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The first aim of the Australian Traumatic Brain Injury Initiative (AUS-TBI) encompasses development of a set of measures that comprehensively predict outcomes for people with moderate-severe TBI across Australia. This process engaged diverse stakeholders and information sources across six areas: social, health, and clinical factors; biological markers; treatments; and longer-term outcomes. Here, we report the systematic review of pre-existing health conditions as predictors of outcome for people with moderate-severe TBI. Standardized searches were implemented across databases until March 31, 2022. English-language reports of studies evaluating association between pre-existing health conditions and clinical outcome in at least 10 patients with moderate-severe TBI were included. A predefined algorithm was used to assign a judgement of predictive value to each observed association. The list of identified pre-existing health conditions was then discussed with key stakeholders during a consensus meeting to determine the feasibility of incorporating them into standard care. The searches retrieved 22,217 records, of which 47 articles were included. The process led to identification of 88 unique health predictors (homologized to 21 predictor categories) of 55 outcomes (homologized to 19 outcome categories). Only pre-existing health conditions with high and moderate predictive values were discussed during the consensus meeting. Following the consensus meeting, 5 out of 11 were included (migraine, mental health conditions, ≥4 pre-existing health conditions, osteoporosis, and body mass index [BMI]) as common data elements in the AUS-TBI data dictionary. Upon further discussion, 3 additional pre-existing health conditions were included. These are pre-existing heart disease, frailty score, and previous incidence of TBI.

The Australian Traumatic Brain Injury Initiative (AUS-TBI) is developing a data resource to enable improved outcome prediction for people with moderate-severe TBI (msTBI) across Australia. Fundamental to this resource is the collaboratively designed data dictionary. This systematic review and consultation aimed to identify acute interventions with potential to modify clinical outcomes for people after msTBI, for inclusion in a data dictionary. Standardized searches were implemented across bibliographic databases from inception through April 2022. English-language reports of randomized controlled trials (RCTs) evaluating any association between any acute intervention and clinical outcome in at least 100 patients with msTBI, were included. A predefined algorithm was used to assign a value to each observed association. Consultation with AUS-TBI clinicians and researchers formed the consensus process for interventions to be included in a single data dictionary. Searches retrieved 14,455 records, of which 124 full-length RCTs were screened, with 35 studies included. These studies evaluated 26 unique acute interventions across 21 unique clinical outcomes. Only 4 interventions were considered to have medium modifying value for any outcome from the review, with an additional 8 interventions agreed upon through the consensus process. The interventions with medium value were tranexamic acid and phenytoin, which had a positive effect on an outcome; and decompressive craniectomy surgery and hypothermia, which negatively affected outcomes. From the systematic review and consensus process, 12 interventions were identified as potential modifiers to be included in the AUS-TBI national data resource.

The objective of the Australian Traumatic Brain Injury (AUS-TBI) Initiative is to develop a data dictionary to inform data collection and facilitate prediction of outcomes of people who experience moderate-severe TBI in Australia. The aim of this systematic review was to summarize the evidence of the association between demographic, injury event, and social characteristics with outcomes, in people with moderate-severe TBI, to identify potentially predictive indicators. Standardized searches were implemented across bibliographic databases to March 31, 2022. English-language reports, excluding case series, which evaluated the association between demographic, injury event, and social characteristics, and any clinical outcome in at least 10 patients with moderate-severe TBI were included. Abstracts and full text records were independently screened by at least two reviewers in Covidence. A pre-defined algorithm was used to assign a judgement of predictive value to each observed association. The review findings were discussed with an expert panel to determine the feasibility of incorporation of routine measurement into standard care. The search strategy retrieved 16,685 records; 867 full-length records were screened, and 111 studies included. Twenty-two predictors of 32 different outcomes were identified; 7 were classified as high-level (age, sex, ethnicity, employment, insurance, education, and living situation at the time of injury). After discussion with an expert consensus group, 15 were recommended for inclusion in the data dictionary. This review identified numerous predictors capable of enabling early identification of those at risk for poor outcomes and improved personalization of care through inclusion in routine data collection.

The Australian Traumatic Brain Injury Initiative (AUS-TBI) aims to co-design a data resource to predict outcomes for people with moderate-severe traumatic brain injury (TBI) across Australia. Fundamental to this resource is the data dictionary, which is an ontology of data items. Here, we report the systematic review and consensus process for inclusion of biological markers in the data dictionary. Standardized database searches were implemented from inception through April 2022. English-language studies evaluating association between a fluid, tissue, or imaging marker and any clinical outcome in at least 10 patients with moderate-severe TBI were included. Records were screened using a prioritization algorithm and saturation threshold in Research Screener. Full-length records were then screened in Covidence. A pre-defined algorithm was used to assign a judgement of predictive value to each observed association, and high-value predictors were discussed in a consensus process. Searches retrieved 106,593 records; 1,417 full-length records were screened, resulting in 546 included records. Two hundred thirty-nine individual markers were extracted, evaluated against 101 outcomes. Forty-one markers were judged to be high-value predictors of 15 outcomes. Fluid markers retained following the consensus process included ubiquitin C-terminal hydrolase L1 (UCH-L1), S100, and glial fibrillary acidic protein (GFAP). Imaging markers included computed tomography (CT) scores (e.g., Marshall scores), pathological observations (e.g., hemorrhage, midline shift), and magnetic resonance imaging (MRI) classification (e.g., diffuse axonal injury). Clinical context and time of sampling of potential predictive indicators are important considerations for utility. This systematic review and consensus process has identified fluid and imaging biomarkers with high predictive value of clinical and long-term outcomes following moderate-severe TBI.

Emotional distress is common following moderate-severe traumatic brain injury (TBI) and is associated with poorer post-injury outcomes. Previously investigated sociodemographic, psychological, and injury-related factors account for only a small proportion of variance in post-TBI emotional distress, highlighting a need to consider other factors such as genetic factors. The apolipoprotein E gene (APOE) has been commonly studied in the TBI literature, with the ɛ4 allele linked to worse neuronal repair and recovery. Few studies have investigated the potential relationship between APOE ɛ4 and emotional distress after moderate-severe TBI, and results have been varied. We examined whether APOE ɛ4 was associated with emotional distress 1 year following moderate-severe TBI, and whether this relationship was moderated by age, sex, and TBI severity (as indexed by the duration of post-traumatic amnesia [PTA]). Moderate-severe TBI survivors provided saliva samples following inpatient admission to a TBI rehabilitation hospital. They completed a self-report measure of emotional distress, the Hospital Anxiety and Depression Scale (HADS), at a follow-up interview ∼1 year post-injury. Complete genetic and follow-up data were available for 441 moderate-severe TBI survivors (mean age = 39.42 years; 75% male). We constructed a linear regression model that included APOE ɛ4 carriage status (carrier vs. non-carrier) and interactions with age, sex, and TBI severity (APOE × age, APOE × sex, APOE × age × sex, and APOE × PTA duration) to predict total score on the HADS, while covarying for the main effects of age, sex, PTA duration, and previous head injury. There was a significant main effect of APOE ɛ4, whereby ɛ4 carriers reported less emotional distress than non-carriers ( p  = 0.04). However, we also found a significant interaction with age such that APOE ɛ4 carriers reported increasingly greater emotional distress with older age compared with non-carriers ( p  = 0.01). A sensitivity analysis ( n  = 306) suggested that the APOE × age interaction, and main effects of age and previous head injury, were not unique to individuals with pre-injury mental health problems ( n  = 136). However, the main effect of APOE ɛ4 was no longer significant when individuals with pre-injury mental health problems were removed. Our findings highlight the importance of considering moderation of genetic associations, suggesting that APOE ɛ4 may be a risk factor for emotional distress specifically among older survivors of moderate-severe TBI. If these findings can be independently replicated, APOE ɛ4 carriage status, interpreted in the context of age, could be incorporated into risk prediction models of emotional distress after moderate-severe TBI, enhancing targeted early detection and intervention efforts.

Agitation is a common behavioral problem following traumatic brain injury (TBI); however, the precise proportion of patients who experience agitation in the early stages of recovery is unknown. The aim of this systematic review and meta-analysis was to evaluate the prevalence of agitation in TBI patients undergoing inpatient care, and whether this prevalence differed by post-traumatic amnesia (PTA) status and setting (acute and rehabilitation). We also aimed to describe the prevalence of sub-types of agitated behavior (disinhibited, aggressive, and emotionally labile). We searched five databases and one clinical trials register, with additional review of websites and key journals to identify any relevant records up to July 2020. We included studies describing the proportion of hospitalized TBI patients age 16 years or older demonstrating agitated behavior. We included comparative studies with and without concurrent controls, randomized controlled trials, pseudo-randomized controlled trials, and case series. Methodological quality was critically appraised using a Joanna Briggs Institute checklist. Sixteen studies met eligibility criteria, with a total of 5592 participants. The pooled prevalence of agitation was 31.73% (95% confidence interval [CI], 25.25%-39.00%) during inpatient care (acute and rehabilitation), 32.23% (95% CI, 27.13%-37.80%) during rehabilitative care and 44.06% (95% CI, 36.15%-52.28%) for inpatients in PTA specifically. Disinhibited behaviors were the most common. There was substantial heterogeneity between studies. Additional high-quality research featuring large samples, frequent and long-term measurement of agitation, use of validated scales, and consideration of variables such as PTA status will further improve estimates of agitation prevalence following TBI.

After a traumatic brain injury (TBI), many persons experience significant and debilitating problems with anxiety. The aim of this systematic review was to critically evaluate the evidence regarding efficacy of pharmacological interventions for anxiety after TBI. We reviewed studies published in English before July 2020 and included original research on pharmacological interventions for anxiety after TBI in adults ≥16 years of age. MEDLINE, PubMed, CINAHL, EMBASE, PsycINFO, and CENTRAL databases were searched, with additional searching of key journals, clinical trials registries, and international drug regulators. The primary outcomes of interest were reduction in symptoms of anxiety and occurrence of harms. The secondary outcomes of interest were changes in depression, cognition, quality of life, and participation. Data were summarized in a narrative synthesis, and evidence quality was assessed using the Cochrane Risk of Bias tool. Only a single non-peer-reviewed, randomized controlled trial of 19 male military service members with mild TBI met inclusion criteria. This study found no significant effect of citalopram on anxiety symptoms over a 12-week intervention. The trial was stopped early because of poor recruitment, and much of the study detail was not included in the report. The methodological quality of the study was difficult to assess because of the lack of detail. No recommendations could be drawn from this review. There is a critical need for adequately powered and controlled studies of pharmacological interventions for anxiety after TBI across all severities that examine side-effect profiles and consider issues of comorbidity and effects of long-term pharmacotherapy.

Previous studies convincingly suggest that the biopsychosocial fear-avoidance model (FAM) may be of added value in understanding chronic disability after traumatic brain injury (TBI). In this model, persistent symptoms occur as a result of catastrophizing and fear-avoidance regarding initial symptoms, leading to depression, reduced mental activity, and greater disability in daily functioning. This study examined the FAM in a large English-speaking TBI sample. A cross-sectional study was conducted in 117 individuals with complicated mild, moderate, or severe TBI at 1-5 years post-injury. Participants completed questionnaires assessing personal, injury-related, and psychological characteristics. Reliability, correlational, and regression analyses were performed. Main outcome measures of chronic disability were depression, disuse (e.g., fewer mental activities), and functional disability. The results revealed that all correlations suggested by the FAM were significant. Catastrophizing thoughts were positively associated with TBI-related symptoms and fear-avoidance thoughts. Main outcome measures were positively associated with fear-avoidance thoughts and TBI-related symptoms. Further, variables in the FAM were of additive value to personal, injury-related, and psychological variables in understanding chronic disability after TBI. The separate regression analyses for depression, fewer mental activities, and disability revealed "fear-avoidance thoughts" as the only consistent variable. In conclusion, this study shows the association of the FAM with chronic disability after TBI, which has implications for assessment and future management of the FAM in TBI in English-speaking countries. Longitudinal studies are warranted to further investigate and refine the model.

Despite much previous research stating that traumatic brain injury (TBI) has been confirmed as a risk factor for dementia and Alzheimer disease (AD), findings from observational studies are mixed and are of low methodological quality. This review aimed to critically evaluate the methodologies used in previous studies. Relevant literature was identified by examining reference lists for previous reviews and primary studies, and searches in MEDLINE, PubMed, Google Scholar, and Research Gate. Sixty-eight identified reports, published between 1982 and August 2018, met inclusion criteria. Common methodological weaknesses included self-reported TBI (62%); poor TBI case definition (55%); low prevalence of TBI in samples (range 0.07-28.7%); reverse causality (86% moderate to high risk of reverse causality); not controlling for important confounding factors. There were also key areas of methodological rigor including use of individual matching for cases and controls (57%); gold standard dementia and AD criteria (53%); symmetrical data collection (65%); large sample sizes (max, 2,794,752); long follow-up periods and controlling of analyses for age (82%). The quality assessment revealed methodological problems with most studies. Overall, only one study was identified as having strong methodological rigor. This critical review identified several key areas of methodological weakness and rigor and should be used as a guideline for improving future research. This can be achieved by using longitudinal prospective cohort designs, with medically confirmed and well characterized TBI sustained sufficient time before the onset of dementia, including appropriate controls and informants, and considering the impacts of known protective and risk factors.

Depression is a common psychiatric problem following traumatic brain injury (TBI) with reported prevalence rates of 30-77% in the first year post-TBI. Given the negative influence of post-TBI depression on cognition and interpersonal, social, physical, and occupational functioning, early initiation of pharmacotherapy to prevent post-TBI depression has been considered. This systematic review will synthesize the available evidence from published studies on the effectiveness and harms of pharmacotherapy for the secondary prevention of post-TBI depression. Studies published prior to October 2018 were eligible for inclusion. Six databases were searched, with additional searching of key additional documents. Studies meeting inclusion criteria were evaluated for methodological quality. Six articles addressing five studies met inclusion criteria. Study designs included three randomized controlled trials (RCTs), two retrospective cohorts, and one case-control. Prophylactic pharmacotherapy included antidepressants, beta-blockers and statins. In one RCT, the number needed to treat with sertraline to prevent one case of depression post-TBI at 24 weeks was 5.9 (95% confidence interval [CI]: 3.1-71.1). In a second RCT affected by significant attrition, sertraline had no effect. Prescribing beta-blockers prior to TBI reduced the depression risk regardless of the specific brain trauma. TBI patients with pre-existing hyperlipidemia not treated with statins had an increased risk for depression compared with those without hyperlipidemia. Overall, this systematic review yielded mixed evidence of prophylactic efficacy and insufficient evidence of harm. In the absence of tolerability data, existing data are insufficient to recommend sertraline prophylaxis. Optimal timing and treatment duration with identification of patients most likely to benefit from prophylaxis require further consideration. Dedicated prospective studies assessing the effects of beta-blockers and statins on post-TBI depression are required.

Many individuals in post-traumatic amnesia (PTA) following traumatic brain injury (TBI) experience neurobehavioral symptoms (NBS) in addition to disorientation and amnesia. These symptoms are associated with low rehabilitation engagement, self-inflicted harm, and risk of violence. The aim of this systematic review was to evaluate the efficacy and harms of pharmacological interventions for NBS in PTA following TBI in adults. Studies in English published before December 2017 were reviewed. Six databases were searched, with additional hand searching of key journals, clinical trials registries, and international drug regulators. Evidence quality was assessed using Joanna Briggs Institute Critical Appraisal Instruments. Thirteen studies were identified: three randomized controlled trials (RCTs), three cohort studies, and seven case series. In the RCTs, neither amantadine nor sertraline reduced NBS. Less rigorous studies reported reduced NBS in patients administered haloperidol, ziprasidone, carbamazepine, amitriptyline, desipramine, and varied neuroleptics. There is a paucity of well-designed, adequately powered and controlled studies of pharmacological interventions for NBS in PTA. More research is needed to provide evidence-based treatment recommendations and improve care.