Wnt and Notch signaling govern self-renewal and differentiation in a subset of human glioblastoma stem cells.

Developmental signal transduction pathways act diversely, with context-dependent roles across systems and disease types. Glioblastomas (GBMs), which are the poorest prognosis primary brain cancers, strongly resemble developmental systems, but these growth processes have not been exploited therapeutically, likely in part due to the extreme cellular and genetic heterogeneity observed in these tumors. The role of Wnt/ßcatenin signaling in GBM stem cell (GSC) renewal and fate decisions remains controversial. Here, we report context-specific actions of Wnt/ßcatenin signaling in directing cellular fate specification and renewal. A subset of primary GBM-derived stem cells requires Wnt proteins for self-renewal, and this subset specifically relies on Wnt/ßcatenin signaling for enhanced tumor burden in xenograft models. In an orthotopic Wnt reporter model, Wnthi GBM cells (which exhibit high levels of ßcatenin signaling) are a faster-cycling, highly self-renewing stem cell pool. In contrast, Wntlo cells (with low levels of signaling) are slower cycling and have decreased self-renewing potential. Dual inhibition of Wnt/ßcatenin and Notch signaling in GSCs that express high levels of the proneural transcription factor ASCL1 leads to robust neuronal differentiation and inhibits clonogenic potential. Our work identifies new contexts for Wnt modulation for targeting stem cell differentiation and self-renewal in GBM heterogeneity, which deserve further exploration therapeutically.

Astrogliosis marker 11C-SL25.1188 PET in traumatic brain injury with persistent symptoms.

Traumatic brain injury (TBI) is common but little is known why up to a third of patients have persisting symptoms. Astrogliosis, a pathophysiological response to brain injury, may be a potential therapeutic target, but demonstration of astrogliosis in the brain of humans with TBI and persistent symptoms is lacking. Astroglial marker monoamine oxidase B (MAO-B) total distribution volume (11C-SL25.1188 VT), an index of MAO-B density, was measured in 29 TBI and 29 similarly aged healthy control cases with 11C-SL25.1188 PET, prioritizing prefrontal cortex (PFC) and cortex proximal to cortical convexity. Correlations of PFC 11C-SL25.1188 VT with psychomotor and processing speed; and serum blood measures implicated in astrogliosis were determined. 11C-SL25.1188 VT was greater in TBI in PFC (P = 0.00064) and cortex (P = 0.00038). PFC 11C-SL25.1188 VT inversely correlated with Comprehensive Trail Making Test psychomotor and processing speed (r = -0.48, P = 0.01). In participants scanned within 2 years of last TBI, PFC 11C-SL25.1188 VT correlated with serum glial fibrillary acid protein (r = 0.51, P = 0.037) and total tau (r = 0.74, P = 0.001). Elevated 11C-SL25.1188 VT argues strongly for astrogliosis and therapeutics modifying astrogliosis towards curative phenotypes should be tested in TBI with persistent symptoms. Given substantive effect size, astrogliosis PET markers should be applied to stratify cases and/or assess target engagement for putative therapeutics targeting astrogliosis.

Impact of Automated Prognostication on Traumatic Brain Injury Care: A Focus Group Study.

BACKGROUND: Prognosticating outcomes for traumatic brain injury (TBI) patients is challenging due to the required specialized skills and variability among clinicians. Recent attempts to standardize TBI prognosis have leveraged machine learning (ML) methodologies. This study evaluates the necessity and influence of ML-assisted TBI prognostication through healthcare professionals' perspectives via focus group discussions. METHODS: Two virtual focus groups included ten key TBI care stakeholders (one neurosurgeon, two emergency clinicians, one internist, two radiologists, one registered nurse, two researchers in ML and healthcare and one patient representative). They answered six open-ended questions about their perceptions and potential ML use in TBI prognostication. Transcribed focus group discussions were thematically analyzed using qualitative data analysis software. RESULTS: The study captured diverse perceptions and interests in TBI prognostication across clinical specialties. Notably, certain clinicians who currently do not prognosticate expressed an interest in doing so independently provided they had access to ML support. Concerns included ML's accuracy and the need for proficient ML researchers in clinical settings. The consensus suggested using ML as a secondary consultation tool and promoting collaboration with internal or external research resources. Participants believed ML prognostication could enhance disposition planning and standardize care regardless of clinician expertise or injury severity. There was no evidence of perceived bias or interference during the discussions. CONCLUSION: Our findings revealed an overall positive attitude toward ML-based prognostication. Despite raising multiple concerns, the focus group discussions were particularly valuable in underscoring the potential of ML in democratizing and standardizing TBI prognosis practices.

Fate mapping of human glioblastoma reveals an invariant stem cell hierarchy.

Human glioblastomas harbour a subpopulation of glioblastoma stem cells that drive tumorigenesis. However, the origin of intratumoural functional heterogeneity between glioblastoma cells remains poorly understood. Here we study the clonal evolution of barcoded glioblastoma cells in an unbiased way following serial xenotransplantation to define their individual fate behaviours. Independent of an evolving mutational signature, we show that the growth of glioblastoma clones in vivo is consistent with a remarkably neutral process involving a conserved proliferative hierarchy rooted in glioblastoma stem cells. In this model, slow-cycling stem-like cells give rise to a more rapidly cycling progenitor population with extensive self-maintenance capacity, which in turn generates non-proliferative cells. We also identify rare 'outlier' clones that deviate from these dynamics, and further show that chemotherapy facilitates the expansion of pre-existing drug-resistant glioblastoma stem cells. Finally, we show that functionally distinct glioblastoma stem cells can be separately targeted using epigenetic compounds, suggesting new avenues for glioblastoma-targeted therapy.

Predicting Severity of Head Collision Events in Elite Soccer Using Preinjury Data: A Machine Learning Approach.

OBJECTIVE: To develop machine learning (ML) models that predict severity of head collision events (HCEs) based on preinjury variables and to investigate which variables are important to predicting severity. DESIGN: Data on HCEs were collected with respect to severity and 23 preinjury variables to create 2 datasets, a male dataset using men's tournaments and mixed dataset using men's and women's tournaments, to perform ML analysis. Machine learning analysis used a random forest classifier based on preinjury variables to predict HCE severity. SETTING: Four elite international soccer tournaments. PARTICIPANTS: Elite athletes participating in analyzed tournaments. INDEPENDENT VARIABLES: The 23 preinjury variables collected for each HCE. MAIN OUTCOME MEASURES: Predictive ability of the ML models and association of important variables. RESULTS: The ML models had an average area under the receiver operating characteristic curve for predicting HCE severity of 0.73 and 0.70 for the male and mixed datasets, respectively. The most important variables for prediction were the mechanism of injury and the event before injury. In the male dataset, the mechanisms "head-to-head" and "knee-to-head" were together significantly associated ( P = 0.0244) with severity; they were not significant in the mixed dataset ( P = 0.1113). In both datasets, the events "corner kicks" and "throw-ins" were together significantly associated with severity (male, P = 0.0001; mixed, P = 0.0004). CONCLUSIONS: ML models accurately predicted the severity of HCE. The mechanism and event preceding injury were most important for predicting severity of HCEs. These findings support the use of ML to inform preventative measures that will mitigate the impact of these preinjury factors on player health.

Editor's Choice - Peri-Operative Outcomes of Carotid Endarterectomy are Not Improved on Dual Antiplatelet Therapy vs. Aspirin Monotherapy: A Systematic Review and Meta-Analysis.

OBJECTIVE: A systematic review and meta-analysis of the peri-operative outcomes of carotid endarterectomy (CEA) on dual antiplatelet therapy (DAPT) vs. aspirin monotherapy was carried out, to determine optimal peri-operative management with these antiplatelet agents. DATA SOURCES: The Web of Science, Pubmed, and Embase databases were searched from inception to July 2021. The corresponding authors of excluded articles were contacted to obtain additional data for possible inclusion. REVIEW METHODS: The main outcomes included ischaemic complications (stroke, transient ischaemic attack [TIA], and transcranial Doppler [TCD] measured micro-emboli), haemorrhagic complications (haemorrhagic stroke, neck haematoma, and re-operation for bleeding), and composite outcomes. Pooled estimates using odds ratios (ORs) were combined using a random or fixed effects model based on the results of the chi square test and calculation of I2. RESULTS: In total, 47 411 patients were included in 11 studies, with 14 345 (30.2%) receiving DAPT and 33 066 (69.7%) receiving aspirin only. There was no significant difference in the rates of peri-operative stroke (OR 0.87, 95% confidence interval [CI] 0.72 - 1.05) and TIA (OR 0.78, 95% CI 0.52 - 1.17) despite a significant reduction in TCD measured micro-emboli (OR 0.19, 95% CI 0.10 - 0.35) in the DAPT compared with the aspirin monotherapy group. Subgroup analysis did not reveal any significant difference in ischaemic stroke risk between patients with asymptomatic and symptomatic carotid artery stenosis. DAPT was associated with an increased risk of neck haematoma (OR 2.79, 95% CI 1.87 - 4.18) and re-operation for bleeding (OR 1.98, 95% CI 1.77 - 2.23) vs. aspirin. Haemorrhagic stroke was an under reported outcome in the literature. CONCLUSION: This meta-analysis found that CEA while on DAPT increased the risk of haemorrhagic complications, with similar rates of ischaemic complications, vs. aspirin monotherapy. This suggests that the risks of performing CEA on DAPT outweigh the benefits, even in patients with symptomatic carotid stenosis. The overall quality of studies was low, and improved reporting of CEA outcomes in the literature is necessary.

Protective responses of older adults for avoiding injury during falls: evidence from video capture of real-life falls in long-term care.

BACKGROUND: falls are common in older adults, and any fall from standing height onto a rigid surface has the potential to cause a serious brain injury or bone fracture. Safe strategies for falling in humans have traditionally been difficult to study. OBJECTIVE: to determine whether specific 'safe landing' strategies (body rotation during descent, and upper limb bracing) separate injurious and non-injurious falls in seniors. DESIGN: observational cohort study. SETTING: two long-term care homes in Vancouver BC. METHODS: videos of 2,388 falls experienced by 658 participants (mean age 84.0 years; SD 8.1) were analysed with a structured questionnaire. General estimating equations were used to examine how safe landing strategies associated with documented injuries. RESULTS: injuries occurred in 38% of falls, and 4% of falls caused injuries treated in hospitals. 32% of injuries were to the head. Rotation during descent was common and protective against injury. In 43% of falls initially directed forward, participants rotated to land sideways, which reduced their odds for head injury 2-fold. Upper limb bracing was used in 58% of falls, but rather than protective, bracing was associated with an increased odds for injury, possibly because it occurred more often in the demanding scenario of forward landings. CONCLUSIONS: the risk for injury during falls in long-term care was reduced by rotation during descent, but not by upper limb bracing. Our results expand our understanding of human postural responses to falls, and point towards novel strategies to prevent fall-related injuries.

Effect of a new concussion substitute rule on medical assessment of head collision events in Premier League football.

OBJECTIVE: To investigate the utilisation of additional permanent concussion substitutes (APCSs) and its efficacy with regards to rate and duration of medical assessment of head collision events (HCEs) in the 2020-2021 Premier League season. The present APCS rule allows players with a suspected concussion to be removed from a match without counting towards a team's allocated substitutions. METHODS: Eighty Premier League matches, 40 prior to additional permanent concussion substitutes implementation (Pre-APCS) and 40 after (Post-APCS), were randomly selected and analysed by a team of trained reviewers for HCEs. Data on HCE incidence, rates of medical assessment, duration of medical assessment and return to play were collected for each match. Data for the Pre-APCS and Post-APCS groups were compared to analyse differences in assessment of HCEs. RESULTS: During the 2020-2021 Premier League season, three APCSs were used. There were 38 HCEs identified in the Pre-APCS group (0.95 per match, 28.79 per 1000 athlete-hours of exposure) and 42 in the Post-APCS group (1.05 per match, 31.82 per 1000 athlete-hours of exposure). Incidence of HCEs (p=0.657), rates of medical assessment (23.7% Pre-APCS vs 21.4% Post-APCS; p=0.545) and duration of medical assessment (median 81 s Pre-APCS vs 102 s Post-APCS; p=0.466) did not significantly differ between the two groups. CONCLUSIONS: The implementation of APCSs in the Premier League did not impact the rate or duration of medical assessement of HCEs. Despite the introduction of APCSs, the consensus protocols for HCE assessment were rarely followed. We recommend changes to APCS and its implementation that would be aimed at protecting player health.

Injuries from falls by older adults in long-term care captured on video: Prevalence of impacts and injuries to body parts.

BACKGROUND: Falls are the leading cause of injuries in older adults. However, most falls in older adults do not cause serious injury, suggesting that older adults may fall in a manner that reduces the likelihood of impact to body sites that are most vulnerable to injury. In this observational study of falls in long-term care (LTC), we tested whether body parts differed in their probability of impact and injury. METHODS: We recorded and analyzed videos of 2388 falls by 658 LTC residents (mean age 84.0 (SD = 8.1); 56.4% female). We used Linear Mixed Models to test for differences between body parts in the probability of impact and injury, and injury when impacts occurred. RESULTS: Injuries were reported in 38.2% of falls, and 85.9% of injuries involved direct impact to the injured body part. Impact occurred most often to the hip/pelvis (probability (standard error) = 0.95 (0.01); p < .001 relative to other body parts), and least often to the head (0.35 (0.01)). Conversely, injury occurred most often to the head (p < .001 relative to other body parts). The probability of injury when impacts occurred was 0.40 (0.01) for the head, and 0.11 or less for all other body parts. CONCLUSION: Our results help to explain why most falls by older adults in LTC do not cause serious injury: residents land on body parts that are the most resilient to injury. The high susceptibility of the head to injury reinforces the need to enhance upper limb protective responses for fall arrest. The dominant role of direct impact as the mechanism of injury supports approaches to attenuate impact forces through strategies like protective clothing and compliant flooring.

Pituitary neuroendocrine tumors: a model for neuroendocrine tumor classification.

The classification of adenohypophysial neoplasms as "pituitary neuroendocrine tumors" (PitNETs) was proposed in 2017 to reflect their characteristics as epithelial neuroendocrine neoplasms with a spectrum of clinical behaviors ranging from small indolent lesions to large, locally invasive, unresectable tumors. Tumor growth and hormone hypersecretion cause significant morbidity and mortality in a subset of patients. The proposal was endorsed by a WHO working group that sought to provide a unified approach to neuroendocrine neoplasia in all body sites. We review the features that are characteristic of neuroendocrine cells, the epidemiology and prognosis of these tumors, as well as further refinements in terms used for other pituitary tumors to ensure consistency with the WHO framework. The intense study of PitNETs has provided information about the importance of cellular differentiation in tumor prognosis as a model for neuroendocrine tumors in different locations.

Sinonasal Chondrosarcoma Presenting With Isolated Severe Vision Loss.

ABSTRACT: A 24-year-old man presented with a 2-month history of progressive, painless vision loss in the right eye, with no history of headache, nasal congestion, rhinorrhea, or epistaxis. His visual acuity was counting fingers at 1 ft in the right eye and 20 of 20 in the left eye with a right relative afferent pupillary defect and mild temporal optic disc pallor. MRI of the brain and orbits showed a mass involving bilateral ethmoid and sphenoid sinuses and right nasal cavity. He underwent urgent extended endoscopic endonasal transsphenoidal approach for resection of the sinonasal skull base tumor and photon radiation therapy. Pathology revealed a well-differentiated cartilaginous neoplasm with focal areas of entrapped native bone, consistent with a chondrosarcoma WHO grade I/III. At 6-month follow-up after surgery, he had a visual acuity of 20/40 in the right eye and 20/20 in the left eye. Malignant tumors from the sinonasal area should be kept in the differential diagnosis for compressive optic neuropathies and may present with vision loss even in the absence of nasal or sinus symptoms.

Characteristics of potential concussive events in elite male gaelic football players: A descriptive video-analysis.

Gaelic football (GF) is a high-impact sport and Sport-Related Concussion (SRC) is an issue within the game. Our aim was to evaluate the characteristics of Potential Concussive Events (PCEs) that occur in the Gaelic Athletic Association National Football League and extrapolate this data to reduce the incidence and severity of SRC. PCEs may or may not lead to a clinical diagnosis of SRC, but represent high-risk events and therefore may be a useful indicator. A video-analysis approach was undertaken to identify PCEs throughout two seasons of play using broadcast footage, and characteristics of each PCE were measured based on previously validated methods. A total of 242 PCEs were identified over 111 matches (2.18 per match, 58.14 per 1000 hours of exposure). PCEs were frequently not anticipated by the player (40.5%, n = 98). The most common impact locations were the mandibular region (33.1%, n = 80) and the temporal region (21.1%, n = 51), and the most frequently observed mechanism was hand/fist to head (27.3%, n = 66). A second-hit was observed in 34 PCEs (14.0%). The findings provide initial guidance for the development of player protection strategies to reduce the incidence and severity of SRC in Gaelic Football.

Data Driven Analysis Reveals Shared Transcriptome Response, Immune Cell Composition, and Distinct Mortality Rates Across Differing Etiologies of Critical Illness.

OBJECTIVES: Sepsis and trauma are common health problems and provide great challenges in critical care. Diverse patient responses to these conditions further complicate patient management and outcome prediction. Whole blood transcriptomics provides a unique opportunity to follow the molecular response in the critically ill. Prior results show robust and diverse genomic signal in the acute phase and others have found shared biological mechanisms across divergent disease etiologies. We hypothesize that selected transcriptomics responses, particularly immune mechanisms are shared across disease etiologies. We further hypothesize that these processes may identify homogenous patient subgroups with shared clinical course in critical illness deciphering disease heterogeneity. These processes may serve as universal markers for predicting a complicated clinical course and/or risk of a poor outcome. DESIGN: We present a system level, data driven, genome-wide analysis of whole blood gene expression for a total of 382 patients suffering from either abdominal sepsis (49), pulmonary sepsis (107) or trauma (158) and compare these to gene expression in healthy controls (68). PATIENTS AND SETTING: We relied on available open genetic data from gene expression omnibus for patients diagnosed with abdominal sepsis, community-acquired pneumonia, or trauma which also included healthy control patients. MEASUREMENTS AND MAIN RESULTS: Our results confirm that immune processes are shared across disease etiologies in critical illnesses. We identify two consistent and distinct patient subgroups through deconvolution of serum transcriptomics: 1) increased neutrophils and naïve CD4 cell fractions and 2) suppressed neutrophil fraction. Furthermore, we found immune and inflammatory processes were downregulated in subgroup 2, a configuration previously shown to be more susceptible to multiple organ failure. Correspondingly, this subgroup had significantly higher mortality rates in all three etiologies of illness (0% vs 6.1%, p = 3.1 × 10 for trauma; 15.0% vs 25.4%, p = 4.4 × 10 for community-acquired pneumonia, and 7.1% vs 20.0%, p = 3.4 × 10 for abdominal sepsis). CONCLUSIONS: We identify two consistent subgroups of critical illness based on serum transcriptomics and derived immune cell fractions, with significantly different survival rates. This may serve as a universal predictor of complicated clinical course or treatment response and, importantly, may identify opportunities for subgroup-specific immunomodulatory intervention.

Machine learning applications in imaging analysis for patients with pituitary tumors: a review of the current literature and future directions.

PURPOSE: To provide an overview of fundamental concepts in machine learning (ML), review the literature on ML applications in imaging analysis of pituitary tumors for the last 10 years, and highlight the future directions on potential applications of ML for pituitary tumor patients. METHOD: We presented an overview of the fundamental concepts in ML, its various stages used in healthcare, and highlighted the key components typically present in an imaging-based tumor analysis pipeline. A search was conducted across four databases (PubMed, Ovid, Embase, and Google Scholar) to gather research articles from the past 10 years (2009-2019) involving imaging related to pituitary tumor and ML. We grouped the studies by imaging modalities and analyzed the ML tasks in terms of the data inputs, reference standards, methodologies, and limitations. RESULTS: Of the 16 studies included in our analysis, 10 appeared in 2018-2019. Most of the studies utilized retrospective data and followed a semi-automatic ML pipeline. The studies included use of magnetic resonance imaging (MRI), facial photographs, surgical microscopic video, spectrometry, and spectroscopy imaging. The objectives of the studies covered 14 distinct applications and majority of the studies addressed a binary classification problem. Only five of the 11 MRI-based studies had an external validation or a holdout set to test the performance of a final trained model. CONCLUSION: Through our concise evaluation and comparison of the studies using the concepts presented, we highlight future directions so that potential ML applications using different imaging modalities can be developed to benefit the clinical care of pituitary tumor patients.

Characteristics of potential concussive events in three elite football tournaments.

OBJECTIVE: Identify patterns in the nature and characteristics of potential concussive events (PCEs) in football. METHODS: This study analysed the incidence and characteristics of PCEs that occurred during the 2014 and 2018 Fédération Internationale de Football Association World Cups, and the 2016 UEFA Euro Cup. PCEs were defined as direct head collision incidents resulting in the athlete being unable to immediately resume play for at least 5 sec following impact. RESULTS: A total of 218 incidents were identified in 179 matches (1.22 per match, 36.91 per 1000 hours of exposure). The most common mechanism of PCE was elbow-to-head (28.7%, n=68). The frontal region was the most frequently affected location of impact with 22.8% (n=54). CONCLUSION: Our study defined the identification, prevalence and nature of PCEs in professional international soccer tournaments. Our findings indicate the different contexts and mechanisms of head contact and contact to different regions of the head can be associated with varying signs of concussion. The results highlight targets for future injury prevention strategies.

Professional assessment of potential concussions in elite football tournaments.

BACKGROUND: Potential concussive events (PCEs) are a major health concern in football. Though there are protocols set in place for assessments of PCEs, there has been no evidence of adherence in major football tournaments. METHODS: Our research goal is to determine if PCEs in elite football are professionally assessed according to the International Conference on Concussion in Sport (ICCS) consensus statement recommendations. Identification and analysis of PCEs in the 2018 World Cup (WC) were accomplished through standardised observation of video footage by trained observers. Results were contrasted with data from the 2014 WC and 2016 Euro Cup. Our primary outcomes include frequency and professional assessment of PCEs, signs of concussions and time stopped for assessments. FINDINGS: In the 64 games of the 2018 WC, 87 PCEs (1.36 per game) were identified. Thirty-one (35.6%) PCEs were professionally assessed, resulting in the removal of three (3.5%) players from the match. Six (6.9%) PCEs showed one sign of concussion, 60 (69.0%) showed two signs, 20 (23.0%) showed three signs and 1 (1.2%) showed four or more signs. The mean time stopped for assessment was 63.3 s. No significant change in the percentage of professional assessments (mean=33.4%, 95% CI 20.7% to 46.1%) were identified across tournaments (p=0.42). INTERPRETATION: These findings demonstrate a need for adherence to concussion protocols in order to improve the brain-health of athletes. Proper enforcement of the ICCS protocols during these tournaments and promoting player health and safety can influence the officiating, coaching and playing of football worldwide by promoting player safety.

Effect of bilateral scalp nerve blocks on postoperative pain and discharge times in patients undergoing supratentorial craniotomy and general anesthesia: a randomized-controlled trial.

PURPOSE: Post-craniotomy pain is a common clinical issue and its optimal management remains incompletely studied. Utilization of a regional scalp block has the potential advantage of reducing perioperative pain and opioid consumption, thereby facilitating optimal postoperative neurologic assessment. The purpose of this study was to assess the efficacy of regional scalp block on post-craniotomy pain and opioid consumption. METHODS: We performed a prospective randomized-controlled trial in adults scheduled to undergo elective supratentorial craniotomy under general anesthesia to assess the efficacy of postoperative bilateral scalp block with 0.5% bupivacaine with 1:200,000 epinephrine compared with placebo on postoperative pain and opioid consumption. The primary outcome was the visual analogue scale (VAS) for pain at 24 hr postoperatively. RESULTS: Eighty-nine patients were enrolled (n = 44 in block group; n = 45 in control group). There was no difference in the mean (standard deviation) VAS score at 24 hr postoperatively between the treatment group and the control group [31.2 (21.4) mm vs 23.0 (19.2) mm, respectively; mean difference, 6.6; 95% confidence interval, -2.3, 15.5; P = 0.15]. There was also no significant difference in postoperative opioid consumption. Distribution of individual VAS score and opioid consumption revealed that postoperative pain was highly variable following craniotomy. Time to hospital discharge was not different between treatment and placebo groups. No adverse events associated with scalp block were identified. CONCLUSION: These data show that bilateral scalp blocks using bupivacaine with epinephrine did not reduce mean postoperative VAS score or overall opioid consumption at 24 hr nor the time-to-discharge from the postanesthesia care unit or from hospital. TRIAL REGISTRATION: www.ClinicalTrials.gov, NCT00972790; registered 9 September, 2009.

A population-based study of fall-related traumatic brain injury identified in older adults in hospital emergency departments.

OBJECTIVE: The purpose of this study was to examine the population-based trends and factors associated with hospitalization of patients with traumatic brain injury (TBI) treated in the Emergency Department (ED) among those 65 years and older. The implications of these trends for neurosurgery and the broader society are discussed. METHOD: With a national, mandatory reporting system of ED visits, the authors used Poisson regression controlling for age and sex to analyze trends in fall-related TBI of those aged 65 years and older between 2002 and 2017. RESULTS: The overall rate of ED visits for TBI increased by 78%-from 689.51 per 100,000 (95% CI 676.5-702.8) to 1229 per 100,000 (95% CI 1215-1243) between 2002 and 2017. Females consistently experienced higher rates of fall-related TBI than did males. All age groups 65 years and older experienced significant increases in fall-related TBI rate over the study period; however, the highest rates occurred among the oldest individuals (90+ and 85-89 years). The hospital admission rate increased with age and Charlson Comorbidity Index. Males experienced both a higher admission rate and a greater percentage change in admission rate than females. CONCLUSIONS: Rates of ED visits for fall-related TBI, hospitalization, and in-ED mortality in those aged 65 years and older are increasing for both sexes. The increasing hospital admission rate is related to more advanced comorbidities, male sex, and increasing age. These findings have significant implications for neurosurgical resources; they emphasize that health professionals should work proactively with patients, families, and caregivers to clarify goals of care, and they also outline the need for more high-level and, preferably, randomized evidence to support outcomes-based decisions. Additionally, the findings highlight the urgent need for improved population-based measures for prevention in not only this age demographic but in younger ones, and the need for changes in the planning of health service delivery and long-term care.

Development and validation of the disease-specific QOL-CD quality of life questionnaire for patients with Cushing's disease.

OBJECTIVE: Cushing's disease (CD) patients experience a range of debilitating symptoms that impair quality of life (QOL) as assessed using generic measures. These generic measures are inadequate to capture the disease-specific burden of illness. The development of the CD-specific QOL-CD measure of QOL using items generated by CD patients and healthcare professionals will provide a holistic assessment of patient outcomes and efficacy of novel therapies. METHODS: A total of 96 CD patients participated. A list of 177 items (version 1.0) was generated by treated CD patients (n = 9), caregivers (n = 2), healthcare providers (n = 7), and results of a MEDLINE search. Item reduction was performed through content analysis and dual scaling. Patients' rating of importance was incorporated to reduce to a final version of 56 items (version 3.0). Evidence for test-retest reliability was sought through administering the QOL-CD 1 week apart and Cronbach's α of each subscale. Construct validity was assessed through extreme group analysis and comparison with the normal Canadian population. Concurrent validity was sought through comparison with the SF-36, Functional Assessment of Cancer Therapy-Brain (FACT-Br), and Karnofsky Performance Status (KPS). Perioperative testing was conducted on CD patients (n = 25) against nonfunctioning pituitary adenoma controls (n = 25) through pre- and postoperative testing. RESULTS: A total of 96 CD patients (86 females and 10 males; mean age 45.23 ± 14.16 years) participated. The QOL-CD was feasible (mean completion time 15 minutes, with 70% believing accurate capture of QOL), reliable (CD 1 week apart: r = 0.86; control 1 week apart: r = 0.83; Cronbach's α: general health = 0.73, emotional health = 0.85, physical health = 0.78, mental status = 0.82, social well-being = 0.63, medical treatment = 0.54), and valid (extreme group testing p < 0.001; SF-36 and QOL-CD general health: r = 0.56, social well-being: r = 0.21, emotional health: r = 0.61, total score: r = 0.58; FACT-Br and QOL-CD physical health: r = 0.47, social well-being: r = 0.21, emotional health: r = 0.34, total score: r = 0.68; KPS and QOL-CD general health: r = 0.32, total score: r = 0.14). Perioperative testing of CD patients (n = 25) demonstrated improvement in all subscales postoperatively, with a significant difference in emotional health (p < 0.001) and physical health (p < 0.001). CONCLUSIONS: The QOL-CD questionnaire has been developed for patients with CD and has demonstrated evidence for validity and reliability.

Characterization of a Clival Chordoma Xenograft Model Reveals Tumor Genomic Instability.

Patient-derived xenografts retain the genotype of the parent tumors more readily than tumor cells maintained in culture. The two previously reported clival chordoma xenografts were derived from recurrent tumors after radiation. To study the genetics of clival chordoma in the absence of prior radiation exposure we established a patient-derived xenograft at primary resection of a clival chordoma. Epicranial grafting of clival chordoma collected during surgery was performed. Tumor growth was established in a nonobese diabetic/severe combined immunodeficiency mouse and tumors have been passaged serially for seven generations. Physaliferous cell architecture was shown in the regenerated tumors, which stained positive for Brachyury, cytokeratin, and S100 protein. The tumors showed bone invasion. Single-nucleotide polymorphism analysis of the tumor xenograft was compared with the parental tumor. Copy number gain of the T gene (brachyury) and heterozygous loss of cyclin dependent kinase inhibitor 2A (CDKN2A) was observed. Heterozygous loss of the tumor-suppressor fragile histidine triad (FHIT) gene also was observed, although protein expression was preserved. Accumulation of copy number losses and gains as well as increased growth rate was observed over three generations. The patient-derived xenograft reproduces the phenotype of clival chordoma. This model can be used in the future to study chordoma biology and to assess novel treatments.