Do preinjury life events moderate the outcomes of mild traumatic brain injuries in children? An A-CAP Study.

OBJECTIVE: To examine preinjury life events as moderators of postconcussive symptoms (PCS) and quality of life (QoL) in children with pediatric mild traumatic brain injury (mTBI) versus orthopedic injury (OI). METHODS: Participants were 633 children with mTBI and 334 with OI, ages 8-16.99, recruited from 5 pediatric emergency departments and followed for 6 months postinjury as part of a prospective cohort study. Preinjury life events were measured retrospectively using the Child and Adolescent Survey of Experiences, PCS using the Health and Behavior Inventory (HBI) and Post-Concussion Symptom Interview (PCS-I), and QoL using the Pediatric Quality of Life Inventory (PedsQL). Analyses involved longitudinal regression using restricted cubic splines, with group, positive and negative life events, and time as primary predictors. Covariates included age, sex, race, socioeconomic status, preinjury history (i.e., headache, migraine, previous concussion), and parent-rated retrospective PCS-I, HBI, and PedsQL scores. RESULTS: PCS and QoL were worse after mTBI than OI, but group differences declined with time (all p < .001). Group differences in PCS were larger at higher levels of positive life events, which predicted lower PCS (p= .03 to p < .001) and higher QoL (p = .048) after OI but not after mTBI. Negative life events predicted worse PCS and QoL in both groups (p = .002 to p < .001). CONCLUSIONS: Preinjury positive life events moderate outcomes after pediatric injury, with a protective effect seen in OI but not in mTBI. Negative life events are consistently associated with worse outcomes regardless of injury type.

Brain metabolites measured with magnetic resonance spectroscopy in pediatric concussion and orthopedic injury: An Advancing Concussion Assessment in Pediatrics (A-CAP) study.

Millions of children sustain a concussion annually. Concussion disrupts cellular signaling and neural pathways within the brain but the resulting metabolic disruptions are not well characterized. Magnetic resonance spectroscopy (MRS) can examine key brain metabolites (e.g., N-acetyl Aspartate (tNAA), glutamate (Glx), creatine (tCr), choline (tCho), and myo-Inositol (mI)) to better understand these disruptions. In this study, we used MRS to examine differences in brain metabolites between children and adolescents with concussion versus orthopedic injury. Children and adolescents with concussion (n = 361) or orthopedic injury (OI) (n = 184) aged 8 to 17 years were recruited from five emergency departments across Canada. MRS data were collected from the left dorsolateral prefrontal cortex (L-DLPFC) using point resolved spectroscopy (PRESS) at 3 T at a mean of 12 days post-injury (median 10 days post-injury, range 2-33 days). Univariate analyses for each metabolite found no statistically significant metabolite differences between groups. Within each analysis, several covariates were statistically significant. Follow-up analyses designed to account for possible confounding factors including age, site, scanner, vendor, time since injury, and tissue type (and interactions as appropriate) did not find any metabolite group differences. In the largest sample of pediatric concussion studied with MRS to date, we found no metabolite differences between concussion and OI groups in the L-DLPFC. We suggest that at 2 weeks post-injury in a general pediatric concussion population, brain metabolites in the L-DLPFC are not specifically affected by brain injury.

Can quantitative susceptibility mapping help diagnose and predict recovery of concussion in children? An A-CAP study.

BACKGROUND: Quantitative susceptibility mapping (QSM) is an MRI technique that is a potential biomarker for concussion. We performed QSM in children following concussion or orthopaedic injury (OI), to assess QSM performance as a diagnostic and prognostic biomarker. METHODS: Children aged 8-17 years with either concussion (N=255) or OI (N=116) were recruited from four Canadian paediatric emergency departments and underwent QSM postacutely (2-33 days postinjury) using 3 Tesla MRI. QSM Z-scores within nine regions of interest (ROI) were compared between groups. QSM Z-scores were also compared with the 5P score, the current clinical benchmark for predicting persistent postconcussion symptoms (PPCS), at 4 weeks postinjury, with PPCS defined using reliable change methods based on both participant and parent reports. RESULTS: Concussion and OI groups did not differ significantly in QSM Z-scores for any ROI. Higher QSM Z-scores within frontal white matter (WM) independently predicted PPCS based on parent ratings of cognitive symptoms (p=0.001). The combination of frontal WM QSM Z-score and 5P score was better at predicting PPCS than 5P score alone (p=0.004). The area under the curve was 0.72 (95% CI 0.63 to 0.81) for frontal WM susceptibility, 0.69 (95% CI 0.59 to 0.79) for the 5P score and 0.74 (95% CI 0.65 to 0.83) for both. CONCLUSION: The findings suggest that QSM is a potential MRI biomarker that can help predict PPCS in children with concussion, over and above the current clinical benchmark, and thereby aid in clinical management. They also suggest a frontal lobe substrate for PPCS, highlighting the potential for QSM to clarify the neurophysiology of paediatric concussion.

Factor structure and measurement invariance of post-concussion symptom ratings on the Health and Behaviour Inventory across time, raters, and groups: An A-CAP study.

OBJECTIVES: To validate the two-factor structure (i.e., cognitive and somatic) of the Health and Behaviour Inventory (HBI), a widely used post-concussive symptom (PCS) rating scale, through factor analyses using bifactor and correlated factor models and by examining measurement invariance (MI). METHODS: PCS ratings were obtained from children aged 8-16.99 years, who presented to the emergency department with concussion (n = 565) or orthopedic injury (OI) (n = 289), and their parents, at 10-days, 3-months, and 6-months post-injury. Item-level HBI ratings were analyzed separately for parents and children using exploratory and confirmatory factor analyses (CFAs). Bifactor and correlated models were compared using various fit indices and tested for MI across time post-injury, raters (parent vs. child), and groups (concussion vs. OI). RESULTS: CFAs showed good fit for both a three-factor bifactor model, consisting of a general factor with two subfactors (i.e., cognitive and somatic), and a correlated two-factor model with cognitive and somatic factors, at all time points for both raters. Some results suggested the possibility of a third factor involving fatigue. All models demonstrated strict invariance across raters and time. Group comparisons showed at least strong or strict invariance. CONCLUSIONS: The findings support the two symptom dimensions measured by the HBI. The three-factor bifactor model showed the best fit, suggesting that ratings on the HBI also can be captured by a general factor. Both correlated and bifactor models showed substantial MI. The results provide further validation of the HBI, supporting its use in childhood concussion research and clinical practice.

Concurrent Psychosocial Concerns and Post-Concussive Symptoms Following Pediatric mTBI: An A-CAP Study.

OBJECTIVES: To measure the association between psychosocial problems and persistent post-concussive symptoms (PCS) in youth who were seen in the emergency department with mild traumatic brain injury (mTBI) or orthopedic injury (OI). METHODS: From a larger prospective cohort study, Advancing Concussion Assessment in Pediatrics (A-CAP), 122 child-guardian pairs who presented to the emergency department with mTBI (N = 70) or OI (N = 52) were recruited for this cross-sectional sub-study. Each pair completed 2 measures assessing PCS burden at 2 weeks, 3 months, and 6 months post-injury. At one visit, pairs concurrently completed MyHEARTSMAP, a comprehensive, psychosocial self-assessment tool to evaluate 4 domains of mental wellness. RESULTS: When measured at the same visit, children who self-reported moderate or severe Psychiatry domain concerns concurrently experienced a greater burden of cognitive symptoms (ß = 5.49; 0.93-10.05) and higher overall PCS count (ß = 2.59; 0.70-4.48) after adjusting for covariables, including retrospective pre-injury symptoms and injury group. Additionally, reports indicating mild Function domain severity were associated with increased cognitive (ß = 3.34; 95% CI: 0.69-5.99) and somatic symptoms (ß = 6.79; 2.15-11.42) and total symptom count (ß = 1.29; 0.18-2.39). CONCLUSION: Increasing severity in multiple domains of mental health is associated with more PCS in youth. While the differences in PCS between the mTBI and OI groups appeared somewhat larger for children with more mental health concerns, the interaction was not statistically significant; larger sample sizes are needed to evaluate the moderating effect of psychosocial difficulties on post-concussion symptoms.

A Prospective Cohort Study of the Association Between Preinjury Psychosocial Function and Postconcussive Symptoms in Pediatric Mild Traumatic Brain Injury: An A-CAP Study.

OBJECTIVE: We evaluated the moderating effect of preinjury psychosocial function on postconcussion symptoms for children with mild traumatic brain injury (mTBI). DESIGN, SETTING, AND POPULATION: We conducted a prospective cohort study of children ages 8.0 to 16.9 years with mTBI ( n = 633) or orthopedic injury (OI; n = 334), recruited from 5 pediatric emergency departments from September 2016 to December 2018. MAIN MEASURES: Participants completed baseline assessments within 48 hours of injury, and postconcussion symptoms assessments at 7 to 10 days, weekly to 3 months, and biweekly to 6 months post-injury. Preinjury psychosocial function was measured using parent ratings on the Pediatric Quality of Life Inventory (PedsQL) and the Strengths and Difficulties Questionnaire (SDQ), retrospectively evaluating their child's status prior to the injury. Parent and child ratings on the Health and Behavior Inventory (HBI) (cognitive and somatic subscales) and the Post-Concussion Symptom Interview (PCS-I) were used as measures of postconcussion symptoms. We fitted 6 longitudinal regression models, which included 747 to 764 participants, to evaluate potential interactions between preinjury psychosocial function and injury group as predictors of child- and parent-reported postconcussion symptoms. RESULTS: Preinjury psychosocial function moderated group differences in postconcussion symptoms across the first 6 months post-injury. Higher emotional and conduct problems were significantly associated with more severe postconcussion symptoms among children with mTBI compared with OI. Wald's χ 2 for interaction terms (injury group × SDQ subscales) ranged from 6.3 to 10.6 ( P values <.001 to .043) across parent- and child-reported models. In contrast, larger group differences (mTBI > OI) in postconcussion symptoms were associated with milder hyperactivity (Wald's χ 2 : 15.3-43.0, all P < .001), milder peer problems (Wald's χ 2 : 11.51, P = .003), and higher social functioning (Wald's χ 2 : 12.435, P = .002). CONCLUSIONS: Preinjury psychosocial function moderates postconcussion symptoms in pediatric mTBI, highlighting the importance of assessing preinjury psychosocial function in children with mTBI.

Convergent Validity of Myheartsmap: A Pediatric Psychosocial Health Screening Tool.

Recognition of pediatric mental health concerns often depends on assessment by parents, educators, and primary care professionals. Therefore, a psychosocial screening instrument suitable for routine use in schools and primary care is needed. The Pediatric Quality of Life (PedsQL) and the Strengths and Difficulties Questionnaire (SDQ) are widely used for screening but lack adolescent-specific mental health measures. MyHEARTSMAP is an instrument assessing aspects of youth psychosocial health via four domains: Psychiatry, Function, Social, and Youth Health. We evaluated MyHEARTSMAP convergent validity with PedsQL and SDQ among 122 child-parent dyads participating in a larger concussion study. Convergent validity was assessed via correlations: MyHEARTSMAP Psychiatry and Function domains correlated strongly (r ≥ 0.44) and Social domain correlated weakly (r ≤ 0.25) to corresponding PedsQL and SDQ subscales, while Youth Health domain correlated moderately (r ≥ 0.31) to the tools' total scales. In conclusion, MyHEARTSMAP converges with PedsQL and SDQ, and benefits from the inclusion of adolescent-specific psychosocial measures.

Structural connectome differences in pediatric mild traumatic brain and orthopedic injury.

Sophisticated network-based approaches such as structural connectomics may help to detect a biomarker of mild traumatic brain injury (mTBI) in children. This study compared the structural connectome of children with mTBI or mild orthopedic injury (OI) to that of typically developing (TD) children. Children aged 8-16.99 years with mTBI (n = 83) or OI (n = 37) were recruited from the emergency department and completed 3T diffusion MRI 2-20 days postinjury. TD children (n = 39) were recruited from the community and completed diffusion MRI. Graph theory metrics were calculated for the binarized average fractional anisotropy among 90 regions. Multivariable linear regression and linear mixed effects models were used to compare groups, with covariates age, hemisphere, and sex, correcting for multiple comparisons. The two injury groups did not differ on graph theory metrics, but both differed from TD children in global metrics (local network efficiency: TD > OI, mTBI, d = 0.49; clustering coefficient: TD < OI, mTBI, d = 0.49) and regional metrics for the fusiform gyrus (lower degree centrality and nodal efficiency: TD > OI, mTBI, d = 0.80 to 0.96; characteristic path length: TD < OI, mTBI, d = -0.75 to -0.90) and in the superior and middle orbital frontal gyrus, paracentral lobule, insula, and thalamus (clustering coefficient: TD > OI, mTBI, d = 0.66 to 0.68). Both mTBI and OI demonstrated reduced global and regional network efficiency and segregation as compared to TD children. Findings suggest a general effect of childhood injury that could reflect pre- and postinjury factors that can alter brain structure. An OI group provides a more conservative comparison group than TD children for structural neuroimaging research in pediatric mTBI.

Longitudinal white matter microstructural changes in pediatric mild traumatic brain injury: An A-CAP study.

In the largest sample studied to date, white matter microstructural trajectories and their relation to persistent symptoms were examined after pediatric mild traumatic brain injury (mTBI). This prospective, longitudinal cohort study recruited children aged 8-16.99 years with mTBI or mild orthopedic injury (OI) from five pediatric emergency departments. Children's pre-injury and 1-month post-injury symptom ratings were used to classify mTBI with or without persistent symptoms. Children completed diffusion-weighted imaging at post-acute (2-33 days post-injury) and chronic (3 or 6 months via random assignment) post-injury assessments. Mean diffusivity (MD) and fractional anisotropy (FA) were derived for 18 white matter tracts in 560 children (362 mTBI/198 OI), 407 with longitudinal data. Superior longitudinal fasciculus FA was higher in mTBI without persistent symptoms relative to OI, d (95% confidence interval) = 0.31 to 0.37 (0.02, 0.68), across time. In younger children, MD of the anterior thalamic radiations was higher in mTBI with persistent symptoms relative to both mTBI without persistent symptoms, 1.43 (0.59, 2.27), and OI, 1.94 (1.07, 2.81). MD of the arcuate fasciculus, -0.58 (-1.04, -0.11), and superior longitudinal fasciculus, -0.49 (-0.90, -0.09) was lower in mTBI without persistent symptoms relative to OI at 6 months post-injury. White matter microstructural changes suggesting neuroinflammation and axonal swelling occurred chronically and continued 6 months post injury in children with mTBI, especially in younger children with persistent symptoms, relative to OI. White matter microstructure appears more organized in children without persistent symptoms, consistent with their better clinical outcomes.

Paediatric post-concussive symptoms: symptom clusters and clinical phenotypes.

OBJECTIVE: To assess the co-occurrence and clustering of post-concussive symptoms in children, and to identify distinct patient phenotypes based on symptom type and severity. METHODS: We performed a secondary analysis of the prospective, multicentre Predicting and Preventing Post-concussive Problems in Pediatrics (5P) cohort study, evaluating children 5-17 years of age presenting within 48 hours of an acute concussion. Our primary outcome was the simultaneous occurrence of two or more persistent post-concussive symptoms on the Post-Concussion Symptom Inventory at 28 days post-injury. Analyses of symptom and patient clusters were performed using hierarchical cluster analyses of symptom severity ratings. RESULTS: 3063 patients from the parent 5P study were included. Median age was 12.1 years (IQR: 9.2-14.6 years), and 1857 (60.6%) were male. Fatigue was the most common persistent symptom (21.7%), with headache the most commonly reported co-occurring symptom among patients with fatigue (55%; 363/662). Headache was common in children reporting any of the 12 other symptoms (range: 54%-72%). Physical symptoms occurred in two distinct clusters: vestibular-ocular and headache. Emotional and cognitive symptoms occurred together more frequently and with higher severity than physical symptoms. Fatigue was more strongly associated with cognitive and emotional symptoms than physical symptoms. We identified five patient groups (resolved/minimal, mild, moderate, severe and profound) based on symptom type and severity. CONCLUSION: Post-concussive symptoms in children occur in distinct clusters, facilitating the identification of distinct patient phenotypes based on symptom type and severity. Care of children post-concussion must be comprehensive, with systems designed to identify and treat distinct post-concussion phenotypes.

Symptom Burden, School Function, and Physical Activity One Year Following Pediatric Concussion.

OBJECTIVES: To characterize symptom burden, school function, and physical activity in youth 1 year following acute concussion and those with subsequent repeat concussion. STUDY DESIGN: Secondary analysis of Predicting Persistent Postconcussive Problems in Pediatrics prospective, multicenter cohort study conducted in 9 Canadian emergency departments. Participants were children between ages 5 and 18 years who presented consecutively ≤48 hours of concussion and agreed to participate in a post hoc electronic survey 1 year after injury. Outcomes were assessed using a standardized 25-question symptom scale derived from the Post-Concussion Symptom Inventory-Parent; school function and physical activity outcomes were queried. The primary outcome was total symptom score 1 year following concussion, defined as the number of symptoms experienced more than before injury. RESULTS: Of 3052 youth enrolled in the Predicting Persistent Postconcussive Problems in Pediatrics study, 432 (median [IQR] age, 11.5 [9,14] years; 266 [62%] male) completed the 1-year survey; 34 respondents reported a repeat concussion. Following acute concussion, youth were more likely to be symptom-free than following repeat concussion (75% vs 50%; difference = 25% [95% CI 8-41]; P = .002) and to have recovered fully (90% vs 74%; difference = 17% [95% CI 5-34]; P = .002) after 1 year. Although physical symptoms were less 1 year after initial emergency department presentation for both groups (P < .001), youth with a repeat concussion reported greater headache persistence (26% vs 13%; difference = 13% [95% CI 1,31]; P = .024). Both groups returned to their normal school routine (100% vs 95%; difference = 5% [95% CI -5 to 8; P = .618). Youth without repeat concussion more frequently returned to normal physical activities (98% vs 85%; difference = 13% [95% CI 4-28]; P < .0001) and sport (95% vs 82%; difference = 13% [95% CI 3-29]; P = .009). CONCLUSIONS: Most youth are symptom-free and fully recovered 1 year following concussion. Some children with repeat concussion have worse outcomes and have delays in returning to normal school routines and sport.

Extended hard-X-ray emission in the inner few parsecs of the Galaxy.

The Galactic Centre hosts a puzzling stellar population in its inner few parsecs, with a high abundance of surprisingly young, relatively massive stars bound within the deep potential well of the central supermassive black hole, Sagittarius A* (ref. 1). Previous studies suggest that the population of objects emitting soft X-rays (less than 10 kiloelectronvolts) within the surrounding hundreds of parsecs, as well as the population responsible for unresolved X-ray emission extending along the Galactic plane, is dominated by accreting white dwarf systems. Observations of diffuse hard-X-ray (more than 10 kiloelectronvolts) emission in the inner 10 parsecs, however, have been hampered by the limited spatial resolution of previous instruments. Here we report the presence of a distinct hard-X-ray component within the central 4 × 8 parsecs, as revealed by subarcminute-resolution images in the 20-40 kiloelectronvolt range. This emission is more sharply peaked towards the Galactic Centre than is the surface brightness of the soft-X-ray population. This could indicate a significantly more massive population of accreting white dwarfs, large populations of low-mass X-ray binaries or millisecond pulsars, or particle outflows interacting with the surrounding radiation field, dense molecular material or magnetic fields. However, all these interpretations pose significant challenges to our understanding of stellar evolution, binary formation, and cosmic-ray production in the Galactic Centre.

Normative and Psychometric Characteristics of the Health and Behavior Inventory Among Children With Mild Orthopedic Injury Presenting to the Emergency Department: Implications for Assessing Postconcussive Symptoms Using the Child Sport Concussion Assessment Tool 5th Edition (Child SCAT5).

OBJECTIVE: The study sought to present normative and psychometric data and reliable change formulas for the Health and Behavior Inventory (HBI), a postconcussive symptom rating scale embedded in the Child Sport Concussion Assessment Tool 5th edition (Child SCAT5). DESIGN: Prospective cohort study with longitudinal follow-up. SETTING: Pediatric emergency departments (EDs). PARTICIPANTS: As part of 3 studies conducted in the United States and Canada between 2001 and 2019, 450 children aged 8 to 16 years with mild orthopedic injuries were recruited during ED visits and assessed postacutely (M = 9.38 days, SD = 3.31) and 1 month and 3 months postinjury. Independent variables were rater (child vs parent), sex, and age at injury. MAIN OUTCOME MEASURE: HBI ratings. METHODS: Children and parents rated children's symptoms at each time point; parents also rated children's preinjury symptoms retrospectively. Normative data (mean, SD, skewness, kurtosis, and percentiles) were computed for child and parent ratings. Internal consistency was assessed using Cronbach alpha (α), and test-retest reliability and interrater agreement were assessed with intraclass correlations (ICCs). Reliable change formulas were computed using linear regression and mixed models. RESULTS: HBI ratings were positively skewed. Mean ratings and percentiles were stable over time. Child and parent ratings demonstrated good-to-excellent internal consistency (α 0.76-0.94) and moderate-to-good test-retest reliability (ICC 0.51-0.76 between adjacent assessments). However, parent-child agreement was poor to moderate (ICC 0.31-0.69). CONCLUSIONS: The HBI demonstrates acceptable normative and psychometric characteristics. Modest parent-child agreement highlights the importance of multiple informants when assessing postconcussive symptoms. The results will facilitate the use of the HBI in research and clinical practice.

Paediatric injuries due to falls from windows and balconies: an 8-year prospective and retrospective review.

BACKGROUND: Unintentional falls from windows and balconies pose a serious health risk to children. Limited Canadian data describing such falls currently exist. This study aimed to describe the frequency, demographic characteristics, injury patterns, and risk factors associated with paediatric falls from windows and balconies. METHODS: This study employed both prospective data collection and retrospective medical record review. Prospectively, consenting families were enrolled from February 2015 to February 2017; retrospectively, charts from January 2009 to December 2014 were reviewed. Children 0 to 16 years of age, who presented to the Stollery Children's Hospital (Edmonton, Alberta) emergency department due to a fall from a window or balcony, were included. RESULTS: A total of 102 children were included; thirty were enrolled prospectively and 72 retrospectively. Median age was 4.5 years (interquartile range 2.83 to 6.83) with 63.7% (65 of 102) males. About 87.2% (89 of 102) of falls were from windows and 12.8% (13 of 102) from balconies. The median estimated height of fall was 4.1 m (interquartile range 3.04 to 4.73). About 58.4% (59 of 101) had at least one major injury (i.e., concussion, fractured skull, internal injury, fractured limb, severe laceration), 36.6% had minor injuries only (i.e., abrasions, contusions, sprains), and 5.0% had no documented injuries. There were no fatalities. About 30.4% (31 of 102) were admitted, with 48.4% of these children (15 of 31) requiring surgery. CONCLUSION: Most falls from windows and balconies occurred in children under the age of 5 years and were associated with serious morbidity, high admission rates, and need for surgery. Child supervision as well as installation of key safety features in windows may help minimize paediatric fall-related injuries.

Identification of populations likely to benefit from pharmacogenomic testing.

OBJECTIVES: Pharmacogenomic testing (PGX) implementation is rapidly expanding, including pre-emptive testing funded by health systems. PGX continues to develop an evidence base that it saves money and improves clinical outcomes. Identifying the potential impact of pre-emptive testing in specific populations may aid in the development of a business case. METHODS: We utilized a software tool that can evaluate patient drug lists and identified groups of patients most likely to benefit from implementation of a PGX testing program in a major medical system population. RESULTS: Medication lists were obtained for sixteen patient groups with a total of 82 613 patients. The percent of patients in each group with testing 'Recommended', 'Strongly recommended', or 'Required' ranged from 12.7% in the outpatient pediatric psychiatry group to 75.7% in the any adult inpatient age >50 years group. Some of the highest yield drugs identified were citalopram, simvastatin, escitalopram, metoprolol, clopidogrel, tramadol, and ondansetron. CONCLUSION: We demonstrate a significant number of patients in each group may have benefit, but targeting certain ones for pre-emptive testing may result in the initial highest yield for a health system.

Early versus delayed emergency department presentation following mild Traumatic Brain Injury and the presence of symptom at 1, 4 and 12 weeks in children.

OBJECTIVES: We evaluated the association between timing of presentation and postconcussive symptoms (PCS) at 1, 4 and 12 weeks after injury. METHODS: This was a secondary analysis of a prospective cohort study conducted in nine Canadian paediatric EDs in 2013-2015 (5P study). Participants were children who suffered a head injury within the preceding 48 hours and met Zurich consensus concussion diagnostic criteria. The exposure was the time between head injury and ED presentation. The primary outcome was the presence of PCS at 1 week defined by the presence of at least three symptoms on the Post-Concussion Symptom Inventory (PCSI). Secondary outcomes evaluated PCS at 4 and 12 weeks. Multivariable logistic regression analyses were adjusted for ED PCSI and other potential confounders. RESULTS: There were 3041 patients with a concussion in which timing of the injury was known. 2287 (75%) participants sought care in the first 12 hours, 388 (13%) 12-24 hours after trauma and 366 (12%) between 24 and 48 hours. Compared with children who sought care >24 hours after trauma, children who sought care in the first 12 hours had a significantly lower incidence of PCS at 1 week (OR: 0.55 (95% CI 0.41 to 0.75)) and 4 weeks (OR: 0.74 (95% CI 0.56 to 0.99)) but not at 12 weeks (OR: 0.88 (95% CI 0.63 to 1.23)). CONCLUSIONS: Patients who present early after a concussion appear to have a shorter duration of PCS than those presenting more than 12 hours later. Patients/families should be informed of the higher probability of PCS in children with delayed presentation.

Hydrogeological characterization of an alpine aquifer system in the Canadian Rocky Mountains.

Groundwater storage in alpine regions is essential for maintaining baseflows in mountain streams. Recent studies have shown that common alpine landforms (e.g., talus and moraine) have substantial groundwater storage capacity, but the hydrogeological connectivity between individual landforms has not been understood. This study characterizes the hydrogeology of an alpine cirque basin in the Canadian Rocky Mountains that contains typical alpine landforms (talus, meadow, moraines) and hydrological features (tarn, streams, and springs). Geological, hydrological, and hydrochemical observations were used to understand the overall hydrogeological setting of the study basin, and three different geophysical methods (electrical resistivity tomography, seismic refraction tomography, and ground penetrating radar) were used to characterize the subsurface structure and connectivity, and to develop a hydrogeological conceptual model. Geophysical imaging shows that the talus is typically 20-40 m thick and highly heterogeneous. The meadow sediments are only up to 11 m thick but are part of a 30-40-m-thick accumulation of unconsolidated material that fills a bedrock overdeepening (i.e. a closed, subglacial basin). A minor, shallow groundwater system feeds springs on the talus and streams on the meadow, whereas a deep system in the moraine supplies most of the water to the basin outlet springs, thereby serving as a 'gate keeper' of the basin. Although the hydrologic functions of the talus in this study are substantially different from other locations, primarily due to differences in bedrock lithology and geomorphic processes, the general conceptual framework developed in this study is expected to be applicable to other alpine regions.

Dans les régions alpines, le stockage des eaux souterraines est essentiel au maintien du débit de base des cours d'eau de montagne. De récentes études ont montré que les formes de relief alpin courants (par exemple le talus et la moraine) ont une capacité de stockage des eaux souterraines substantielle, mais la connectivité hydrogéologique entre les formes particulières de relief n'a pas été comprise. La présente étude caractérise l'hydrogéologie d'un bassin d'un cirque alpin des Montagnes Rocheuses Canadiennes qui présente des formes typiques de relief (talus, prairie, moraines) et des caractéristiques hydrogéologiques (petits lacs, cours d'eau et sources). Des observations géologiques, hydrologiques et hydrochimiques ont été utilisées pour comprendre le contexte hydrogéologique général du bassin étudié, et trois méthodes géophysiques différentes (tomographie par résistivité électrique, tomographie par sismique réfraction et géoradar) ont été utilisées pour caractériser la structure et la connectivité du sous-sol et pour développer un modèle conceptuel hydrogéologique. L'imagerie géophysique montre que le talus a généralement une épaisseur de 20­40 m et est fortement hétérogène. Les sédiments de la prairie n'ont que 11 m d'épaisseur mais font partie d'une accumulation épaisse de 30­40 m de matériel non consolidé, qui remplit un surcreusement profond dans le substratum (c-à-d, un bassin fermé sous-glaciaire). Un petit système aquifère phréatique nourrit des sources sur le talus et des cours d'eau sur la prairie, tandis que le système profond de la moraine fournit la plus grande partie de l'eau aux sources sortant du bassin, servant ainsi de « portier ¼ du bassin. Bien que les fonctions hydrologiques du talus soient dans cette étude substantiellement différentes de celles d'autres localisations, surtout en raison des différences de lithologie du socle et des processus géomorphologiques, on escompte que le schéma conceptuel général développé ici est applicable à d'autres régions alpines.

El almacenamiento de aguas subterráneas en las regiones alpinas es esencial para mantener los flujos de base en los cursos de agua de las montañas. Estudios recientes han demostrado que las formas de relieve alpino comunes (por ejemplo, el talud y la morena) tienen una capacidad importante de almacenamiento de aguas subterráneas, pero no se ha comprendido la interrelación hidrogeológica entre las distintas formas de relieve. Este estudio caracteriza la hidrogeología de una cuenca de circo alpino en las Rocky Mountains del Canadá que contiene las típicas formas de relieve alpino (talud, pradera, morenas) y características hidrológicas (lagunas, arroyos y manantiales). Se utilizaron observaciones geológicas, hidrológicas e hidroquímicas para comprender el contexto hidrogeológico general de la cuenca de estudio, y se emplearon tres métodos geofísicos diferentes (tomografía de resistividad eléctrica, tomografía de refracción sísmica y georradar) para caracterizar la estructura y la conectividad en el subsuelo, y para elaborar un modelo conceptual hidrogeológico. Las imágenes geofísicas muestran que el talud suele tener un espesor de 20 a 40 m y es muy heterogéneo. Los sedimentos de la pradera sólo tienen un espesor de hasta 11 m, pero forman parte de una acumulación de material no consolidado de 30­40 m de espesor que rellena un basamento sobreexcavado (es decir, una cuenca subglacial cerrada). Un sistema menor de aguas subterráneas poco profundas alimenta los manantiales en el talud y los arroyos en la pradera, mientras que un sistema profundo en la morena suministra la mayor parte del agua a los manantiales de salida de la cuenca, sirviendo, así como "portadora" de la cuenca. Aunque las funciones hidrológicas del talud en este estudio son sustancialmente diferentes de las de otros lugares, principalmente debido a las diferencias en la litología del basamento y los procesos geomórficos, se espera que el marco conceptual general desarrollado en este estudio sea aplicable a otras regiones alpinas.

O armazenamento de águas subterrâneas em regiões alpinas é essencial para manter os fluxos de base nos córregos das montanhas. Estudos recentes mostraram que formas de relevo alpinas comuns (por exemplo, tálus e morena) têm capacidade substancial de armazenamento de águas subterrâneas, mas a conectividade hidrogeológica entre formas de relevo individuais não foi compreendida. Este estudo caracteriza a hidrogeologia de uma bacia de circo alpino nas Montanhas Rochosas Canadenses que contém formas de relevo alpinas típicas (talus, prados, morenas) e características hidrológicas (tarn, córregos e nascentes). Observações geológicas, hidrológicas e hidroquímicas foram usadas para entender o cenário hidrogeológico geral da bacia em estudo e três métodos geofísicos diferentes (tomografia de resistividade elétrica, tomografia de refração sísmica e radar de penetração no solo) foram usados ​​para caracterizar a estrutura e a conectividade do subsolo, e desenvolver um modelo conceitual hidrogeológico. As imagens geofísicas mostram que o tálus tem tipicamente 20­40 m de espessura e é altamente heterogêneo. Os sedimentos dos prados têm apenas 11 m de espessura, mas fazem parte de um acúmulo de material não consolidado com 30­40 m de espessura que preenche um afundamento no leito de rocha (isto é, uma bacia subglacial fechada). Um sistema menor de águas subterrâneas rasas alimenta fontes no tálus e córregos no prado, enquanto um sistema profundo na morena fornece a maior parte da água às fontes de saída da bacia, servindo assim como um 'guardião' da bacia. Embora as funções hidrológicas do tálus neste estudo sejam substancialmente diferentes de outros locais, principalmente devido a diferenças na litologia dos leitos de rocha e nos processos geomórficos, espera-se que o quadro conceitual geral desenvolvido neste estudo seja aplicável a outras regiões alpinas.

One Bite, Two Patients: Disparate Clinical Courses Following Simultaneous Crotalus oreganus abyssus Envenomation.

A number of crotaline species have been associated with neurotoxic envenomation in North America. One clinical sign that can occur is myokymia: fine, involuntary, wave-like muscle movements occurring at regular intervals. We report an unusual scenario in which a single snakebite resulted in simultaneous envenomation of 2 patients. Both developed myokymia, with 1 having respiratory compromise. One patient also developed a hypersensitivity reaction to antivenom. Envenomation by the Grand Canyon rattlesnake, Crotalus oreganus abyssus, can produce significant neurotoxicity and resultant respiratory compromise. Antivenom may be helpful but can produce hypersensitivity reactions.

In vivo pharmacodynamics of lefamulin, the first systemic pleuromutilin for human use, in a neutropenic murine thigh infection model.

OBJECTIVES: To characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of lefamulin in the neutropenic murine thigh infection model to ascertain (i) which PK/PD index best correlates with efficacy and (ii) whether the magnitude of the index that drives efficacy varies for different pathogens. METHODS: We evaluated the in vivo PK/PD of lefamulin against five Streptococcus pneumoniae and five Staphylococcus aureus strains using a neutropenic murine thigh infection model. The relationships between bacterial burden in the thigh of normal and neutropenic mice after 24 h of lefamulin treatment and various PK/PD indices were determined. RESULTS: The kinetics of the three doses was linear by AUC. Rate of killing was maximal at concentrations near the MIC; suppression of regrowth was dose dependent, with a post-antibiotic effect of 3.0-3.5 and 1.0-1.5 h against S. pneumoniae and S. aureus, respectively. The efficacy of lefamulin correlated most strongly with the AUC0-24/MIC ratio; coefficient of determination was 79.9% for S. pneumoniae and 78.3% for S. aureus. The magnitude of the 24 h AUC/MIC of total drug required ranged from 9.92 to 32.1 for S. pneumoniae and 40.2 to 82.5 for S. aureus, corresponding to free drug values (∼20% free fraction) of 1.98-6.42 and 8.04-16.5, respectively. CONCLUSIONS: Lefamulin, the first systemically available pleuromutilin in humans, exhibits time- and concentration-dependent killing. The presence of white blood cells had only a slight effect in enhancing the activity of the drug, indicating a leucocyte-independent effect. The identified driver of efficacy, the AUC0-24/MIC ratio and the ratios determined against various S. aureus and S. pneumoniae strains, will inform further non-clinical and clinical trials.

Challenges in the Discovery and Optimization of mGlu2/4 Heterodimer Positive Allosteric Modulators.

BACKGROUND: This article describes the challenges in the discovery and optimization of mGlu2/4 heterodimer Positive Allosteric Modulators (PAMs). METHODS: Initial forays based on VU0155041, a PAM of both the mGlu4 homodimer and the mGlu2/4 heterodimer, led to flat, intractable SAR that precluded advancement. Screening of a collection of 1,152 FDA approved drugs led to the discovery that febuxostat, an approved xanthine oxidase inhibitor, was a moderately potent PAM of the mGlu2/4 heterodimer (EC50 = 3.4 µM), but was peripherally restricted (rat Kp = 0.03). Optimization of this hit led to PAMs with improved potency (EC50s <800 nM) and improved CNS penetration (rat Kp >2, an ~100-fold increase). RESULTS: However, these new amide analogs of febuxostat proved to be either GIRK1/2 and GIRK1/4 activators (primary carboxamide congeners) or mGlu2 PAMs (secondary and tertiary amides) and not selective mGlu2/4 heterodimer PAMs. CONCLUSION: These results required the team to develop a new screening cascade paradigm, and exemplified the challenges in developing allosteric ligands for heterodimeric receptors.