.108], P < 0.0001) while international medical school with U.S. residency (OR = 0.471 [95% CI: 0.231-0.914], P = 0.0352) was associated with decreased promotion. Significant predictors of associate versus full professorship were decades out of training (OR = 2.781 [95% CI: 2.268-3.444], P < 0.0001) and Scopus h-index (OR = 1.064 [95% CI: 1.049-1.080], P < 0.0001). Attending medical school or residency internationally was not associated with odds of full professorship. CONCLUSIONS: Time out of residency and Scopus h-index were associated with higher academic rank regardless of career level. Attending medical school internationally with U.S. residency was associated with lower odds of associate professorship promotion over 10 years. There was no relationship between IMG and full professorship promotion. IMGs who attended residency internationally did not have lower promotion rates. These findings suggest it may be harder for IMGs to earn promotion from assistant to associate professor in neurosurgery.

A multicenter, longitudinal survey of headaches and concussions among youth athletes in the United States from 2009 to 2019.

OBJECTIVE/ BACKGROUND: Chronic headaches and sports-related concussions are among the most common neurological morbidities in adolescents and young adults. Given that the two can overlap in presentation, studying the effects of one on another has proven difficult. In this longitudinal study, we sought to assess the relationship between chronic headaches and concussions, analyzing the role of historic concussions on chronic headaches, as well as that of premorbid headaches on future concussion incidence, severity, and recovery. METHODS: This multi-center, longitudinal cohort study followed 7,453 youth athletes who were administered demographic and clinical surveys as well as a total of 25,815 Immediate Post-concussion Assessment and Cognitive Testing (ImPACT) assessments between 2009 and 2019. ImPACT was administered at baseline. Throughout the season concussions were examined by physicians and athletic trainers, followed by re-administration of ImPACT post-injury (PI), and at follow-up (FU), a median of 7 days post-concussion. Concussion incidence was calculated as the total number of concussions per patient years. Concussion severity and recovery were calculated as standardized deviations from baseline to PI and then FU in Symptom Score and the four neurocognitive composite ImPACT scores: Verbal Memory, Visual Memory, Processing Speed, and Reaction Time. Data were collected prospectively in a well-organized electronic format supervised by a national research-oriented organization with rigorous quality assurance. Analysis was preformed retrospectively. RESULTS: Of the eligible athletes, 1,147 reported chronic headaches (CH) at the start of the season and 6,306 reported no such history (NH). Median age of the cohort was 15.4 ± 1.6 years, and students were followed for an average of 1.3 ± 0.6 years. A history of concussions (OR 2.31, P < 0.0001) was associated with CH. Specifically, a greater number of past concussions (r2 = 0.95) as well as concussions characterized by a loss of consciousness (P < 0.0001) were associated with more severe headache burden. The CH cohort had a greater future incidence of concussion than the NH cohort (55.6 vs. 43.0 per 100 patient-years, P < 0.0001). However, multivariate analysis controlling for demographic, clinical, academic, and sports-related variables yielded no such effect (OR 0.99, P = 0.85). On multivariable analysis the CH cohort did have greater deviations from baseline to PI and FU in Symptom Score (PI OR per point 1.05, P = 0.01, FU OR per point 1.11, P = 0.04) and Processing Speed (OR per point 1.08, P = 0.04), suggesting greater concussion severity and impaired symptomatic recovery as compared to the NH cohort. CONCLUSION: A history of concussions was a significant contributor to headache burden among American adolescents and young adults. However, those with chronic headaches were not more likely to be diagnosed with a concussion, despite presenting with more severe concussions that had protracted recovery. Our findings not only suggest the need for conservative management among youth athletes with chronic headaches, they also indicate a potential health care gap in this population, in that those with chronic headaches may be referred for concussion diagnosis and management at lower rates than those with no such comorbidity.

Novel Grading Scales for Static and Flexion-Extension Magnetic Resonance Imaging in Patients with Cervical Spondylotic Myelopathy.

BACKGROUND: Flexion-extension magnetic resonance imaging (MRI) has potential to identify cervical pathology not detectable on conventional static MRI. Our study evaluated standard quantitative and novel subjective grading scales for assessing the severity of cervical spondylotic myelopathy in dynamic sagittal MRI as well as in static axial and sagittal images. METHODS: Forty-five patients underwent both conventional and flexion-extension MRI prior to anterior cervical discectomy and fusion from C4 through C7. In addition to measuring Cobb angles and cervical canal diameter, grading scales were developed for assessment of vertebral body translation, loss of disc height, change in disc contour, deformation of cord contour, and cord edema. Data were collected at all levels from C2-C3 through C7-T1. Variations in measurements between cervical levels and from flexion through neutral to extension were assessed using Mann-Whitney, Kruskal-Wallis, and two-way ANOVA tests. RESULTS: Cervical canal diameter, vertebral translation, and posterior disc opening changed significantly from flexion to neutral to extension positions (P < 0.01). When comparing operative versus nonoperative cervical levels, significant differences were found when measuring sagittal cervical canal dimensions, vertebral translation, and posterior disc opening (P < 0.01). Degenerative loss of disc height, disc dehydration, deformation of ventral cord contour, and cord edema were all significantly increased at operative levels versus nonoperative levels (P < 0.01). CONCLUSIONS: Flexion-extension MRI demonstrated significant changes not available from conventional MRI. Subjective scales for assessing degenerative changes were significantly more severe at levels with operative cervical spondylotic myelopathy. The utility of these scales for planning surgical intervention at specific and adjacent levels is currently under investigation.

Quantitative approaches to guide epilepsy surgery from intracranial EEG.

Over the past 10 years, the drive to improve outcomes from epilepsy surgery has stimulated widespread interest in methods to quantitatively guide epilepsy surgery from intracranial EEG (iEEG). Many patients fail to achieve seizure freedom, in part due to the challenges in subjective iEEG interpretation. To address this clinical need, quantitative iEEG analytics have been developed using a variety of approaches, spanning studies of seizures, interictal periods, and their transitions, and encompass a range of techniques including electrographic signal analysis, dynamical systems modeling, machine learning and graph theory. Unfortunately, many methods fail to generalize to new data and are sensitive to differences in pathology and electrode placement. Here, we critically review selected literature on computational methods of identifying the epileptogenic zone from iEEG. We highlight shared methodological challenges common to many studies in this field and propose ways that they can be addressed. One fundamental common pitfall is a lack of open-source, high-quality data, which we specifically address by sharing a centralized high-quality, well-annotated, multicentre dataset consisting of >100 patients to support larger and more rigorous studies. Ultimately, we provide a road map to help these tools reach clinical trials and hope to improve the lives of future patients.

The Effect of Multiple Scopus Profiles on the Perceived Academic Productivity of Neurosurgeons in the United States.

OBJECTIVE: Bibliometrics assessing academic productivity plays a significant role in neurosurgeons' career advancement. This study aimed to evaluate the influence of multiple author profiles on Scopus on neurosurgeon author-level metrics (h-index, document number, citation number). METHODS: A list of 1671 academic neurosurgeons was compiled through public searches of hospital and faculty websites for 115 neurosurgical residency training programs. The h-index, document number, and citation number for each neurosurgeon were collected using the Scopus algorithm. For surgeons with multiple profiles, total document number and citation number were calculated by summing results of each profile. Cumulative h-indices were calculated manually. Comparisons were made between surgeons with a single Scopus profile and surgeons with multiple profiles. RESULTS: A total of 124 neurosurgeons with multiple profiles were identified. Gender distribution (P = 0.47), years in practice (P = 0.06), subspecialty (P = 0.32), and academic rank (P = 0.16) between neurosurgeons with a single profile versus multiple profiles were similar. Primary profile h-index median was 16 (interquartile range [IQR]: 8-34), combined profiles median was 20 (IQR: 11-36), and percent loss median was 17.3% (IQR: 3%-33%) (P < 0.001). For document number, primary profile median was 46 (IQR: 16-127), combined profiles median was 55 (IQR: 22-148), and percent loss median was 16.2% (IQR: 7%-36%) (P < 0.001). For citation number, primary profile median was 1030 (IQR: 333-4082), combined profiles median was 1319 (IQR: 546-4439), and percent loss median was 14.1% (IQR: 4%-32%) (P < 0.001). CONCLUSIONS: U.S. academic neurosurgeons with multiple existing profiles on Scopus experience a 17.3% loss in h-index, a 16.2% loss in document number, and a 14.1% loss in citations, heavily undercounting their perceived academic productivity.

Seasonal Effects on Postoperative Complications After Spinal Surgery: A National Database Analysis.

OBJECTIVE: To investigate the role of seasonality on postoperative complications after spinal surgery. METHODS: Data were obtained from the American College of Surgeons National Surgical Quality Improvement Program database from 2011 to 2018. Current Procedural Terminology codes were used to identify the following procedures: posterior cervical decompression and fusion, cervical laminoplasty, posterior lumbar fusion, lumbar laminectomy, and spinal deformity surgery. The database was queried for deep vein thrombosis (DVT), pulmonary embolism, pneumonia, sepsis, septic shock, Clostridium difficile infection, stroke, cardiac arrest, myocardial infarction, urinary tract infection (UTI), and early unplanned hospital readmission (readmission). Warm season was defined as April-September, whereas cold season was defined as October-March. Statistical analysis included computing overall complication rates and comparison between seasons using univariate analysis and multivariable logistic regression. RESULTS: A total of 208,291 individuals underwent spinal surgery from 2011 to 2018. There was a statistically significant increase in UTI (odds ratio [OR], 1.16; 95% confidence interval [CI], 1.07-1.26; P = 0.0002) and readmission (OR, 1.06; 95% CI, 1.02-1.11, P = 0.007) in the warm season compared with the cold season. An investigation into the July effect showed increases in DVT (OR, 1.24; 95% CI, 1.03-1.48; P = 0.020) and thromboembolic events (OR 1.17; 95% CI, 1.01-1.35; P = 0.032) in July-September compared with the preceding 3 months. CONCLUSIONS: The results showed a higher incidence of UTI and readmission among spine surgery patients in the warm season and a higher incidence of DVT and thromboembolic events from July to September. In both cases, the effect of seasonality is statistically significant, but the absolute difference is small and may not suggest policy changes.

Source-sink connectivity: a novel interictal EEG marker for seizure localization.

Over 15 million epilepsy patients worldwide have drug-resistant epilepsy. Successful surgery is a standard of care treatment but can only be achieved through complete resection or disconnection of the epileptogenic zone, the brain region(s) where seizures originate. Surgical success rates vary between 20% and 80%, because no clinically validated biological markers of the epileptogenic zone exist. Localizing the epileptogenic zone is a costly and time-consuming process, which often requires days to weeks of intracranial EEG (iEEG) monitoring. Clinicians visually inspect iEEG data to identify abnormal activity on individual channels occurring immediately before seizures or spikes that occur interictally (i.e. between seizures). In the end, the clinical standard mainly relies on a small proportion of the iEEG data captured to assist in epileptogenic zone localization (minutes of seizure data versus days of recordings), missing opportunities to leverage these largely ignored interictal data to better diagnose and treat patients. IEEG offers a unique opportunity to observe epileptic cortical network dynamics but waiting for seizures increases patient risks associated with invasive monitoring. In this study, we aimed to leverage interictal iEEG data by developing a new network-based interictal iEEG marker of the epileptogenic zone. We hypothesized that when a patient is not clinically seizing, it is because the epileptogenic zone is inhibited by other regions. We developed an algorithm that identifies two groups of nodes from the interictal iEEG network: those that are continuously inhibiting a set of neighbouring nodes ('sources') and the inhibited nodes themselves ('sinks'). Specifically, patient-specific dynamical network models were estimated from minutes of iEEG and their connectivity properties revealed top sources and sinks in the network, with each node being quantified by source-sink metrics. We validated the algorithm in a retrospective analysis of 65 patients. The source-sink metrics identified epileptogenic regions with 73% accuracy and clinicians agreed with the algorithm in 93% of seizure-free patients. The algorithm was further validated by using the metrics of the annotated epileptogenic zone to predict surgical outcomes. The source-sink metrics predicted outcomes with an accuracy of 79% compared to an accuracy of 43% for clinicians' predictions (surgical success rate of this dataset). In failed outcomes, we identified brain regions with high metrics that were untreated. When compared with high frequency oscillations, the most commonly proposed interictal iEEG feature for epileptogenic zone localization, source-sink metrics outperformed in predictive power (by a factor of 1.2), suggesting they may be an interictal iEEG fingerprint of the epileptogenic zone.

Temporal and morphological characteristics of high-frequency oscillations in an acute in vivo model of epilepsy.

Approximately 30% of patients with epilepsy do not respond to anti-epileptogenic drugs. Surgical removal of the epileptogenic zone (EZ), the brain regions where the seizures originate and spread, can be a possible therapy for these patients, but localizing the EZ is challenging due to a variety of clinical factors. High-frequency oscillations (HFOs) in intracranial electroencephalography (EEG) are a promising biomarker of the EZ, but it is currently unknown whether HFO rates and HFO morphology modulate as pathological brain networks evolve in a way that gives rise to seizures. To address this question, we assessed the temporal evolution of the duration of HFO events, amplitude of HFO events, and rates of HFOs per minute. HFO events were quantified using the 4AP in vivo rodent model of epilepsy, inducing seizures in two different brain areas. We found that the duration and amplitude of HFO events were significantly increased for the cortex model when compared to the hippocampus model. Additionally, the duration and amplitude increased significantly between baseline and pre-ictal HFOs in both models. On the other hand, the two models did not display a consistent increasing or decreasing trend in amplitude, duration or rate when comparing ictal and postictal intervals. Clinical Relevance- We assessed the amplitude, duration, and rate of HFOs in two acute in vivo rodent models of epilepsy. The significant modulation of HFO morphology from baseline to pre-ictal periods suggests that these features may be a robust biomarker for pathological tissue involved in epileptogenesis. Moreover, the differences in HFO morphology observed between cortex and hippocampus animal models possibly indicate that different structural network characteristics of the EZ cause this modulation. In all, we found that HFO features modulate significantly with the onset of seizures, further highlighting the need to consider of HFO morphology in EZ-localizing studies.

Novel feature selection methods for construction of accurate epigenetic clocks.

Epigenetic clocks allow us to accurately predict the age and future health of individuals based on the methylation status of specific CpG sites in the genome and are a powerful tool to measure the effectiveness of longevity interventions. There is a growing need for methods to efficiently construct epigenetic clocks. The most common approach is to create clocks using elastic net regression modelling of all measured CpG sites, without first identifying specific features or CpGs of interest. The addition of feature selection approaches provides the opportunity to optimise the identification of predictive CpG sites. Here, we apply novel feature selection methods and combinatorial approaches including newly adapted neural networks, genetic algorithms, and 'chained' combinations. Human whole blood methylation data of ~470,000 CpGs was used to develop clocks that predict age with R2 correlation scores of greater than 0.73, the most predictive of which uses 35 CpG sites for a R2 correlation score of 0.87. The five most frequent sites across all clocks were modelled to build a clock with a R2 correlation score of 0.83. These two clocks are validated on two external datasets where they maintain excellent predictive accuracy. When compared with three published epigenetic clocks (Hannum, Horvath, Weidner) also applied to these validation datasets, our clocks outperformed all three models. We identified gene regulatory regions associated with selected CpGs as possible targets for future aging studies. Thus, our feature selection algorithms build accurate, generalizable clocks with a low number of CpG sites, providing important tools for the field.

Evaluation of differences across age groups in the incidence, severity, and recovery of concussion in adolescent student-athletes from 2009 to 2019.

OBJECTIVE: Concussion incidence is known to be highest in children and adolescents; however, there is conflicting evidence about the effect of age on concussion risk and recovery within the adolescent age range. The heterogeneity of results may be partially due to the use of age groupings based on convenience, making comparisons across studies difficult. This study evaluated the independent effect of age on concussion incidence, severity, and recovery in student-athletes aged 12-18 years using cluster analysis to define groupings. METHODS: Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) scores of 11,403 baseline tests and 4922 postinjury tests were used to calculate the incidence rates for adolescent student-athletes grouped into 3 age bands (12-13, 14-15, and 16-18 years of age) on the basis of clustering analysis. The recently created Severity Index was used to compare concussion severity between groups. Follow-up tests for subjects who sustained a concussion were used to evaluate recovery time. The chi-square test and 1-way ANOVA were used to compare differences in demographic characteristics and concussion incidence, severity, and recovery. Multivariable logistic and linear regressions were used to evaluate the independent effects of age on concussion incidence and severity, respectively. Multivariable Cox hazard regression was used to evaluate differences in recovery time. Further analyses were conducted to directly compare findings across studies on the basis of the age groupings used in prior studies. RESULTS: Multivariable regression analyses demonstrated that the 14- to 15-year-old age group had a significantly higher concussion incidence than both the 12- to 13-year-old (14- to 15-year-old group vs 12- to 13-year-old group, OR 1.57, 95% CI 1.16-2.17, p = 0.005) and 16- to 18-year-old (16- to 18-year-old group vs 14- to 15-year-old group, OR 0.79, 95% CI 0.69-0.91, p = 0.0008) age groups. There was no difference in incidence between the 12- to 13-year-old and 16- to 18-year-old groups (16- to 18-year group vs 12- to 13-year group, OR 1.26, 95% CI 0.93-1.72, p = 0.15). There were also no differences in concussion severity or recovery between any groups. CONCLUSIONS: This study found that concussion incidence was higher during mid-adolescence than early and late adolescence, suggesting a U-shaped relationship between age and concussion risk over the course of adolescence. Age had no independent effect on concussion severity or recovery in the 12- to 13-, 14- to 15-, and 16- to 18-year-old groups. Further analysis of the various age groups revealed that results may vary significantly with minor changes to groupings, which may explain the divergent results in the current literature on this topic. Thus, caution should be taken when interpreting the results of this and all similar studies, especially when groupings are based on convenience.

Effects of a history of headache and migraine treatment on baseline neurocognitive function in young athletes.

OBJECTIVE/BACKGROUND: Despite the prevalence of concussions in young athletes, the impact of headaches on neurocognitive function at baseline is poorly understood. We analyze the effects of a history of headache treatment on baseline ImPACT composite scores in young athletes. METHODS: A total of 11,563 baseline ImPACT tests taken by 7,453 student-athletes ages 12-22 between 2009 and 2019 were reviewed. The first baseline test was included. There were 960 subjects who reported a history of treatment for headache and/or migraine (HA) and 5,715 controls (CT). The HA cohort included all subjects who self-reported a history of treatment for migraine or other type of headache on the standardized questionnaire. Chi-squared tests were used to compare demographic differences. Univariate and multivariate regression analyses were used to assess differences in baseline composite scores between cohorts while controlling for demographic differences and symptom burden. RESULTS: Unadjusted analyses demonstrated that HA was associated with increased symptoms (ß=2.30, 95% CI: 2.18-2.41, p<.0001), decreased visual memory (ß=-1.35, 95% CI: -2.62 to -0.43, p=.004), and increased visual motor speed (ß=0.71, 95% CI: 0.23-1.19, p=.004) composite scores. Baseline scores for verbal memory, reaction time, and impulse control were not significantly different between cohorts. Adjusted analyses demonstrated similar results with HA patients having greater symptom burden (ß=1.40, 95% CI: 1.10-1.70, p<.0001), lower visual memory (ß=-1.25, 95% CI: -2.22 to -0.27, p=.01), and enhanced visual motor speed (ß=0.60, 95% CI: 0.11-1.10, p=.02) scores. CONCLUSION: HA affected symptom, visual motor speed, and visual memory ImPACT composite scores. Visual memory scores and symptom burden were significantly worse in the HA group while visual motor speed scores were better, which may have been due to higher stimulant use in the HA group. The effects of HA on visual motor speed and visual memory scores were independent of the effects of the increased symptom burden.

Epigenetic aging: Biological age prediction and informing a mechanistic theory of aging.

Numerous studies have shown that epigenetic age-an individual's degree of aging based on patterns of DNA methylation-can be computed and is associated with an array of factors including diet, lifestyle, genetics, and disease. One can expect that still further associations will emerge with additional aging research, but to what end? Prediction of age was an important first step, but-in our view-the focus must shift from chasing increasingly accurate age computations to understanding the links between the epigenome and the mechanisms and physiological changes of aging. Here, we outline emerging areas of epigenetic aging research that prioritize biological understanding and clinical application. First, we survey recent progress in epigenetic clocks, which are beginning to predict not only chronological age but aging outcomes such as all-cause mortality and onset of disease, or which integrate aging signals across multiple biological processes. Second, we discuss research that exemplifies how investigation of the epigenome is building a mechanistic theory of aging and informing clinical practice. Such examples include identifying methylation sites and the genes most strongly predictive of aging-a subset of which have shown strong potential as biomarkers of neurodegenerative disease and cancer; relating epigenetic clock predictions to hallmarks of aging; and using longitudinal studies of DNA methylation to characterize human disease, resulting in the discovery of epigenetic indications of type 1 diabetes and the propensity for psychotic experiences.

Subspecialty and Training Preferences for U.S. Neurosurgery Faculty with International Training.

BACKGROUND: Academic neurosurgeons with international medical training play a large role in the U.S. neurosurgical workforce. We aimed to compare U.S.-trained neurosurgeons with internationally trained neurosurgeons to reveal differences in subspecialty preferences and training opportunities abroad. METHODS: We identified 1671 neurosurgeons from 115 Accreditation Council for Graduate Medical Education (ACGME)-accredited neurosurgical residency programs. Data on demographics, institution characteristics, and chosen subspecialty were collected, and faculty were divided based on location of training. Univariate analysis and multivariable logistic regression compared faculty characteristics between training locations. RESULTS: Compared with the U.S. medical school + U.S. residency group, the international medical graduate + U.S. residency group was more likely to subspecialize in oncology/skull base and vascular neurosurgery and complete a fellowship in the United States or internationally (P < 0.05). The international medical graduate + international residency group was more likely to subspecialize in oncology/skull base neurosurgery, more likely to complete an international fellowship, and less likely to practice general neurosurgery (P < 0.05). Neurosurgeons in pediatrics, radiosurgery, and vascular subspecialties were more likely to receive fellowship training in any location (P < 0.05). Additionally, functional neurosurgeons were more likely to complete fellowships internationally, spinal neurosurgeons were less likely to pursue international fellowships, and peripheral nerve neurosurgeons were more likely to have dual fellowship training in both the United States and abroad (P < 0.05). CONCLUSIONS: International medical training affected subspecialty choice and fellowship training. Internationally trained neurosurgeons more often specialized in oncology and vascular neurosurgery. Functional neurosurgeons were more likely to complete international fellowships, spine neurosurgeons were less likely to complete international fellowships, and peripheral nerve neurosurgeons more often had both U.S. and international fellowships.

High altitude modulates concussion incidence, severity, and recovery in young athletes.

BACKGROUND: High altitude may affect concussion, but prior studies are limited . We tested whether high altitude affects sport-related concussion (SRC) incidence, severity, and recovery. METHODS: Twenty-five thousand eight hundred fifteen baseline and post-injury Immediate Post-Concussion Assessment and Cognitive Testing results were compiled from Florida and Colorado, low (27 m or 62 m) and high (1,640 m or 1,991 m) altitude locations, respectively. Incidence, severity, and recovery of injury were compared between altitudes. RESULTS: High altitude was associated with increased suspected concussion incidence (adjusted OR, 2.04 [95% CI, 1.86 to 2.24];P < .0001). However, high altitude was associated with lower concussion severity measured by Severity Index (SI) (adjusted OR, 0.42 [95% CI, 0.37 to 0.49];P < .0001). High altitude was associated with decreased recovery from post-concussive symptoms in the migraine (ß, -2.72 [95% CI, -3.31 to -2.13]; P < .0001), cognitive (ß, -1.88 [95% CI, -2.40 to -1.36]; P < .0001), and sleep symptom clusters (ß, -0.30 [95% CI, -0.52 to -0.08]; P = .007). Athletes with initial SI≥8 showed prolonged neurocognitive dysfunction at high altitude (HR, 1.38 [95% CI, 1.06 to 1.81]; P = .02). CONCLUSIONS: High altitude was associated with increased suspected concussions and prolonged recovery but less severe initial injury.