Twenty four-hour blood pressure and cognitive outcomes in adolescents born extremely preterm and at term.

AIM: To explore the impact of blood pressure on cognitive outcomes at 18 years of age in individuals born extremely preterm (<28 weeks' gestation) and at term (≥37 weeks' gestation). METHODS: Prospective longitudinal cohort comprising 136 young adults born extremely preterm and 120 matched term controls born in Victoria, Australia in 1991 and 1992. Using linear regression, we analysed the relationships between 24-h mean ambulatory blood pressure, systolic and diastolic hypertension with cognitive outcomes. RESULTS: For both birth groups combined, higher 24-h mean ambulatory blood pressure and systolic hypertension were associated with similar or worse cognitive outcomes. The strongest relationships were between higher 24-h mean ambulatory blood pressure and systolic hypertension with poorer general intellect, visual learning and visual memory. We found little evidence that relationships between ambulatory blood pressure and cognitive outcomes differed by birth group. CONCLUSION: Higher 24-h mean ambulatory blood pressure and systolic hypertension were associated with poorer cognitive outcomes in individuals born extremely preterm and at term, particularly in general intelligence and visual memory.

Longitudinal neurocognitive trajectories and risk factors in the first three months following pediatric concussion.

OBJECTIVE: To identify differential trajectories of neurocognitive outcomes following pediatric concussion and investigate predictors associated with patterns of recovery up to 3 months. METHODS: 74 participants aged 8-17 years completed attention/working memory, processing speed, and executive function measures at 2 weeks, 1 month, and 3 months post-injury. We used principal component analysis to generate a composite of information processing. Group-based trajectory modeling identified latent trajectories. Multinominal logistic regression was used to examine associations between risk factors and trajectory groups. RESULTS: We identified three trajectories of neurocognitive outcomes. The medium (54.6%) and high improving groups (35.8%) showed ongoing increase in information processing, while the low persistent group showed limited change 3 months post-injury. This group recorded below average scores on Digit Span Forward and Backward at 3 months. History of pre-injury headache was significantly associated with the persistent low scoring group, relative to the medium improving (p = 0.03) but not the high improving group (p = 0.09). CONCLUSIONS: This study indicates variability in neurocognitive outcomes according to three differential trajectories, with groups partially distinguished by preexisting child factors (history of frequent headaches). Modelling that accounts for heterogeneity in individual outcomes is essential to identify clinically meaningful indices that are indicative of children requiring intervention.

Fatigue recovery and connected factors following paediatric concussion.

OBJECTIVE: Using a biopsychosocial framework and the three-factor fatigue model, we aimed to (1) plot recovery of fatigue over the 3 months following paediatric concussion and (2) explore factors associated with persisting fatigue during the first 3 months postconcussion. METHODS: 240 children and adolescents aged 5-18 years (M=11.64, SD=3.16) completed assessments from time of injury to 3 months postinjury. Separate linear mixed effects models were conducted for child and parent ratings on the PedsQL-Multidimensional Fatigue Scale to plot recovery across domains (General, Cognitive, Sleep/Rest) and Total fatigue, from 1 week to 3 months postinjury. Two-block hierarchical regression analyses were then conducted for parent and child ratings of fatigue at each time point, with age, sex and acute symptoms in block 1 and child and parent mental health variables added to block 2. RESULTS: There was a significant reduction in both child and parent ratings across the 3 months postinjury for all fatigue domains (all p<0.001). For both child and parent fatigue ratings, child mental health was the most significant factor associated with fatigue at all time points. Adding child and parent mental health variables in the second block of the regression substantially increased the variance explained for both child and parent ratings of fatigue. CONCLUSION: Our findings confirm that fatigue improves during the first 3 months postconcussion and highlights the importance of considering child and parent mental health screening when assessing patients with persisting postconcussive symptoms.

Feasibility of Concussion Essentials: A multimodal intervention for persisting post-concussion symptoms among children and adolescents.

This study examined the feasibility of "Concussion Essentials" (CE), an individualized, multimodal intervention for persisting post-concussion symptoms (pPCS). Thirteen 6-18 year-olds with pPCS at 1-month post-concussion, as determined by the Post Concussion Symptom Inventory - Parent Report (PCSI-P), completed education, physiotherapy, and psychology modules, for up to 8-weeks or until pPCS resolved. Intervention participants were matched to a longitudinal observational cohort who received usual care (n = 13). The study enrolled 70% of participants symptomatic on screening and the dropout rate was <30% between baseline and post-programme assessments (4-weeks to 3-months post-injury). Symptoms improved for 100% of CE participants, with the number of symptomatic items on the PCSI-P reducing from 4-weeks, Median (IQR) = 14.0 (8.0-19.0) to 3-months, Median (IQR) = 1.0 (0.0-5.0). Comparatively, symptoms improved for approximately half of matched usual care participants. CE participants (n = 8) and their parents (n = 11) completed acceptability questionnaires. Most parents (91%) agreed CE was acceptable for children with concussion. All participants agreed CE was appropriate for concussion, while approximately 88% agreed they enjoyed the intervention and would recommend CE to others. Findings suggest CE is a feasible and acceptable treatment for paediatric pPCS. Further investigation within a larger scale randomized clinical trial is warranted.

Prevention strategies and modifiable risk factors for sport-related concussions and head impacts: a systematic review and meta-analysis.

OBJECTIVES: To evaluate prevention strategies, their unintended consequences and modifiable risk factors for sport-related concussion (SRC) and/or head impact risk. DESIGN: This systematic review and meta-analysis was registered on PROSPERO (CRD42019152982) and conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. DATA SOURCES: Eight databases (MEDLINE, CINAHL, APA PsycINFO, Cochrane (Systematic Review and Controlled Trails Registry), SPORTDiscus, EMBASE, ERIC0 were searched in October 2019 and updated in March 2022, and references searched from any identified systematic review. ELIGIBILITY CRITERIA: Study inclusion criteria were as follows: (1) original data human research studies, (2) investigated SRC or head impacts, (3) evaluated an SRC prevention intervention, unintended consequence or modifiable risk factor, (4) participants competing in any sport, (5) analytic study design, (6) systematic reviews and meta-analyses were included to identify original data manuscripts in reference search and (7) peer-reviewed. Exclusion criteria were as follows: (1) review articles, pre-experimental, ecological, case series or case studies and (2) not written in English. RESULTS: In total, 220 studies were eligible for inclusion and 192 studies were included in the results based on methodological criteria as assessed through the Scottish Intercollegiate Guidelines Network high ('++') or acceptable ('+') quality. Evidence was available examining protective gear (eg, helmets, headgear, mouthguards) (n=39), policy and rule changes (n=38), training strategies (n=34), SRC management strategies (n=12), unintended consequences (n=5) and modifiable risk factors (n=64). Meta-analyses demonstrated a protective effect of mouthguards in collision sports (incidence rate ratio, IRR 0.74; 95% CI 0.64 to 0.89). Policy disallowing bodychecking in child and adolescent ice hockey was associated with a 58% lower concussion rate compared with bodychecking leagues (IRR 0.42; 95% CI 0.33 to 0.53), and evidence supports no unintended injury consequences of policy disallowing bodychecking. In American football, strategies limiting contact in practices were associated with a 64% lower practice-related concussion rate (IRR 0.36; 95% CI 0.16 to 0.80). Some evidence also supports up to 60% lower concussion rates with implementation of a neuromuscular training warm-up programme in rugby. More research examining potentially modifiable risk factors (eg, neck strength, optimal tackle technique) are needed to inform concussion prevention strategies. CONCLUSIONS: Policy and rule modifications, personal protective equipment, and neuromuscular training strategies may help to prevent SRC. PROSPERO REGISTRATION NUMBER: CRD42019152982.

Accuracy of Components of the SCAT5 and ChildSCAT5 to Identify Children with Concussion.

The Sport Concussion Assessment Tool 5th Edition (SCAT5) is a standardized measure of concussion. In this prospective observational study, the ability of the SCAT5 and ChildSCAT5 to differentiate between children with and without a concussion was examined. Concussed children (n=91) and controls (n=106) were recruited from an emergency department in three equal-sized age bands (5-8/9-12/13-16 years). Analysis of covariance models (adjusting for participant age) were used to analyze group differences on components of the SCAT5. On the SCAT5 and ChildSCAT5, respectively, youth with concussion reported a greater number (d=1.47; d=0.52) and severity (d=1.27; d=0.72) of symptoms than controls (all p<0.001). ChildSCAT5 parent-rated number (d=0.98) and severity (d=1.04) of symptoms were greater for the concussion group (all p<0.001). Acceptable levels of between-group discrimination were identified for SCAT5 symptom number (AUC=0.86) and severity (AUC=0.84) and ChildSCAT5 parent-rated symptom number (AUC=0.76) and severity (AUC=0.78). Our findings support the utility of the SCAT5 and ChildSCAT5 to accurately distinguish between children with and without a concussion.

Mental health after paediatric concussion: a systematic review and meta-analysis.

OBJECTIVE: This systematic review and meta-analysis sought to rigorously examine mental health outcomes following paediatric concussion. To date, heterogeneous findings and methodologies have limited clinicians' and researchers' ability to meaningfully synthesise existing literature. In this context, there is a need to clarify mental health outcomes in a homogeneous sample, controlling for key methodological differences and applying a consistent definition of concussion across studies. DESIGN: Systematic review and meta-analysis. DATA SOURCES: We searched Medline, Embase, PsycINFO, CINAHL, SportDiscus, Scopus and PubMed. ELIGIBILITY: Peer-reviewed studies published between 1980 and June 2020 that prospectively examined mental health outcomes after paediatric concussion, defined as per the Berlin Consensus Statement on Concussion in Sport. RESULTS: Sixty-nine articles characterising 60 unique samples met inclusion criteria, representing 89 114 children with concussion. Forty articles (33 studies) contributed to a random effects meta-analysis of internalising (withdrawal, anxiety, depression, post-traumatic stress), externalising (conduct problems, aggression, attention, hyperactivity) and total mental health difficulties across three time points post-injury (acute, persisting and chronic). Overall, children with concussion (n=6819) experienced significantly higher levels of internalising (g=0.41-0.46), externalising (g=0.25-0.46) and overall mental health difficulties compared with controls (g=0.18-0.49; n=56 271), with effects decreasing over time. SUMMARY/CONCLUSIONS: Our review highlights that mental health is central to concussion recovery. Assessment, prevention and intervention of mental health status should be integrated into standard follow-up procedures. Further research is needed to clarify the mechanisms underlying observed relationships between mental health, post-concussion symptoms and other psychosocial factors. Results suggest that concussion may both precipitate and exacerbate mental health difficulties, thus impacting delayed recovery and psychosocial outcomes.

Neuroanatomical alterations in people with high and low cannabis dependence.

OBJECTIVES: We aimed to investigate whether severity of cannabis dependence is associated with the neuroanatomy of key brain regions of the stress and reward brain circuits. METHODS: To examine dependence-specific regional brain alterations, we compared the volumes of regions relevant to reward and stress, between high-dependence cannabis users (CD+, n = 25), low-dependence cannabis users (CD-, n = 20) and controls (n = 37). RESULTS: Compared to CD- and/or controls, the CD+ group had lower cerebellar white matter and hippocampal volumes, and deflation of the right hippocampus head and tail. CONCLUSION: These findings provide initial support for neuroadaptations involving stress and reward circuits that are specific to high-dependence cannabis users.

Use of the sport concussion assessment tools in the emergency department to predict persistent post-concussive symptoms in children.

AIM: The Sport Concussion Assessment Tool v3 (SCAT3) and its child version (ChildSCAT3) are composite tools including a symptom scale, a rapid cognitive assessment (standardised assessment of concussion (SAC)) and the modified Balance Error Scoring System (mBESS). It is unclear whether their use for the acute assessment of paediatric concussion in the emergency department (ED) may help predict persistent post-concussive symptoms (PPCS). We aim to assess the predictive value of the main SCAT3/ChildSCAT3 components for PPCS when applied in the ED. METHODS: A single-site, prospective longitudinal cohort study of children aged 5-18 years assessed within 48 h of their concussion at the ED of a state-wide tertiary paediatric hospital and followed up at the affiliated concussion clinic, between November 2013 and August 2017. PPCS was defined as ≥2 new or worsening symptoms at 1 month post-injury using the Post-Concussive Symptom Inventory. RESULTS: Of the 370 children enrolled, 213 (57.7% <13 years old) provided complete data. Of these, 34.7% had PPCS at 1 month post-injury (38.2% of children <13 years and 30.0% ≥13 years of age, P = 0.272). The adjusted ORs from multiple logistic regression models, for number and severity of symptoms, and for the SAC and mBESS performance in both the ChildSCAT3/SCAT3, were all not significant. The area under the curve of receiver operator characteristic curves for all analysed ChildSCAT3/SCAT3 components was below 0.6. CONCLUSIONS: Although SCAT3 and ChildSCAT3 are recommended tools to assist with concussion diagnosis and monitoring of patient recovery, their use in the ED does not seem to help predict PPCS.

Acute cognitive postconcussive symptoms follow longer recovery trajectories than somatic postconcussive symptoms in young children.

Objective: To investigate somatic and cognitive postconcussive symptoms (PCS) using the symptom evaluation subtest (cSCAT3-SE) of the Child Sports Concussion Assessment Tool 3 (Child SCAT) in tracking PCS up to 2 weeks postinjury.Methods: A total of 96 participants aged 5 to 12 years (Mage = 9.55, SD = 2.20) completed three assessment time points: 48 h postinjury (T0), 2 to 4 days postinjury (T1), and 2 weeks postinjury (T2). The Wilcoxon signed-rank test was used to analyze differences between cognitive and somatic symptoms over time, while the Friedman test was used to analyze differences within symptom type over time.Results: Cognitive PCS were found to be significantly higher than somatic PCS at all assessment time points and were also found to significantly decline from 4 days onwards postinjury; in contrast, somatic PCS significantly declined as early as 48 hpostinjury.Discussion: Differences between cognitive and somatic PCS emerge as early as a few days postinjury, with cognitive PCS being more persistent than somatic PCS across 2 weeks. Research in symptom-specific interventions may be of benefit in helping young children manage severe PCS as early as 2 weeks postinjury.

A Systematic Critical Appraisal of Evidence-Based Clinical Practice Guidelines for the Rehabilitation of Children With Moderate or Severe Acquired Brain Injury.

OBJECTIVE: The aim of this review was to critically appraise the quality of evidence-based clinical practice guidelines (CPGs) for the rehabilitation of children with moderate or severe acquired brain injury (ABI). DATA SOURCES: A systematic search of MEDLINE, PsycINFO, Embase, CINAHL, and the Cochrane Library was conducted and an extensive website search of prominent professional rehabilitation society websites. STUDY SELECTION: CPGs were eligible for inclusion if they incorporated recommendation statements for inpatient and/or community rehabilitation for children with ABI and they were based on a systematic evidence search. DATA EXTRACTION: Methodological quality of eligible CPGs were appraised by 3 independent reviewers using the AGREE II instrument. Characteristics of eligible CPGs and strength of supporting evidence for included recommendations were extracted. DATA SYNTHESIS: Of the 9 included guidelines, 2 covered all ABIs, 5 focused specifically on traumatic brain injury, and 2 on stroke. Five of the CPGs were classified as high quality and 4 were of average quality. In general, CPGs scored better for scope and purpose, rigor of development, and clarity of presentation. They scored most poorly in applicability, involvement of target users, and procedures for updating the guidelines. Interrater reliability for the AGREE II was generally high across domains. Very few of the 445 recommendations included across the 9 CPGs were evidence based. CONCLUSIONS: Despite variability in quality of the guideline development process, the included CPGs generally provided clear descriptions of their overall objectives, scope and purpose, employed systematic methods for searching, selecting, and appraising research evidence, and produced unambiguous, clearly identifiable recommendations for children with ABI. Overall, existing CPGs focusing on rehabilitation for children with ABI are based on low-quality evidence or expert consensus. Future work should focus on addressing the limitations of most of the current CPGs, particularly related to supporting implementation and integrating stakeholder involvement.

Predicting Concussion Recovery in Children and Adolescents in the Emergency Department.

PURPOSE OF REVIEW: Concussion, or mild traumatic brain injury (mTBI), represents the majority of pediatric Emergency Department (ED) presentations of TBI. While most children and adolescents will recover within 4 weeks of injury, approximately one third will continue to experience persisting symptoms. This review aimed to provide an overview of literature from the past 5 years examining predictors of recovery in the ED. RECENT FINDINGS: Predictors could be characterized into three categories; (i) cognition, (ii) proteomics, and (iii) pre-injury/injury-related factors. There is preliminary support for the use of computerized neuropsychological testing. The prognostic use of proteomics is a promising area of future research. Pre-injury and injury-related characteristics have been thoroughly examined and developed into a clinical risk score for predicting delayed recovery. Substantial progress has been made in identifying risk factors for delayed recovery at ED presentation. The current evidence provides a platform for additional research that can refine and validate these predictors.

Neurodevelopmental outcome at 2 years of age after general anaesthesia and awake-regional anaesthesia in infancy (GAS): an international multicentre, randomised controlled trial.

BACKGROUND: Preclinical data suggest that general anaesthetics affect brain development. There is mixed evidence from cohort studies that young children exposed to anaesthesia can have an increased risk of poor neurodevelopmental outcome. We aimed to establish whether general anaesthesia in infancy has any effect on neurodevelopmental outcome. Here we report the secondary outcome of neurodevelopmental outcome at 2 years of age in the General Anaesthesia compared to Spinal anaesthesia (GAS) trial. METHODS: In this international assessor-masked randomised controlled equivalence trial, we recruited infants younger than 60 weeks postmenstrual age, born at greater than 26 weeks' gestation, and who had inguinal herniorrhaphy, from 28 hospitals in Australia, Italy, the USA, the UK, Canada, the Netherlands, and New Zealand. Infants were randomly assigned (1:1) to receive either awake-regional anaesthesia or sevoflurane-based general anaesthesia. Web-based randomisation was done in blocks of two or four and stratified by site and gestational age at birth. Infants were excluded if they had existing risk factors for neurological injury. The primary outcome of the trial will be the Wechsler Preschool and Primary Scale of Intelligence Third Edition (WPPSI-III) Full Scale Intelligence Quotient score at age 5 years. The secondary outcome, reported here, is the composite cognitive score of the Bayley Scales of Infant and Toddler Development III, assessed at 2 years. The analysis was as per protocol adjusted for gestational age at birth. A difference in means of five points (1/3 SD) was predefined as the clinical equivalence margin. This trial is registered with ANZCTR, number ACTRN12606000441516 and ClinicalTrials.gov, number NCT00756600. FINDINGS: Between Feb 9, 2007, and Jan 31, 2013, 363 infants were randomly assigned to receive awake-regional anaesthesia and 359 to general anaesthesia. Outcome data were available for 238 children in the awake-regional group and 294 in the general anaesthesia group. In the as-per-protocol analysis, the cognitive composite score (mean [SD]) was 98.6 (14.2) in the awake-regional group and 98.2 (14.7) in the general anaesthesia group. There was equivalence in mean between groups (awake-regional minus general anaesthesia 0.169, 95% CI -2.30 to 2.64). The median duration of anaesthesia in the general anaesthesia group was 54 min. INTERPRETATION: For this secondary outcome, we found no evidence that just less than 1 h of sevoflurane anaesthesia in infancy increases the risk of adverse neurodevelopmental outcome at 2 years of age compared with awake-regional anaesthesia. FUNDING: Australia National Health and Medical Research Council (NHMRC), Health Technologies Assessment-National Institute for Health Research UK, National Institutes of Health, Food and Drug Administration, Australian and New Zealand College of Anaesthetists, Murdoch Childrens Research Institute, Canadian Institute of Health Research, Canadian Anesthesiologists' Society, Pfizer Canada, Italian Ministry of Heath, Fonds NutsOhra, and UK Clinical Research Network (UKCRN).

What is the difference in concussion management in children as compared with adults? A systematic review.

AIM: To evaluate the evidence regarding the management of sport-related concussion (SRC) in children and adolescents. The eight subquestions included the effects of age on symptoms and outcome, normal and prolonged duration, the role of computerised neuropsychological tests (CNTs), the role of rest, and strategies for return to school and return to sport (RTSp). DESIGN: Systematic review. DATA SOURCES: MEDLINE (OVID), Embase (OVID) and PsycInfo (OVID). ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Studies were included if they were original research on SRC in children aged 5 years to 18 years, and excluded if they were review articles, or did not focus on childhood SRC. RESULTS: A total of 5853 articles were identified, and 134 articles met the inclusion criteria. Some articles were common to multiple subquestions. Very few studies examined SRC in young children, aged 5-12 years. SUMMARY/CONCLUSIONS: This systematic review recommends that in children: child and adolescent age-specific paradigms should be applied; child-validated symptom rating scales should be used; the widespread routine use of baseline CNT is not recommended; the expected duration of symptoms associated with SRC is less than 4 weeks; prolonged recovery be defined as symptomatic for greater than 4 weeks; a brief period of cognitive and physical rest should be followed with gradual symptom-limited physical and cognitive activity; all schools be encouraged to have a concussion policy and should offer appropriate academic accommodations and support to students recovering from SRC; and children and adolescents should not RTSp until they have successfully returned to school, however early introduction of symptom-limited physical activity is appropriate. SYSTEMATIC REVIEW REGISTRATION: PROSPERO 2016:CRD42016039184.

A signal detection analysis of executive control performance among adolescent inhalant and cannabis users.

BACKGROUND: Inhalant users have multiple comorbid issues (e.g., polydrug use) that complicate identifying inhalant-specific cognitive deficits. OBJECTIVES: The aim of the present study was to use signal detection theory to identify inhalant-specific differences in executive control. METHODS: We examined three well-matched groups: 19 inhalant users, 19 cannabis users, and 19 controls using Stroop and Go/No-Go tasks. RESULTS: Inhalant users demonstrated significantly lower d-prime scores relative to controls, but not cannabis users, on both tasks, suggesting possible executive deficits relative to controls. CONCLUSIONS/IMPORTANCE: The results of this study raise questions regarding inhalant toxicity and the vulnerability of the adolescent brain to drugs of abuse.

Post-traumatic headache pathophysiology in paediatric concussion: A systematic review.

Post-traumatic headache (PTH) represents the most common acute and persistent symptom following concussion in children, yet the underlying pathophysiology remains unclear. This systematic review sought to: (i) rigorously examine the current evidence of PTH pathophysiology in paediatric concussion (0-18 years), (ii) assess the quality of evidence, and (iii) provide directions for future research in accordance with PRISMA guidelines. Eligible studies (n = 19) totalling 1214 concussion participants investigated cerebrovascular function (n = 6), white matter integrity (n = 3), functional connectivity (n = 3), electrophysiology (n = 1), neurometabolics (n = 2), biological fluid markers (n = 4), vestibular and oculomotor function (n = 4); two studies used a multi-modal approach. Majority of studies were rated as fair quality (90%) and Level 3 evidence (84%). The true underlying mechanisms of PTH following paediatric concussion remain unclear. Overall quality of the available evidence is generally weak with a fair risk of bias and characterised by relative scarcity and lack of specificity of PTH pathophysiology. Future research is required to rigorously isolate pathophysiology specific to PTH with strict adherence to clinical definitions and standardised measurement tools of PTH.

Psychological Predictors of Mental Health Difficulties After Pediatric Concussion.

Children often experience mental health difficulties after a concussion. Yet, the extent to which a concussion precipitates or exacerbates mental health difficulties remains unclear. This study aimed to examine psychological predictors of mental health difficulties after pediatric concussion. Children (5 to <18 years of age, M = 11.7, SD = 3.3) with concussion were recruited in a single-site longitudinal prospective cohort study conducted at a tertiary children's hospital (n = 115, 73.9% male). The primary outcomes included internalizing (anxious, depressed, withdrawn behaviors), externalizing (risk-taking, aggression, attention difficulties), and total mental health problems, as measured by the Child Behavior Checklist at 2 weeks (acute) and 3 months (post-acute) after concussion. Predictors included parents' retrospective reports of premorbid concussive symptoms (Post-Concussion Symptom Inventory; PCSI), the child and their family's psychiatric history, child-rated perfectionism (Adaptive-Maladaptive Perfectionism Scale), and child-rated resilience (Youth Resilience Measure). Higher premorbid PCSI ratings consistently predicted acute and post-acute mental health difficulties. This relationship was significantly moderated by child psychiatric history. Furthermore, pre-injury learning difficulties, child psychiatric diagnoses, family psychiatric history, lower resilience, previous concussions, female sex, and older age at injury were associated with greater mental health difficulties after concussion. Pre-injury factors accounted for 23.4-39.9% of acute mental health outcomes, and 32.3-37.8% of post-acute mental health outcomes. When acute mental health was factored into the model, a total of 47.0-68.8% of variance was explained by the model. Overall, in this sample of children, several pre-injury demographic and psychological factors were observed to predict mental health difficulties after a concussion. These findings need to be validated in future research involving larger, multi-site studies that include a broader cohort of children after concussion.

White matter fiber morphology in persisting postconcussive symptoms and posttraumatic headache after pediatric concussion: a fixel-based analysis.

OBJECTIVE: Posttraumatic headache (PTH) represents the most common acute and persistent postconcussive symptom (PCS) in children after concussion, yet there remains a lack of valid and objective biomarkers to facilitate risk stratification and early intervention in this patient population. Fixel-based analysis of diffusion-weighted imaging, which overcomes constraints of traditional diffusion tensor imaging analyses, can improve the sensitivity and specificity of detecting white matter changes postconcussion. The aim of this study was to investigate whole-brain and tract-based differences in white matter morphology, including fiber density (FD) and fiber bundle cross-section (FC) area in children with PCSs and PTH at 2 weeks after concussion. METHODS: This prospective longitudinal study recruited children aged 5-18 years who presented to the emergency department of a tertiary pediatric hospital with a concussion sustained within the previous 48 hours. Participants underwent diffusion-weighted MRI at 2 weeks postinjury. Whole-brain white matter statistical analysis was performed at the level of each individual fiber population within an image voxel (fixel) to compute FD, FC, and a combined metric (FD and bundle cross-section [FDC]) using connectivity-based fixel enhancement. Tract-based Bayesian analysis was performed to examine FD in 23 major white matter tracts. RESULTS: Comparisons of 1) recovered (n = 27) and symptomatic (n = 16) children, and those with 2) PTH (n = 13) and non-PTH (n = 30; overall mean age 12.99 ± 2.70 years, 74% male) found no fiber-specific white matter microstructural differences in FD, FC, or FDC at 2 weeks postconcussion, when adjusting for age and sex (family-wise error rate corrected p value > 0.05). Tract-based Bayesian analysis showed evidence of no effect of PTH on FD in 10 major white matter tracts, and evidence of no effect of recovery group on FD in 3 white matter tracts (Bayes factor < 1/3). CONCLUSIONS: Using whole-brain fixel-wise and tract-based analyses, these findings indicate that fiber-specific properties of white matter microstructure are not different between children with persisting PCSs compared with recovered children 2 weeks after concussion. These data extend the limited research on white matter fiber-specific morphology while overcoming limitations inherent to traditional diffusion models. Further validation of our findings with a large-scale cohort is warranted.

Discovery of Alpha-1-Antichymotrypsin as a Marker of Delayed Recovery from Concussion in Children.

Of the four million children who experience a concussion each year, 30-50% of children will experience delayed recovery, where they will continue to experience symptoms more than two weeks after their injury. Delayed recovery from concussion encompasses emotional, behavioral, physical, and cognitive symptoms, and as such, there is an increased focus on developing an objective tool to determine risk of delayed recovery. This study aimed to identify a blood protein signature predictive of delayed recovery from concussion in children. Plasma samples were collected from children who presented to the Emergency Department at the Royal Children's Hospital, Melbourne, within 48h post-concussion. This study involved a discovery and validation phase. For the discovery phase, untargeted proteomics analysis was performed using single window acquisition of all theoretical mass spectra to identify blood proteins differentially abundant in samples from children with and without delayed recovery from concussion. A subset of these proteins was then validated in a separate participant cohort using multiple reaction monitoring and enzyme linked immunosorbent assay. A blood protein signature predictive of delayed recovery from concussion was modeled using a Support Vector Machine, a machine learning approach. In the discovery phase, 22 blood proteins were differentially abundant in age- and sex-matched samples from children with (n = 9) and without (n = 9) delayed recovery from concussion, six of whom were chosen for validation. In the validation phase, alpha-1-ACT was shown to be significantly lower in children with delayed recovery (n = 12) compared with those without delayed recovery (n = 28), those with orthopedic injuries (n = 7) and healthy controls (n = 33). A model consisting of alpha-1-ACT concentration stratified children based on recovery from concussion with an 0.88 area under the curve. We have identified that alpha-1-ACT differentiates between children at risk of delayed recovery from those without delayed recovery from concussion. To our knowledge, this is the first study to identify alpha-1-ACT as a potential marker of delayed recovery from concussion in children. Multi-site studies are required to further validate this finding before use in a clinical setting.

Capillary blood protein markers of posttraumatic headache in children after concussion.

OBJECTIVE: Posttraumatic headache (PTH) represents the most common acute and persistent symptom in children after concussion, yet there is no blood protein signature to stratify the risk of PTH after concussion to facilitate early intervention. This discovery study aimed to identify capillary blood protein markers, at emergency department (ED) presentation within 48 hours of concussion, to predict children at risk of persisting PTH at 2 weeks postinjury. METHODS: Capillary blood was collected using the Mitra Clamshell device from children aged 8-17 years who presented to the ED of the Royal Children's Hospital, Melbourne, Australia, within 48 hours of sustaining a concussion. Participants were followed up at 2 weeks postinjury to determine PTH status. PTH was defined per clinical guidelines as a new or worsened headache compared with preinjury. An untargeted proteomics analysis using data-independent acquisition (DIA) was performed. Principal component analysis and hierarchical clustering were used to reduce the dimensionality of the protein dataset. RESULTS: A total of 907 proteins were reproducibly identified from 82 children within 48 hours of concussion. The mean participant age was 12.78 years (SD 2.54 years, range 8-17 years); 70% of patients were male. Eighty percent met criteria for acute PTH in the ED, while one-third of participants with follow-up experienced PTH at 2 weeks postinjury (range 8-16 days). Hemoglobin subunit zeta (HBZ), cystatin B (CSTB), beta-ala-his dipeptidase (CNDP1), hemoglobin subunit gamma-1 (HBG1), and zyxin (ZYX) were weakly associated with PTH at 2 weeks postinjury based on up to a 7% increase in the PTH group despite nonsignificant Benjamini-Hochberg adjusted p values. CONCLUSIONS: This discovery study determined that no capillary blood protein markers, measured at ED presentation within 48 hours of concussion, can predict children at risk of persisting PTH at 2 weeks postinjury. While HBZ, CSTB, CNDP1, HBG1, and ZYX were weakly associated with PTH at 2 weeks postinjury, there was no specific blood protein signature predictor of PTH in children after concussion. There is an urgent need to discover new blood biomarkers associated with PTH to facilitate risk stratification and improve clinical management of pediatric concussion.