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Epigenetic Effects on Pediatric Traumatic Brain Injury Recovery (EETR): An Observational, Prospective, Longitudinal Concurrent Cohort Study Protocol.

ABSTRACT: Introduction: Unexplained heterogeneity in outcomes following pediatric traumatic brain injury (TBI) is one of the most critical barriers to the development of effective prognostic tools and therapeutics. The addition of personal biological factors to our prediction models may account for a significant portion of unexplained variance and advance the field toward precision rehabilitation medicine. The overarching goal of the Epigenetic Effects on Pediatric Traumatic Brain Injury Recovery (EETR) study is to investigate an epigenetic biomarker involved in both childhood adversity and postinjury neuroplasticity to better understand heterogeneity in neurobehavioral outcomes following pediatric TBI. Our primary hypothesis is that childhood adversity will be associated with worse neurobehavioral recovery in part through an epigenetically mediated reduction in brain-derived neurotrophic factor (BDNF) expression in response to TBI. Methods and analysis: EETR is an observational, prospective, longitudinal concurrent cohort study of children aged 3-18 years with either TBI (n = 200) or orthopedic injury (n = 100), recruited from the UPMC Children's Hospital of Pittsburgh. Participants complete study visits acutely and at 6 and 12 months postinjury. Blood and saliva biosamples are collected at all time points-and cerebrospinal fluid (CSF) when available acutely-for epigenetic and proteomic analysis of BDNF. Additional measures assess injury characteristics, pre- and postinjury child neurobehavioral functioning, childhood adversity, and potential covariates/confounders. Recruitment began in July 2017 and will occur for ~6 years, with data collection complete by mid-2023. Analyses will characterize BDNF DNA methylation and protein levels over the recovery period and investigate this novel biomarker as a potential biological mechanism underlying the known association between childhood adversity and worse neurobehavioral outcomes following pediatric TBI. Ethics and dissemination: The study received ethics approval from the University of Pittsburgh Institutional Review Board. Participants and their parents provide informed consent/assent. Research findings will be disseminated via local and international conference presentations and manuscripts submitted to peer-reviewed journals. Trial Registration: The study is registered with clinicaltrials.org (ClinicalTrials.gov Identifier: NCT04186429).

SUBMITTER: Treble-Barna A

PROVIDER: S-EPMC7303323 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Epigenetic Effects on Pediatric Traumatic Brain Injury Recovery (EETR): An Observational, Prospective, Longitudinal Concurrent Cohort Study Protocol.

Treble-Barna Amery A Patronick Jamie J Uchani Srivatsan S Marousis Noelle C NC Zigler Christina K CK Fink Ericka L EL Kochanek Patrick M PM Conley Yvette P YP Yeates Keith Owen KO

Frontiers in neurology 20200612

<b>Introduction:</b> Unexplained heterogeneity in outcomes following pediatric traumatic brain injury (TBI) is one of the most critical barriers to the development of effective prognostic tools and therapeutics. The addition of personal biological factors to our prediction models may account for a significant portion of unexplained variance and advance the field toward precision rehabilitation medicine. The overarching goal of the Epigenetic Effects on Pediatric Traumatic Brain Injury Recovery ( ...[more]

PMID: 32595586

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Project description:IntroductionMild traumatic brain injury (mTBI) is a complex injury with heterogeneous physical, cognitive, emotional and functional outcomes. Many who sustain mTBI recover within 2 weeks of injury; however, approximately 10%-20% of individuals experience mTBI symptoms beyond this 'typical' recovery timeframe, known as persistent post-concussion symptoms (PPCS). Despite increasing interest in PPCS, uncertainty remains regarding its prevalence in community-based populations and the extent to which poor recovery may be identified using early predictive markers.Objective(1) Establish a research dataset of people who have experienced mTBI and document their recovery trajectories; (2) Evaluate a broad range of novel and established prognostic factors for inclusion in a predictive model for PPCS.Methods and analysisThe Concussion Recovery Study (CREST) is a prospective, longitudinal observational cohort study conducted in Perth, Western Australia. CREST is recruiting adults aged 18-65 from medical and community-based settings with acute diagnosis of mTBI. CREST will create a state-wide research dataset of mTBI cases, with data being collected in two phases. Phase I collates data on demographics, medical background, lifestyle habits, nature of injury and acute mTBI symptomatology. In Phase II, participants undergo neuropsychological evaluation, exercise tolerance and vestibular/ocular motor screening, MRI, quantitative electroencephalography and blood-based biomarker assessment. Follow-up is conducted via telephone interview at 1, 3, 6 and 12 months after injury. Primary outcome measures are presence of PPCS and quality of life, as measured by the Post-Concussion Symptom Scale and the Quality of Life after Brain Injury questionnaires, respectively. Multivariate modelling will examine the prognostic value of promising factors.Ethics and disseminationHuman Research Ethics Committees of Royal Perth Hospital (#RGS0000003024), Curtin University (HRE2019-0209), Ramsay Health Care (#2009) and St John of God Health Care (#1628) have approved this study protocol. Findings will be published in peer-reviewed journals and presented at scientific conferences.Trial registration numberACTRN12619001226190.

Project description:INTRODUCTION:Traumatic brain injury (TBI) is considered one of the most pervasive causes of disability in people under the age of 45. TBI often results in disorders of consciousness, and clinical assessment of the state of consciousness in these patients is challenging due to the lack of behavioural responsiveness. Functional neuroimaging offers a means to assess these patients without the need for behavioural signs, indicating that brain connectivity plays a major role in consciousness emergence and maintenance. However, little is known regarding how changes in connectivity during recovery from TBI accompany changes in the level of consciousness. Here, we aim to combine cutting-edge neuroimaging techniques to follow changes in brain connectivity in patients recovering from severe TBI. METHODS AND ANALYSIS:A multimodal, longitudinal assessment of 30 patients in the subacute stage after severe TBI will be made comprising an MRI session combined with electroencephalography (EEG), a positron emission tomography session and a transcranial magnetic stimulation (TMS) combined with EEG (TMS/EEG) session. A group of 20 healthy participants will be included for comparison. Four sessions for patients and two sessions for healthy participants will be planned. Data analysis techniques will focus on whole-brain, both data-driven and hypothesis-driven, connectivity measures that will be specific to the imaging modality. ETHICS AND DISSEMINATION:The project has received ethical approval by the local ethics committee of the Capital Region of Denmark and by the Danish Data Protection. Results will be published as original research articles in peer-reviewed journals and disseminated in international conferences. None of the measurements will have any direct clinical impact on the patients included in the study but may benefit future patients through a better understanding of the mechanisms underlying the recovery process after TBI. TRIAL REGISTRATION NUMBER NCT02424656; PRE-RESULTS.

Project description:INTRODUCTION:Paediatric mild traumatic brain injury (mTBI) is a public health burden. Clinicians urgently need evidence-based guidance to manage mTBI, but gold standards for diagnosing and predicting the outcomes of mTBI are lacking. The objective of the Advancing Concussion Assessment in Pediatrics (A-CAP) study is to assess a broad pool of neurobiological and psychosocial markers to examine associations with postinjury outcomes in a large sample of children with either mTBI or orthopaedic injury (OI), with the goal of improving the diagnosis and prognostication of outcomes of paediatric mTBI. METHODS AND ANALYSIS:A-CAP is a prospective, longitudinal cohort study of children aged 8.00-16.99?years with either mTBI or OI, recruited during acute emergency department (ED) visits at five sites from the Pediatric Emergency Research Canada network. Injury information is collected in the ED; follow-up assessments at 10 days and 3 and 6 months postinjury measure a variety of neurobiological and psychosocial markers, covariates/confounders and outcomes. Weekly postconcussive symptom ratings are obtained electronically. Recruitment began in September 2016 and will occur for approximately 24 months. Analyses will test the major hypotheses that neurobiological and psychosocial markers can: (1) differentiate mTBI from OI and (2) predict outcomes of mTBI. Models initially will focus within domains (eg, genes, imaging biomarkers, psychosocial markers), followed by multivariable modelling across domains. The planned sample size (700 mTBI, 300 OI) provides adequate statistical power and allows for internal cross-validation of some analyses. ETHICS AND DISSEMINATION:The ethics boards at all participating institutions have approved the study and all participants and their parents will provide informed consent or assent. Dissemination will follow an integrated knowledge translation plan, with study findings presented at scientific conferences and in multiple manuscripts in peer-reviewed journals.

Project description:Traumatic brain injury (TBI) is a leading cause of death and disability for children and adolescents in the U.S. and other developed and developing countries. Injury to the immature brain varies greatly from that of the mature, adult brain due to numerous developmental, pre-injury, and injury-related factors that work together to influence the trajectory of recovery during the course of typical brain development. Substantial damage to brain structure often underlies subsequent functional limitations that persist for years following pediatric TBI. Advances in neuroimaging have established an important role in the acute management of pediatric TBI, and magnetic resonance imaging (MRI) techniques have a particular relevance for the sequential assessment of long-term consequences from injuries sustained to the developing brain. The present paper will discuss the various factors that influence recovery and review the findings from the present neuroimaging literature to assess altered development and long-term outcome following pediatric TBI. Four MR-based neuroimaging modalities have been used to examine recovery from pediatric TBI longitudinally: (1) T1-weighted structural MRI is sensitive to morphological changes in gray matter volume and cortical thickness, (2) diffusion-weighted MRI is sensitive to changes in the microstructural integrity of white matter, (3) MR spectroscopy provides a sensitive assessment of metabolic and neurochemical alterations in the brain, and (4) functional MRI provides insight into the functional changes that occur as a result of structural damage and typical developmental processes. As reviewed in this paper, 13 cohorts have contributed to only 20 studies published to date using neuroimaging to examine longitudinal changes after TBI in pediatric patients. The results of these studies demonstrate considerable heterogeneity in post-injury outcome; however, the existing literature consistently shows that alterations in brain structure, function, and metabolism can persist for an extended period of time post-injury. With larger sample sizes and multi-site cooperation, future studies will be able to further examine potential moderators of outcome, such as the developmental, pre-injury, and injury-related factors discussed in the present review.

Project description:To assess (1) whether visual disturbances can be demonstrated with objective measures more often in patients with mild traumatic brain injury (mTBI) than in orthopaedic controls and non-injured controls, (2) whether such objectively demonstrated disturbances change over time and (3) whether self-reported visual symptoms after mTBI correlate with objectively measurable changes in visuomotor performance.A prospective, controlled, observational study, with assessments planned 7-10 and 75-100 days after injury.Emergency department of a general hospital in Sweden.15 patients with mTBI, 15 patients with minor orthopaedic injury, 15 non-injured controls, aged 18-40 years.Visual examination, including assessment of visual acuity, accommodation, eye alignment, saccades and stereoacuity. Symptom assessment using Convergence Insufficiency Symptoms Survey (CISS) and Rivermead PostConcussion Symptoms Questionnaire.Assessments were performed 4-13 and 81-322 days after injury (extended time frames for logistical reasons). No statistically significant difference was found between the mTBI and control groups regarding saccade performance and stereoacuity at any time point. The accommodative amplitude was significantly lower in the mTBI group compared with non-injured controls at baseline. 6 out of 13 patients with mTBI had accommodative insufficiency at follow-up. Near point of convergence in the mTBI group was receded at baseline and improved statistically significantly at follow-up. At baseline, patients with mTBI had significantly higher CISS score than orthopaedic and non-injured controls. For patients with mTBI, the CISS score correlated with fusional vergence.There were some transient measurable visual changes regarding convergence in patients with mTBI during the subacute period after the injury. Our findings of persistence of accommodative insufficiency in a considerable proportion of patients with mTBI suggest that this visual function should not be overlooked in clinical assessment.

Project description:BackgroundWe aimed to study the associations between pre- and in-hospital tracheal intubation and outcomes in traumatic brain injury (TBI), and whether the association varied according to injury severity.MethodsData from the international prospective pan-European cohort study, Collaborative European NeuroTrauma Effectiveness Research for TBI (CENTER-TBI), were used (n=4509). For prehospital intubation, we excluded self-presenters. For in-hospital intubation, patients whose tracheas were intubated on-scene were excluded. The association between intubation and outcome was analysed with ordinal regression with adjustment for the International Mission for Prognosis and Analysis of Clinical Trials in TBI variables and extracranial injury. We assessed whether the effect of intubation varied by injury severity by testing the added value of an interaction term with likelihood ratio tests.ResultsIn the prehospital analysis, 890/3736 (24%) patients had their tracheas intubated at scene. In the in-hospital analysis, 460/2930 (16%) patients had their tracheas intubated in the emergency department. There was no adjusted overall effect on functional outcome of prehospital intubation (odds ratio=1.01; 95% confidence interval, 0.79-1.28; P=0.96), and the adjusted overall effect of in-hospital intubation was not significant (odds ratio=0.86; 95% confidence interval, 0.65-1.13; P=0.28). However, prehospital intubation was associated with better functional outcome in patients with higher thorax and abdominal Abbreviated Injury Scale scores (P=0.009 and P=0.02, respectively), whereas in-hospital intubation was associated with better outcome in patients with lower Glasgow Coma Scale scores (P=0.01): in-hospital intubation was associated with better functional outcome in patients with Glasgow Coma Scale scores of 10 or lower.ConclusionThe benefits and harms of tracheal intubation should be carefully evaluated in patients with TBI to optimise benefit. This study suggests that extracranial injury should influence the decision in the prehospital setting, and level of consciousness in the in-hospital setting.Clinical trial registrationNCT02210221.

Project description:ImportancePediatric mild traumatic brain injury (TBI) and concussion are a public health challenge with up to 30% of patients experiencing prolonged recovery. Pediatric patients presenting to concussion clinics often have ongoing impairments and may be at increased risk for persistent symptoms. Understanding this population is critical for improved prognostic estimates and optimal treatment.ObjectiveTo describe pediatric patients presenting to concussion clinics and characterize factors associated with their recovery.Design, setting, and participantsThis prospective cohort study included patients enrolled at multicenter concussion specialty clinics from the Four Corners Youth Consortium from December 2017 to July 2019, with up to 12-month follow-up. Patients were eligible if they were aged 5 to 18.99 years with a diagnosis of mild TBI or concussion presenting to participating clinics within 8 weeks of injury. Patients were excluded if the patient or their parents were unable to read or sign the consent document, or if the patient had a Glasgow Coma Scale score less than 13 or a penetrating injury. Data were analyzed from February 2019 to April 2020.ExposuresDiagnosis of mild TBI or concussion.Main outcomes and measuresThis study used National Institute of Neurological Disorders and Stroke common data elements, including data on demographic characteristics, injury details, history, neurological and neuropsychological assessments, and treatment.ResultsA total of 600 patients were consecutively enrolled, among whom 324 (54.0%) were female and 435 (72.5%) were adolescents (ie, aged 13-18 years). A higher proportion of girls and women (248 patients [76.5%]) were adolescents compared with boys and men (187 patients [67.8%]) (P = .02), and girls and women reported significantly more preexisting anxiety compared with boys and men (80 patients [26.7%] vs 46 patients [18.7%]; P = .03). Significantly more adolescents reported preexisting migraines compared with preadolescents (82 patients [20.9%] vs 15 patients [10.9%]; P = .01). Girls and women recovered more slowly than boys and men (persistent symptoms after injury: week 4, 217 patients [81.6%] vs 156 patients [71.2%]; week 8, 146 patients [58.9%] vs 89 patients [44.3%]; week 12, 103 patients [42.6%] vs 58 patients [30.2%]; P = .01). Patients with history of migraine or anxiety or depression recovered more slowly than those without, regardless of sex.Conclusions and relevanceThese findings suggest that identification of subgroups of pediatric patients with mild TBI or concussion at risk for prolonged recovery could aid in better prognostic estimates and more targeted treatment interventions.

Project description:BACKGROUND:Little is known about the effect of a splenic rupture on the quality of life (QOL) of patients, although the spleen is one of the most frequently injured organs in blunt abdominal trauma. It is essential to obtain more knowledge about QOL after traumatic spleen injury so that this can be taken into account when choosing treatment. OBJECTIVE:The primary objective of the SPLENic Injury and Quality of life (SPLENIQ) study is to determine QOL after treatment for traumatic spleen injury. The secondary objective is to investigate clinical and imaging outcome in relation to QOL. METHODS:A combination of a retrospective single-center and a prospective multicenter observational cohort study will be conducted. Patients in the retrospective study have had a splenic injury after blunt abdominal trauma and were admitted for treatment to the ETZ Hospital (Elisabeth-TweeSteden Ziekenhuis) in Tilburg between January 2005 and February 2017. Concerning the prospective cohort study, patients with splenic injury admitted to 1 of the 10 participating hospitals between March 2017 and December 2018 will be asked to participate. The follow-up period will be 1 year regarding QOL, clinical symptoms, and imaging. Patients in the retrospective study will complete 2 questionnaires: World Health Organization QOL assessment instrument-Bref (WHOQOL-Bref) and 12-Item Short-Form Health Survey (SF-12). Patients in the prospective study will complete 5 questionnaires at 1 week, 1 month, 3 months, 6 months, and 12 months after treatment: WHOQOL-Bref, SF-12, Euroqol 5-Dimensional 5-Level (EQ-5D-5L) questionnaire, Institute for Medical Technology Assessment (iMTA) Productivity Cost Questionnaire (iPCQ), and iMTA Medical Consumption Questionnaire (iMCQ). In both the retrospective and prospective study, patients treated with splenic artery embolization will undergo magnetic resonance imaging (MRI). The retrospective group will undergo MRI once, and the prospective group will undergo MRI 1 month and 1 year after treatment. Treatment of splenic injury depends on the severity of the splenic injury, the hemodynamic condition of the patient, and the hospital's or doctor's preference. This study is observational in nature without randomization. Concerning the retrospective data, multivariate analysis of covariance will be done. With regard to the prospective data, mixed linear modeling will be performed. RESULTS:This project was funded in April 2015 by ZonMw. The results of the retrospective study will be expected in March 2019. With regard to the prospective study, inclusion of patients was completed in December 2018 and data collection will be completed in December 2019. The first results will be expected in 2019. CONCLUSIONS:To our knowledge, this is the first study that examines QOL in patients with a traumatic spleen injury. The SPLENIQ study responds to the shortage of information about QOL after treatment for traumatic spleen injury and may result in the development of a patient-oriented protocol. TRIAL REGISTRATION:ClinicalTrials.gov NCT03099798; https://clinicaltrials.gov/ct2/show/NCT03099798 (Archived by WebCite at http://www.webcitation.org/714ZKV6A0). INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID):DERR1-10.2196/12391.

Project description:Brain connectivity after mild traumatic brain injury (mTBI) has not been investigated longitudinally with respect to both functional and structural networks together within the same patients, crucial to capture the multifaceted neuropathology of the injury and to comprehensively monitor the course of recovery and compensatory reorganizations at macro-level. We performed a prospective study with 49 mTBI patients at an average of 5 days and 1 year post-injury and 49 healthy controls. Neuropsychological assessments as well as resting-state functional and diffusion-weighted magnetic resonance imaging were obtained. Functional and structural connectome analyses were performed using network-based statistics. They included a cross-sectional group comparison and a longitudinal analysis with the factors group and time. The latter tracked the subnetworks altered at the early phase and, in addition, included a whole-brain group × time interaction analysis. Finally, we explored associations between the evolution of connectivity and changes in cognitive performance. The early phase of mTBI was characterized by a functional hypoconnectivity in a subnetwork with a large overlap of regions involved within the classical default mode network. In addition, structural hyperconnectivity in a subnetwork including central hub areas such as the cingulate cortex was found. The impaired functional and structural subnetworks were strongly correlated and revealed a large anatomical overlap. One year after trauma and compared to healthy controls we observed a partial normalization of both subnetworks along with a considerable compensation of functional and structural connectivity subsequent to the acute phase. Connectivity changes over time were correlated with improvements in working memory, divided attention, and verbal recall. Neuroplasticity-induced recovery or compensatory processes following mTBI differ between brain regions with respect to their time course and are not fully completed 1 year after trauma.

Dataset Information

Epigenetic Effects on Pediatric Traumatic Brain Injury Recovery (EETR): An Observational, Prospective, Longitudinal Concurrent Cohort Study Protocol.

Publications

Epigenetic Effects on Pediatric Traumatic Brain Injury Recovery (EETR): An Observational, Prospective, Longitudinal Concurrent Cohort Study Protocol.

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