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Blood biomarkers are an emerging diagnostic and prognostic tool that reflect a range of neuropathological processes following traumatic brain injury (TBI). Their effectiveness in identifying long-term neuropathological processes after TBI is unclear. Studying biomarkers in the chronic phase is vital because elevated levels in TBI might result from distinct neuropathological mechanisms during acute and chronic phases. Here, we examine plasma biomarkers in the chronic period following TBI and their association with amyloid and tau PET, white matter microarchitecture, brain age and cognition. We recruited participants ≥40 years of age who had suffered a single moderate-severe TBI ≥10 years previously between January 2018 and March 2021. We measured plasma biomarkers using single molecule array technology [ubiquitin C-terminal hydrolase L1 (UCH-L1), neurofilament light (NfL), tau, glial fibrillary acidic protein (GFAP) and phosphorylated tau (P-tau181)]; PET tracers to measure amyloid-β (18F-NAV4694) and tau neurofibrillary tangles (18F-MK6240); MRI to assess white matter microstructure and brain age; and the Rey Auditory Verbal Learning Test to measure verbal-episodic memory. A total of 90 post-TBI participants (73% male; mean = 58.2 years) were recruited on average 22 years (range = 10-33 years) post-injury, and 32 non-TBI control participants (66% male; mean = 57.9 years) were recruited. Plasma UCH-L1 levels were 67% higher {exp(b) = 1.67, P = 0.018, adjusted P = 0.044, 95% confidence interval (CI) [10% to 155%], area under the curve = 0.616} and P-tau181 were 27% higher {exp(b) = 1.24, P = 0.011, adjusted P = 0.044, 95% CI [5% to 46%], area under the curve = 0.632} in TBI participants compared with controls. Amyloid and tau PET were not elevated in TBI participants. Higher concentrations of plasma P-tau181, UCH-L1, GFAP and NfL were significantly associated with worse white matter microstructure but not brain age in TBI participants. For TBI participants, poorer verbal-episodic memory was associated with higher concentration of P-tau181 {short delay: b = -2.17, SE = 1.06, P = 0.043, 95% CI [-4.28, -0.07]; long delay: bP-tau = -2.56, SE = 1.08, P = 0.020, 95% CI [-4.71, -0.41]}, tau {immediate memory: bTau = -6.22, SE = 2.47, P = 0.014, 95% CI [-11.14, -1.30]} and UCH-L1 {immediate memory: bUCH-L1 = -2.14, SE = 1.07, P = 0.048, 95% CI [-4.26, -0.01]}, but was not associated with functional outcome. Elevated plasma markers related to neuronal damage and accumulation of phosphorylated tau suggest the presence of ongoing neuropathology in the chronic phase following a single moderate-severe TBI. Plasma biomarkers were associated with measures of microstructural brain disruption on MRI and disordered cognition, further highlighting their utility as potential objective tools to monitor evolving neuropathology post-TBI., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background Little is known about health literacy in traumatic brain injury (TBI) survivors. The aims of this study were to compare health literacy in individuals with TBI with that of a control group; to examine the association between health literacy in individuals with TBI and demographic, injury, and cognitive factors; and compare the relationship between health literacy and physical and mental health outcomes. Methods A cross-sectional observational study design was used. Adults (≥18years) were recruited from an outpatient research centre in Victoria, Australia. There were 209 participants with a complicated mild to severe TBI at least 1year previously (up to 30years 6months) and 206 control participants. Results Individuals with TBI did not have poorer health literacy than controls (IRR=1.31, P =0.102, CI95% [0.947, 1.812]). Further analysis could not be completed due to the highly skewed Health Literacy Assessment Using Talking Touchscreen Technology - Short Form (Health LiTT-SF) data. Conclusion Health literacy performance in individuals with TBI was not significantly different to controls. Premorbid education may provide a critical cognitive reserve upon which TBI survivors can draw to aid their health literacy. These findings are specific to the Health LiTT-SF measure only and require replication using more comprehensive health literacy measures in culturally diverse samples.

There is an urgent critical need for a patient-forward vaginal stent that can prevent debilitating vaginal stenosis that occurs after pelvic radiation treatments and vaginal reconstruction. To this end, we developed a self-fitting vaginal stent based on a shape-memory polymer (SMP) foam that can assume a secondary, compressed shape for ease of deployment. Upon insertion, the change in temperature and hydration initiates foam expansion to shape fit to the individual patient and restore the lumen of the stent to allow egress of vaginal secretions. To achieve rapid actuation at physiological temperature, we investigated the effect of architecture of two photocurable, polycaprolactone (PCL) macromers. Star-PCL-tetraacrylate displayed a reduced melting temperature as compared to a linear-PCL-diacrylate. Upon fabrication into high porosity foams with emulsion-templating, both compositions displayed shape fixity (>90 %) in a crimped, temporary shape. However, only the PCL star-foams displayed shape recovery (∼84 %) at 37 °C with expansion back to its permanent shape. A custom mold and curing system were then used to fabricate the PCL star-foams into hollow, cylindrical stents. The stent was crimped to its temporary insertion shape (50 % reduction in diameter, OD ∼ 11 mm) with a custom radial crimper and displayed excellent shape fixity for deployment (> 95 %) and shape recovery (∼ 100 %). To screen vaginal stents, we developed a custom benchtop pelvic model that simulated vaginal anatomy, temperatures, and pressures with an associated computational model. The crimped SMP vaginal stent was deployed in the model and expanded to walls of the canal (∼70 % increase in cross-sectional area) in less than 5 min after irrigation with warm water. The vaginal stent demonstrated retention of vaginal caliber with less than 10 % decrease in cross-sectional area under physiological pressures. Collectively, this work demonstrates the potential for SMP foams as self-fitting vaginal stents to prevent stenosis and provides new open-source tools for the iterative design of other gynecological devices. STATEMENT OF SIGNIFICANCE: Vaginal stenosis, a painful narrowing of the vaginal canal, is a common complication after pelvic radiation therapy or reconstructive surgery. To address this clinical need, we have created a self-fitting vaginal stent from a shape-memory polymer foam. The stent compresses for easy insertion and then expands to adapt to each patient's anatomy to maintain an open vaginal canal and prevent stenosis. This innovative stent provides a patient-friendly solution that could make a significant difference for women undergoing pelvic treatments by reducing pain, aiding recovery, and improving quality of life., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

The baroreflex system is involved in modulating several physiological functions of the cardiovascular system and can modulate cardiac output, blood pressure, and cardiac electrophysiology directly and indirectly. In addition, it is involved in regulating neurohormonal pathways involved in the cardiovascular function, such as the renin-angiotensin-aldosterone system and vasopressin release. Baroreflex dysfunction is characterized by sympathetic overactivation and parasympathetic withdrawal and is associated with several cardiovascular diseases, such as hypertension, heart failure, and coronary artery disease. Targeting the baroreflex system via invasive (eg, baroreflex activation therapy and endovascular baroreceptor amplification) and noninvasive approaches (eg, slow breathing exercises and exercise training) has emerged as a novel pathway to manage cardiovascular diseases. Studies examining the long-term safety and efficacy of such interventions in various cardiovascular diseases are needed., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The aim of the Australian Traumatic Brain Injury Initiative (AUS-TBI) is to design a data dictionary to inform data collection and facilitate prediction of outcomes for moderate-severe traumatic brain injury (TBI) across Australia. The process has engaged diverse stakeholders across six areas: social, health, clinical, biological, acute interventions, and long-term outcomes. Here, we report the results of the clinical review. Standardized searches were implemented across databases to April 2022. English-language reports of studies evaluating an association between a clinical factor and any clinical outcome in at least 100 patients with moderate-severe TBI were included. Abstracts, and full-text records, were independently screened by at least two reviewers in Covidence. The findings were assessed through a consensus process to determine inclusion in the AUS-TBI data resource. The searches retrieved 22,441 records, of which 1137 were screened at full text and 313 papers were included. The clinical outcomes identified were predominantly measures of survival and disability. The clinical predictors most frequently associated with these outcomes were the Glasgow Coma Scale, pupil reactivity, and blood pressure measures. Following discussion with an expert consensus group, 15 were recommended for inclusion in the data dictionary. This review identified numerous studies evaluating associations between clinical factors and outcomes in patients with moderate-severe TBI. A small number of factors were reported consistently, however, how and when these factors were assessed varied. The findings of this review and the subsequent consensus process have informed the development of an evidence-informed data dictionary for moderate-severe TBI in Australia., (© Ancelin McKimmie et al., 2024; Published by Mary Ann Liebert, Inc.)

Objective: To examine whether aging with a TBI was associated with a greater burden of health-related comorbidities compared with a non-TBI control cohort and examine the associations between comorbidity burden, emotional outcomes, and health-related quality of life (HRQoL) after TBI across ages., Design: Cross-sectional., Setting: Research center or telephone., Participants: The study included 559 participants (N TBI =291, N Controls =268). Participants with TBI were recruited during inpatient rehabilitation and had sustained a moderate-severe TBI 1-33 years previously. Non-TBI controls were a convenience sample recruited through advertisements in the community., Interventions: Not applicable., Main Outcome Measures: The number of cardiovascular, general physical health, and mental health comorbidities was compared between cohorts and age strata using Poisson regression. The relationships between comorbidities, age, emotional outcomes (Generalized Anxiety Disorder Scale-7, Patient Health Questionnaire-9), and HRQoL (PROMIS Global Health Measure) were examined with linear regression. Distinct subgroups of comorbidities were identified using latent class analysis. Associations between comorbidity classes with demographic and outcome variables were evaluated using multinomial logistic and linear regressions, respectively., Results: TBI participants had a significantly higher comorbidity burden than controls, primarily driven by elevated rates of mental health disorders (RR=2.71, 95% confidence interval [1.37, 5.35]). Cardiovascular and physical health comorbidities were not elevated in the TBI group compared with controls. Both cohorts had 3 similar comorbidity subgroups, suggesting consistent patterns of co-occurring health conditions regardless of TBI exposure. Physical and mental health comorbidities were associated with elevated depression and anxiety symptoms and diminished HRQoL after TBI compared with controls., Conclusion: TBI was associated with greater mental, but not physical, health comorbidities in the decades after injury. However, physical and mental health comorbidities significantly affected emotional and HRQoL status after TBI, underscoring a greater need for long-term support for individuals with TBI coping with both physical and mental health comorbidities., (Copyright © 2024 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

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) aims to develop a health informatics approach to collect data predictive of outcomes for persons with moderate-severe TBI across Australia. Central to this approach is a data dictionary; however, no systematic reviews of methods to define and develop data dictionaries exist to-date. This rapid systematic review aimed to identify and characterize methods for designing data dictionaries to collect outcomes or variables in persons with neurological conditions. Database searches were conducted from inception through October 2021. Records were screened in two stages against set criteria to identify methods to define data dictionaries for neurological conditions (International Classification of Diseases, 11th Revision: 08, 22, and 23). Standardized data were extracted. Processes were checked at each stage by independent review of a random 25% of records. Consensus was reached through discussion where necessary. Thirty-nine initiatives were identified across 29 neurological conditions. No single established or recommended method for defining a data dictionary was identified. Nine initiatives conducted systematic reviews to collate information before implementing a consensus process. Thirty-seven initiatives consulted with end-users. Methods of consultation were "roundtable" discussion ( n  = 30); with facilitation ( n  = 16); that was iterative ( n  = 27); and frequently conducted in-person ( n  = 27). Researcher stakeholders were involved in all initiatives and clinicians in 25. Importantly, only six initiatives involved persons with lived experience of TBI and four involved carers. Methods for defining data dictionaries were variable and reporting is sparse. Our findings are instructive for AUS-TBI and can be used to further development of methods for defining data dictionaries., Competing Interests: M.K.B. has received personal fees for travel or consulting from Chiropractor's Association of Australia, Memorial University of Newfoundland, Life Ready Health Group, and Active Linc Pty Ltd. M.K.B. has received research funding from the Australian NHMRC, MRFF and RTP schemes, UNSW, and NeuRA. D.J.C. occasionally consults for Pressura Neuro, all funds to Monash University. M.F. is the CEO of the charitable organization Connectivity–Traumatic Brain Injury Australia., (© Matthew K. Bagg et al., 2024; Published by Mary Ann Liebert, Inc.)

The Australian Traumatic Brain Injury Initiative (AUS-TBI) aims to select a set of measures to comprehensively predict and assess outcomes following moderate-to-severe traumatic brain injury (TBI) across Australia. The aim of this article was to report on the implementation and findings of an evidence-based consensus approach to develop AUS-TBI recommendations for outcome measures following adult and pediatric moderate-to-severe TBI. Following consultation with a panel of expert clinicians, Aboriginal and Torres Strait Islander representatives and a Living Experience group, and preliminary literature searches with a broader focus, a decision was made to focus on measures of mortality, everyday functional outcomes, and quality of life. Standardized searches of bibliographic databases were conducted through March 2022. Characteristics of 75 outcome measures were extracted from 1485 primary studies. Consensus meetings among the AUS-TBI Steering Committee, an expert panel of clinicians and researchers and a group of individuals with lived experience of TBI resulted in the production of a final list of 11 core outcome measures: the Functional Independence Measure (FIM); Glasgow Outcome Scale-Extended (GOS-E); Satisfaction With Life Scale (SWLS) (adult); mortality; EuroQol-5 Dimensions (EQ5D); Mayo-Portland Adaptability Inventory (MPAI); Return to Work /Study (adult and pediatric); Functional Independence Measure for Children (WEEFIM); Glasgow Outcome Scale Modified for Children (GOS-E PEDS); Paediatric Quality of Life Scale (PEDS-QL); and Strengths and Difficulties Questionnaire (pediatric). These 11 outcome measures will be included as common data elements in the AUS-TBI data dictionary. Review Registration PROSPERO (CRD42022290954)., Competing Interests: D.J.C. occasionally consults to Pressure P/L, with all funds being given to Monash University. M.F. is the CEO of the charitable organization Connectivity - Traumatic Brain Injury Australia. The other authors have nothing to disclose., (© Jennie L. Ponsford et al., 2024; Published by Mary Ann Liebert, Inc.)

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.

Traumatic brain injury (TBI) alters brain network connectivity. Structural covariance networks (SCNs) reflect morphological covariation between brain regions. SCNs may elucidate how altered brain network topology in TBI influences long-term outcomes. Here, we assessed whether SCN organisation is altered in individuals with chronic moderate-severe TBI (≥ 10 years post-injury) and associations with cognitive performance. This case-control study included fifty individuals with chronic moderate-severe TBI compared to 75 healthy controls recruited from an ongoing longitudinal head injury outcome study. SCNs were constructed using grey matter volume measurements from T1-weighted MRI images. Global and regional SCN organisation in relation to group membership and cognitive ability was examined using regression analyses. Globally, TBI participants had reduced small-worldness, longer characteristic path length, higher clustering, and higher modularity globally (p < 0.05). Regionally, TBI participants had greater betweenness centrality (p < 0.05) in frontal and central areas of the cortex. No significant associations were observed between global network measures and cognitive ability in participants with TBI (p > 0.05). Chronic moderate-severe TBI was associated with a shift towards a more segregated global network topology and altered organisation in frontal and central brain regions. There was no evidence that SCNs are associated with cognition., (© 2024. The Author(s).)

Objective: This study examined the relationship between cognitive reserve measured with the Cognitive Reserve Index questionnaire (CRIq) and cognitive and functional outcomes in a chronic traumatic brain injury (TBI) cohort compared to a non-TBI cohort. The utility of the CRIq was compared to common proxies of cognitive reserve (premorbid IQ and years of education) in TBI and non-TBI cohorts. Method: Participants were 105 individuals with moderate-severe TBI (10-33 years post injury) and 91 participants without TBI. Cognitive outcome was examined across four cognitive factors; verbal memory, visual ability and memory, executive attention, and episodic memory. Functional outcome was measured using the Glasgow Outcome Scale Extended. The CRIq total score and three subscale scores (education, work, leisure) were examined. Results: In the TBI cohort, associations were identified between two CRIq subscales and cognitive factors (CRIq education and verbal memory; CRIq work and executive attention). There were no associations between CRIq leisure and cognitive outcomes, or between CRIq and functional outcome. Model selection statistics suggested premorbid IQ and years of education provided a better fit than the CRIq for the relationship between cognitive reserve with two cognitive factors and functional outcome, with neither model providing an improved fit for the remaining two cognitive factors. This finding was broadly consistent in the non-TBI cohort. Conclusion: Cognitive reserve contributes significantly to long-term clinical outcomes following moderate-severe TBI. The relationship between cognitive reserve and long-term cognitive and functional outcomes following TBI is best characterised with traditional proxies of cognitive reserve, mainly premorbid IQ, rather than the CRIq.

Background: We investigated the value of automated enlarged perivascular spaces (ePVS) quantification to distinguish chronic traumatic brain injury (TBI) patients with post-traumatic epilepsy (PTE + ) from chronic TBI patients without PTE (PTE - ) in a feasibility study., Methods: Patients with and without PTE were recruited and underwent an MRI post-TBI. Multimodal auto identification of ePVS algorithm was applied to T1-weighted MRIs to segment ePVS. The total number of ePVS was calculated and corrected for white matter volume, and an asymmetry index (AI) derived., Results: PTE was diagnosed in 7 out of the 99 participants (male=69) after a median time of less than one year since injury (range 10-22). Brain lesions were observed in all 7 PTE + cases (unilateral=4, 57%; bilateral=3, 43%) as compared to 40 PTE - cases (total 44%; unilateral=17, 42%; bilateral=23, 58%). There was a significant difference between PTE + (M=1.21e -4 , IQR [8.89e -5 ]) and PTE - cases (M=2.79e -4 , IQR [6.25e -5 ]) in total corrected numbers of ePVS in patients with unilateral lesions (p=0.024). No differences in AI, trauma severity and lesion volume were seen between groups., Conclusion: This study has shown that automated quantification of ePVS is feasible and provided initial evidence that individuals with PTE with unilateral lesions may have fewer ePVS compared to TBI patients without epilepsy. Further studies with larger sample sizes should be conducted to determine the value of ePVS quantification as a PTE-biomarker., Competing Interests: Declaration of Competing Interest Author Gernot Hlauschek has served as a lecturer for Eisai, unrelated to this study. Author Morten Ingvar Lossius has served as a paid consultant and lecturer for Eisai, UCB and Arvelle Therapeutics, unrelated to this study. None of the other authors has any conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: Psychopathology following traumatic brain injury (TBI) is a common and debilitating consequence that is often associated with reduced functional and psychosocial outcomes. There is a lack of evidence regarding the neural underpinnings of psychopathology following TBI, and whether there may be transdiagnostic neural markers that are shared across traditional psychiatric diagnoses. The aim of this systematic review and meta-analysis is to examine the association of MRI-derived markers of brain structure and function with both transdiagnostic and specific psychopathology following moderate-severe TBI., Methods and Analysis: A systematic literature search of Embase (1974-2022), Ovid MEDLINE (1946-2022) and PsycINFO (1806-2022) will be conducted. Publications in English that investigate MRI correlates of psychopathology characterised by formal diagnoses or symptoms of psychopathology in closed moderate-severe TBI populations over 16 years of age will be included. Publications will be excluded that: (a) evaluate non-MRI neuroimaging techniques (CT, positron emission tomography, magnetoencephalography, electroencephalogram); (b) comprise primarily a paediatric cohort; (c) comprise primarily penetrating TBI. Eligible studies will be assessed against a modified Joanna Briggs Institute Critical Appraisal Instrument and data will be extracted by two independent reviewers. A descriptive analysis of MRI findings will be provided based on qualitative synthesis of data extracted. Quantitative analyses will include a meta-analysis and a network meta-analysis where there are sufficient data available., Ethics and Dissemination: Ethics approval is not required for the present study as there will be no original data collected. We intend to disseminate the results through publication to a high-quality peer-reviewed journal and conference presentations on completion., Prospero Registration Number: CRD42022358358., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Emotional distress is a common, but poorly addressed, feature of moderate-severe traumatic brain injury (TBI). Previously identified sociodemographic, psychological, and injury-related factors account for only a small proportion of the variability in emotional distress post-TBI. Genetic factors may help to further understand emotional distress in this population. The catechol- O -methyltransferase (COMT) Val158 and brain-derived neurotrophic factor (BDNF) 66Met single-nucleotide polymorphisms (SNPs) have been identified as possible contributory factors to outcomes after TBI. We investigated whether the COMT Val158 and BDNF 66Met SNPs were associated with emotional distress 1 year after moderate-severe TBI, and whether these associations were moderated by age, sex, and TBI severity (as measured by the duration of post-traumatic amnesia [PTA]). Moderate-severe TBI survivors (COMT, n  = 391; BDNF, n  = 311) provided saliva samples after admission to a TBI rehabilitation hospital. At a follow-up interview ∼1 year after injury, participants completed a self-report measure of emotional distress (Hospital Anxiety and Depression Scale; HADS). Multiple linear regression models were constructed for each SNP to predict total scores on the HADS. Neither COMT Val158 nor BDNF 66Met carriage status (carrier vs. non-carrier) significantly predicted emotional distress (COMT, p  = 0.49; BDNF, p  = 0.66). Interactions of SNP × age (COMT, p  = 0.90; BDNF, p  = 0.93), SNP × sex (COMT, p  = 0.09; BDNF, p  = 0.60), SNP × injury severity (COMT, p  = 0.53; BDNF, p  = 0.87), and SNP × sex × age (COMT, p  = 0.08; BDNF, p  = 0.76) were also non-significant. Our null findings suggest that COMT Val158 and BDNF 66Met SNPs do not aid the prediction of emotional distress 1 year after moderate-severe TBI, neither in isolation nor in interaction with age, sex and injury severity. The reporting of null findings such as ours is important to avoid publication bias and prompt researchers to consider the challenges of single-gene candidate studies in understanding post-TBI outcomes. Analyses in larger samples that incorporate multiple genetic factors and their relevant moderating factors may provide a greater understanding of the role of genetics in post-TBI emotional distress., Competing Interests: No competing financial interests exist., (© Chloe Anderson et al., 2023; Published by Mary Ann Liebert, Inc.)

We used network analysis to explore interrelationships between anxiety and depressive symptoms after traumatic brain injury (TBI). At one year post-injury, 882 adult civilians who received inpatient rehabilitation for moderate-severe TBI self-reported anxiety and depressive symptoms (Hospital Anxiety and Depression Scale). The severity of TBI was characterized acutely by the duration of post-traumatic amnesia (PTA), and TBI-related functional disability was rated by an examiner at one year post-injury using a structured interview (Glasgow Outcome Scale - Extended). We estimated two cross-sectional, partial correlation networks. In the first network, anxiety and depressive symptoms were densely interconnected yet formed three distinct, data-driven communities: Hyperarousal, Depression, and General Distress. Worrying thoughts and having difficulty relaxing were amongst the most central symptoms, showing strong connections with other symptoms within and between communities. In the second network, TBI severity was directly negatively associated with hyperarousal symptoms but indirectly positively associated with depressive symptoms via greater functional disability. The results highlight the potential utility of simultaneous, transdiagnostic assessment and treatment of anxiety and depressive symptoms after moderate-severe TBI. Worrying thoughts, having difficulty relaxing, and the experience of disability may be important targets for treatment, although future studies examining symptom dynamics within individuals and over time are required., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Objectives: Enlarged perivascular spaces (ePVS) have been identified as a key signature of glymphatic system dysfunction in neurologic conditions. The incidence and clinical implications of ePVS after traumatic brain injury (TBI) are not yet understood. We investigated whether individuals with chronic moderate-to-severe TBI had an increased burden of ePVS and whether ePVS burden is modulated by the presence of focal lesions, older brain age, and poorer sleep quality. We examined whether an increased burden of ePVS was associated with poorer cognitive and emotional outcomes., Methods: Using a cross-sectional design, participants with a single moderate-to-severe chronic TBI (sustained ≥10 years ago) were recruited from an inpatient rehabilitation program. Control participants were recruited from the community. Participants underwent 3T brain MRI, neuropsychological assessment, and clinical evaluations. ePVS burden in white matter was quantified using automated segmentation. The relationship between the number of ePVS, group membership, focal lesions, brain age, current sleep quality, and outcome was modeled using negative binomial and linear regressions., Results: This study included 100 participants with TBI (70% male; mean age = 56.8 years) and 75 control participants (54.3% male; mean age = 59.8 years). The TBI group had a significantly greater burden of ePVS (prevalence ratio rate [PRR] = 1.29, p = 0.013, 95% CI 1.05-1.57). The presence of bilateral lesions was associated with greater ePVS burden (PRR = 1.41, p = 0.021, 95% CI 1.05-1.90). There was no association between ePVS burden, sleep quality (PRR = 1.01, p = 0.491, 95% CI 0.98-1.048), and sleep duration (PRR = 1.03, p = 0.556, 95% CI 0.92-1.16). ePVS was associated with verbal memory (β = -0.42, p = 0.006, 95% CI -0.72 to -0.12), but not with other cognitive domains. The burden of ePVS was not associated with emotional distress (β = -0.70, p = 0.461, 95% CI -2.57 to 1.17) or brain age (PRR = 1.00, p = 0.665, 95% CI 0.99-1.02)., Discussion: TBI is associated with a greater burden of ePVS, especially when there have been bilateral brain lesions. ePVS was associated with reduced verbal memory performance. ePVS may indicate ongoing impairments in glymphatic system function in the chronic postinjury period., (© 2023 American Academy of Neurology.)

Objective: To characterize trajectories of emotional distress across the first decade after moderate-severe traumatic brain injury (TBI) and explore relations with personal and injury-related factors., Design: Cohort study with follow-ups at 1, 2, 3, 5, and 10 years post-injury., Setting: Community., Participants: Participants were sampled from a larger longitudinal study of 4300 individuals recruited from consecutive inpatient TBI admissions to a rehabilitation hospital between 1985 and 2021 (N=4300). We analyzed data from 596 unique individuals (13.86% of total dataset; 70.81% male; M age =40.11 years, SD age =17.49 years; 7.59% non-English-speaking background) with moderate-severe TBI who had complete data on all personal and injury-related variables (collected on admission) and emotional data at 3 or more time-points. There were 464 participants at the 1-year post-injury time-point, 485 at 2 years, 454 at 3 years, 450 at 5 years, and 248 at 10 years., Interventions: Not applicable., Main Outcome Measure: The Hospital Anxiety and Depression Scale (HADS)., Results: Visualization of the individual HADS symptoms (line graph) showed that the most highly endorsed symptoms at each time-point were feeling slowed down and restlessness. On average, each symptom reduced across the first decade post-TBI, with an overall mild level of emotional distress at 10 years. However, visualization of participants' individual trajectories based on the HADS total score (Sankey diagram) revealed significant heterogeneity. Using latent class analysis, we identified 5 distinct trajectory types based on the HADS total score: "Gradual Improving" (38.93%), "Resilience" (36.41%), "Gradual Worsening" (10.40%), and 2 non-linear trajectories of "Worsening-Remitting" (8.22%) and "Improving-Relapsing" (6.04%). Middle age at injury, lower Glasgow Coma Scale score, comorbid spinal and limb injuries, and receipt of pre-injury mental health treatment predicted earlier and/or worsening post-injury emotional distress., Conclusions: Emotional distress across the first decade after moderate-severe TBI is dynamic, heterogeneous, and often chronic, underscoring a need for ongoing monitoring and responsive treatment., (Copyright © 2023 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Symptoms of depression are common following traumatic brain injury (TBI), impacting survivors' ability to return to work, participate in leisure activities, and placing strain on relationships. Depression symptoms post TBI are often managed with pharmacotherapy, however, there is little research evidence to guide clinical practice. There have been a number of recent systematic reviews examining pharmacotherapy for post TBI depression. The aim of this umbrella review was to synthesize systematic reviews and meta-analyses of the effectiveness of pharmacotherapy for the management of post TBI depression in adults. Eligible reviews examined any pharmacotherapy against any comparators, for the treatment of depression in adults who had sustained TBI. Seven databases were searched, with additional searching of online journals, Research Gate, Google Scholar and the TRIP Medical Database to identify published and unpublished systematic reviews and meta-analyses in English up to May 2020. A systematic review of primary studies available between March 2018 and May 2020 was also conducted. Evidence quality was assessed using Joanna Briggs Institute Critical Appraisal Instruments. The results are presented as a narrative synthesis. Twenty-two systematic reviews were identified, of which ten reviews contained a meta-analysis. No new primary studies were identified in the systematic review. There was insufficient high quality and methodologically rigorous evidence to recommend prescribing any specific drug or drug class for post TBI depression. The findings do show, however, that depression post TBI is responsive to pharmacotherapy in at least some individuals. Recommendations for primary studies, systematic reviews and advice for prescribers is provided. Review Registration PROSPERO (CRD42020184915)., (© 2022. The Author(s).)

Agitation is common in the early recovery period following traumatic brain injury (TBI), known as post-traumatic amnesia (PTA). Non-pharmacological interventions are frequently used to manage agitation, yet their efficacy is largely unknown. This systematic review aims to synthesize current evidence on the effectiveness of non-pharmacological interventions for agitation during PTA in adults with TBI. Key databases searched included MEDLINE Ovid SP interface, PubMed, CINAHL, Excerpta Medica Database, PsycINFO and CENTRAL, with additional online reviewing of key journals and clinical trial registries to identify published or unpublished studies up to May 2020. Eligible studies included participants aged 16 years and older, showing agitated behaviours during PTA. Any non-pharmacological interventions for reducing agitation were considered, with any comparator accepted. Eligible studies were critically appraised for methodological quality using Joanna Briggs Institute Critical Appraisal Instruments and findings were reported in narrative form. Twelve studies were included in the review: two randomized cross-over trials, three quasi-experimental studies, four cases series and three case reports. Non-pharmacological interventions were music therapy, behavioural strategies and environmental modifications, physical restraints and electroconvulsive therapy. Key methodological concerns included absence of a control group, a lack of formalised agitation measurement and inconsistent concomitant use of pharmacology. Interventions involving music therapy had the highest level of evidence, although study quality was generally low to moderate. Further research is needed to evaluate non-pharmacological interventions for reducing agitation during PTA after TBI.Systematic review registration number: PROSPERO (CRD42020186802), registered May 2020., (© 2022. The Author(s).)

Challenging behaviours are distressing sequelae for people with acquired brain injury (ABI) and their families. Positive Behaviour Support (PBS) is a collaborative approach focussing on improving quality of life for individuals with ABI presenting with challenging behaviours. This qualitative study explored clinicians' experiences of a 12-month intervention (PBS+PLUS) for adults with ABI and their family/carers. Semi-structured interviews were conducted with eight clinicians trained in neuropsychology ( n  = 5), occupational therapy ( n  = 3), speech pathology ( n  = 2), with two clinicians trained in two of these disciplines. Interviews were analysed through reflexive thematic analysis. Three themes were identified: Shifting clinical identity; Working as equals; Adapting to the environment. Participants experienced PBS+PLUS as a difficult approach to learn but one which enhanced overt client communication and comfort with their clinical fallibility. PBS+PLUS involved giving clients equal status in the clinician-client relationship which for some clients and families was challenging. Finally, PBS+PLUS was perceived as problematic to implement in some work settings (e.g., involving high staff turnover). Clinicians' recommendations for future implementation included thorough training and supervision and early setting of client expectations. With increasing interest in PBS to address challenging behaviours after ABI, these findings will guide PBS+PLUS translation for community clinicians.

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.

Purpose: There is limited qualitative research exploring challenges experienced following severe traumatic brain injury (TBI). We investigated challenges to recovery identified by individuals who sustained severe TBI three years earlier or their close others (COs), as well as suggestions for managing these challenges., Materials and Methods: Nine participants with TBI and 16 COs completed semi-structured interviews. Using reflexive thematic analysis, challenges were identified across several timeframes (i.e., at the injury, acute care, inpatient rehabilitation, outpatient rehabilitation, and at home/other location)., Results: Challenges experienced across all timeframes included: lack of information and poor communication, pre-existing conditions, missed injuries, and issues with medical staff, and continuity of care. From acute care onwards, there were TBI-related consequences, issues with coping and emotional adjustment, negative outlook, insufficient treatment, lack of support for COs, and issues with compensation and funding for rehabilitation needs. Some challenges were unique to a specific timeframe (e.g., over-stimulating ward setting during acute care, and limited or unsupportive families once injured individuals went home). Suggestions for managing some of the challenges were provided (e.g., information provision, having peer supports)., Conclusion: Suggestions should be considered to promote successful outcomes following severe TBI.IMPLICATIONS FOR REHABILITATIONRecovery following a severe traumatic brain injury can be hindered by challenges, such as poor communication, limited information provision, injury-related consequences, limited services and emotional support for the injured individual and their Close Others, and a need for education of the broader community about traumatic brain injury.Suggestions for managing these challenges (e.g., peer supports; services closer to home) could be used to inform clinical guidelines that could be used in a rehabilitation context.These suggestions ultimately aim to improve the post-injury experience and outcomes of individuals with traumatic brain injury and their Close Others.

Background: Challenging behaviours after acquired brain injury (ABI) cause distress and reduce community participation. Evidence-based and effective interventions are needed. Positive Behaviour Support (PBS) interventions, such as PBS + PLUS, are person-driven and context-sensitive approaches which aim to improve quality of life and enhance behavioural self-regulation. This study aimed to expand the empirical outcomes of a recent waitlist-controlled trial of PBS + PLUS by examining individualized goal attainment., Method: Participants were 44 adults with severe ABI sustained on average nine years previously (Range = 0.6-26) from the combined trial cohort who completed the intervention. Using Goal Attainment Scaling, trial therapists developed and reviewed goals collaboratively with the person with ABI and their natural supports., Results: The 182 goals in the sample focussed on psychological wellbeing, interpersonal relationships, routines and self-care. By the end of 12-month intervention, 84.6% of goals were achieved and 53.3% exceeded their expected outcome., Conclusions: These findings indicate high levels of personally meaningful outcomes in a broad range of life-domains can be obtained for participants with severe ABI using PBS + PLUS. Whilst these results should be considered in combination with the findings of the waitlist-controlled trial, they contribute to the growing literature regarding benefits of PBS in enhancing quality of life post-ABI., Trial Registration: Australian New Zealand Clinical Trials Registry identifier: ACTRN12616001704482.

Challenging behaviours are common following moderate to severe acquired brain injury (ABI). These behaviours cause relationship and community participation difficulties and are a significant source of stress for many individuals with ABI and their close others (COs). A Positive Behaviour Support intervention, PBS + PLUS, was implemented to assist individuals with ABI to collaboratively build meaningful lives and self-regulate their behaviour. This study explored the perspectives of individuals with ABI and COs (family members, friends, and carers) who had completed an individualized 12-month PBS + PLUS intervention. Fifty-two individuals participated in semi-structured interviews, and a thematic analysis of interview transcripts identified the interrelated themes of Openness to Change, Embeddedness, Clinician Connection, and Preparedness for the Future. Participant perceptions of, and engagement with, PBS + PLUS were influenced by an attitude of openness to new ideas and by the intervention itself. Achieving contextual relevance allowed the intervention to become embedded in participants' lives, and the client-clinician relationship was central to participants' positive experiences. While most participants felt better equipped to cope with the future, some experienced difficulties transitioning to post-intervention life. These results suggest PBS + PLUS may assist individuals with ABI to lead meaningful lives and more confidently overcome behavioural challenges, while encouraging supportive and empowered COs.

Background and Objectives: Traumatic brain injury (TBI) has been promoted as a risk factor for Alzheimer disease (AD). There is evidence of elevated β-amyloid (Aβ) and tau, the pathologic hallmarks of AD, immediately following TBI. It is not clear whether Aβ and tau remain elevated in the chronic period. To address this issue, we assessed Aβ and tau burden in long-term TBI survivors and healthy controls using PET imaging., Methods: Using a cross-sectional design, we recruited individuals following a single moderate to severe TBI at least 10 years previously from an inpatient rehabilitation program. A demographically similar healthy control group was recruited from the community. PET data were acquired using 18 F-NAV4694 (Aβ) and 18 F-MK6240 (tau) tracers. Aβ deposition was quantified using the Centiloid scale. Tau deposition was quantified using the standardized uptake value ratio (SUVR) in 4 regions of interest (ROIs). As a secondary measure, PET scans were also visually read as positive or negative. We examined PET data in relation to time since injury and age at injury. PET data were analyzed in a series of regression analyses., Results: The sample comprised 87 individuals with TBI (71.3% male; 28.7% female; mean 57.53 years, SD 11.53) and 59 controls (59.3% male; 40.7% female; mean 60.34 years, SD 11.97). Individuals with TBI did not have significantly higher 18 F-NAV4694 Centiloid values ( p = 0.067) or 18 F-MK6240 tau SUVRs in any ROI ( p ≤ 0.001; SUVR greater for controls). Visual assessment was consistent with the quantification; individuals with TBI were not more likely than controls to have a positive Aβ ( p = 0.505) or tau scan ( p = 0.221). No associations were identified for Aβ or tau burden with time since injury ( p = 0.057 to 0.332) or age at injury., Discussion: A single moderate to severe TBI was not associated with higher burden of Aβ or tau pathologies in the chronic period relative to healthy controls. Aβ and tau burden did not show a significant increase with years since injury, and burden did not appear to be greater for those who were older at the time of injury., (© 2022 American Academy of Neurology.)

This prospective controlled study examined long-term trajectories of neuropsychological performance in individuals with traumatic brain injury (TBI) compared to healthy controls, and the impact of IQ, age at injury, time since injury, and injury severity on change over time. Fifty-three individuals with moderate to severe TBI (60.37% male; M  = 59.77 yrs, SD   = 14.03), and 26 controls (46.15% male; M  = 63.96 yrs, SD   = 14.42) were studied prospectively ( M = 12.72 yrs between assessments). Participants completed measures of premorbid IQ (Weschler Test of Adult Reading), processing speed (Digit Symbol Coding Test), working memory (Digit Span Backwards), memory (Rey Auditory Verbal Learning Test) and executive function (Trail Making Test Part B; Hayling Errors), at a mean of 10.62 yrs (Initial) and 23.91 yrs (Follow-Up) post injury. Individuals with TBI did not show a significantly greater decline in neuropsychological performance over time compared with demographically similar controls. There was no association between change over time with IQ, time since injury or injury severity. Being older at injury had a greater adverse impact on executive function at follow-up. In this small sample, a single moderate to severe TBI was not associated with ongoing cognitive decline up to three decades post injury. Changes in cognitive function were similar between the groups and likely reflect healthy aging.

Background: Challenging behaviours are common and disabling consequences of acquired brain injury (ABI), causing stress for close-others and disrupting community integration. Positive Behaviour Support (PBS) interventions have support from case studies as a means of reducing these behaviours, but controlled trials are lacking., Objectives: This study aimed to evaluate, with a randomised waitlist-controlled trial, the efficacy of a 12-month PBS intervention, termed PBS+PLUS, in reducing challenging behaviours after ABI., Methods: Participants included 49 individuals with ABI (PBS+PLUS Intervention and Waitlist Treatment-as-usual groups) and their close-others. The design was a randomised waitlist-controlled trial with 12-month follow-up. PBS+PLUS involved setting collaborative goals toward a more meaningful life with the individual with ABI and addressing barriers to achieving these, including challenging behaviours, through skill-building, restructuring environments and executive strategies. The primary outcome measure was the Overt Behaviour Scale (OBS). The Challenging Behaviour Self-Efficacy Scale (CBSES) was a secondary outcome, assessing close-others' self-efficacy in addressing challenging behaviour. Measures were completed at baseline and every 4 months. Data analyses involved mixed-effects and negative binomial regressions examining change over time by group., Results: The PBS+PLUS Intervention group included 24 participants and the Waitlist group 25 participants. On the OBS, the Intervention group showed a significant reduction in challenging behaviour over the 12-month intervention. However, the Waitlist group showed similar improvement on the OBS over the 12-month waitlist period. The Waitlist group was not denied an intervention from other providers during this period. Gains continued for 8 months post-intervention. The PBS+PLUS intervention resulted in significantly greater gains in close-others' confidence in addressing challenging behaviours on the CBSES, relative to those in the Waitlist group, who showed no such gains., Conclusions: Although we cannot say this intervention is more effective than any other, the study did show that PBS+PLUS can result in significant and sustained reductions in challenging behaviour in individuals with severe ABI and increased confidence of close-others in addressing these difficult behaviours., Australian New Zealand Clinical Trials Registry: #ACTRN12616001704482., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2021. Published by Elsevier Masson SAS.)

Traumatic brain injury (TBI) is associated with greater 'brain age' that may be caused by atrophy in grey and white matter. Here, we investigated 'brain age' in a chronic TBI (≥10 years) sample. We examined whether 'brain age' increases with years post injury, and whether it is associated with injury severity, cognition and functional outcome. We recruited 102 participants with moderate to severe TBI aged between 40 and 85 years. TBI participants were assessed on average 22 years post-injury. Seventy-seven healthy controls were also recruited. Participants' 'brain age' was determined using T1-weighted MRI images. TBI participants were estimated to have greater 'brain age' compared to healthy controls. 'Brain age' gap was unrelated to time since injury or long-term functional outcome on the Glasgow Outcome Scale-Extended. Greater brain age was associated with greater injury severity measured by post traumatic amnesia duration and Glasgow Coma Scale. 'Brain age' was significantly and inversely associated with verbal memory, but unrelated to visual memory/ability and cognitive flexibility and processing speed. A longitudinal study is required to determine whether TBI leads to a 'one-off' change in 'brain age' or progressive ageing of the brain over time., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Competing Interests: JP declares payments to her institution from the Transport Accident Commission and the National Health and Medical Research Council, and payments of fees for legal consultancy. GS and AJH have no competing interests.

Previous studies examining life after traumatic brain injury (TBI) have taken a predominantly short-term and quantitative perspective, with generally narrow focus, and have not specifically investigated changes in experience over time post-injury to gain a uniquely long-term perspective. This study therefore aimed to qualitatively explore the broad long-term experience of living for 10 years or more with TBI. Thirty participants completed semi-structured interviews investigating the impact of TBI on various life domains, the rehabilitation experience and support received, and overall perspectives of the long-term journey after TBI. Results demonstrated that: (a) although some participants reported full recovery, several experienced persistent physical, cognitive and emotional problems that impacted their independence, employment and interpersonal relationships; (b) early rehabilitation was very helpful, but some participants experienced difficulties accessing ongoing services; (c) family and social support were important to recovery; (d) most participants drew upon inner strength to find positives in their experience. These findings have identified factors that facilitate and impede long-term recovery from TBI, which may inform better support and care for injured individuals over the years after injury to improve their quality of life.

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.

The field of genomics is the principal avenue in the ongoing development of precision/personalised medicine for a variety of health conditions. However, relating genes to outcomes is notoriously complex, especially when considering that other variables can change, or moderate, gene-outcome associations. Here, we comprehensively discuss moderation of gene-outcome associations in the context of traumatic brain injury (TBI), a common, chronically debilitating, and costly neurological condition that is under complex polygenic influence. We focus our narrative review on single nucleotide polymorphisms (SNPs) of three of the most studied genes (apolipoprotein E, brain-derived neurotrophic factor, and catechol-O-methyltransferase) and on three demographic variables believed to moderate associations between these SNPs and TBI outcomes (age, biological sex, and ethnicity). We speculate on the mechanisms which may underlie these moderating effects, drawing widely from biomolecular and behavioural research (n = 175 scientific reports) within the TBI population (n = 72) and other neurological, healthy, ageing, and psychiatric populations (n = 103). We conclude with methodological recommendations for improved exploration of moderators in future genetics research in TBI and other populations., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Managing agitation is a significant challenge in the early stages of recovery after traumatic brain injury (TBI), and research investigating current practice during this period is lacking., Objectives: This study examined how clinicians worldwide conceptualise, measure and manage agitation during early TBI recovery., Methods: A cross-sectional anonymous online survey was distributed via email, newsletters, conferences and social media to clinicians involved in early TBI care worldwide. Respondents were 331 clinicians (66% female) from 34 countries worldwide who worked in inpatient and outpatient settings in disciplines including medicine, nursing and allied health. Participants had an average of 13 years' clinical experience working specifically with an adult TBI population., Results: Agitated behaviour was commonly defined as aggression and restlessness. Three quarters of clinicians reported that their services measure agitation, and clinicians in North America more frequently use standardised assessment tools. Common non-pharmacological approaches used across all regions surveyed included providing familiarising information (85%) and environmental cues (82%), managing patients in single rooms (81%) and reducing noise levels (80%). Most clinicians (90%) reported pharmacology use, particularly atypical antipsychotic agents. Clinicians' mean rating of confidence in managing agitation was 7 out of 10 (10 being excellent) and was higher for services that provided staff with written guidelines for agitation management. Only half of clinicians reported sufficient training for managing agitation and 52% were satisfied with current agitation management practices., Conclusions: Despite high rates of agitation measurement and management, many clinicians reported dissatisfaction with current agitation management and insufficient training. This study supports the development of international guidelines and training to ensure consistent and effective agitation management in early TBI care., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Objective: The objective of this review is to synthesize systematic reviews of the effectiveness of pharmacotherapy vs any other comparator for the management of post-traumatic brain injury depression in adults., Introduction: Depression following a traumatic brain injury can have a considerable impact on the life of the individual, their family members, and the health care system. There have been several recent systematic reviews and meta-analyses on pharmacologic treatment for depression caused by post-traumatic brain injury. These reviews differ in conduct, quality, and reporting, and have discordant results and conclusions. Therefore, an umbrella review can provide prescribers with a summary of the evidence., Inclusion Criteria: This review will consider systematic reviews of studies of adults 16 years or older who have sustained a traumatic brain injury of any severity at any time in the past, who are receiving pharmacotherapy for depression of any severity in any health care setting. Studies that include the following outcomes will be considered: change in symptoms of depression and occurrence of harms., Methods: MEDLINE, Embase, CINAHL, PsycINFO, Cochrane Database of Systematic Reviews, Epistemonikos, and PROSPERO will be searched, as well as Google Scholar, ResearchGate, TRIP Medical Database, and hand searching journals. There will be no restriction on publication date. Only systematic reviews published in English will be considered. Screening of articles, assessment of methodological quality, and data extraction will be performed independently by two reviewers. A Grading of Recommendations, Assessment, Development and Evaluation Summary of Findings will be presented. Data will be summarized in narrative form with supporting tables., Systematic Review Registration Number: PROSPERO CRD42020184915., Competing Interests: The chief investigator MH has given talks on this topic for which travel and accommodation has been paid by the organizers. In addition, he has accepted fees for consulting and research from the pharmaceutical companies: Servier, Bionomics, Novartis, Eli Lilly, and Lundbeck. All other authors declare no conflicts of interest., (Copyright © 2021 JBI.)

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.

Introduction: It is often quoted that 70% of clinical decisions are based on laboratory results, but the evidence to substantiate this claim is lacking. Since clinical guidelines aim to document best-practice decision making for specific disease conditions, inclusion of any laboratory test means that the best available evidence is recommending clinicians use it. Cardiovascular disease (CVD) is the world's most common cause of mortality, so this study reviewed all CVD guidelines published by five national/international authorities to determine what proportion of them recommended laboratory testing., Materials and Methods: Five leading CVD guidelines were examined, namely the European Society of Cardiology (ESC), the UK National Institute for Health and Clinical Excellence (NICE), the American College of Cardiology (ACC), the Australian Heart Foundation (AHF) and the Cardiac Society of Australia and New Zealand (CSANZ)., Results: A total of 101 guidelines were reviewed. Of the 33 individual ESC guidelines relating to CVD, 24/33 made a direct reference to the use of clinical laboratory tests in either diagnosis or follow-up treatment. The same applied to 15/20 of NICE guidelines, 24/32 from the ACC and 15/16 from the AHF/CSANZ. Renal function and blood count testing were the most recommended (39 and 26 times), with lipid, troponin and natriuretic peptide measurement advocated 25, 19 and 19 times respectively., Conclusions: This study has shown that laboratory testing is advocated by between 73% and 94% of individual CVD guideline recommendations from five national/international authorities. This provides an index to assess the potential value of laboratory medicine to healthcare., Competing Interests: Potential conflict of interest None declared., (Croatian Society of Medical Biochemistry and Laboratory Medicine.)

Objective: To synthesize current evidence on the effects and harms of non-pharmacological interventions for managing agitation during post-traumatic amnesia in adults who have sustained a traumatic brain injury., Introduction: Agitation is one of the most disruptive and clinically significant sequelae observed during post-traumatic amnesia. Patients who experience agitation during this period demonstrate reduced engagement in rehabilitation and poorer long-term functional outcomes. Agitation also poses a risk to staff and patient safety. Research for the effects of pharmacological intervention for managing agitation during this period is inconclusive. Thus, synthesis of the research for non-pharmacological interventions for reducing agitation during post-traumatic amnesia is essential for improving long-term outcomes for survivors of traumatic brain injury., Inclusion Criteria: Studies will be considered if they include participants aged 16 years and older who exhibit agitated behaviors during post-traumatic amnesia after sustaining a traumatic brain injury (irrespective of severity or mechanism). Studies will be considered if they evaluate any non-pharmacological intervention for reducing agitation, with all types of comparators accepted. Primary outcomes of interest include a change in agitation severity and any adverse effects., Methods: Key information sources include MEDLINE Ovid SP interface, PubMed, CINAHL, Excerpta Medica Database, PsycINFO, and Cochrane CENTRAL. Studies published in English will be included, irrespective of publication year. Two independent reviewers will be involved in study selection and data extraction. Eligible studies will be critically appraised for methodological quality. Studies will be pooled with statistical meta-analysis where possible; otherwise findings will be reported in narrative form., Systematic Review Registration Number: PROSPERO CRD42020186802., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 JBI.)

Challenging behaviours are a common and distressing consequence of acquired brain injury (ABI). There are no evidence-based guidelines for managing challenging behaviours after ABI, leaving clinicians with few resources to guide practice. Findings from case studies and single-subject experimental designs support the use of positive behaviour support (PBS) interventions for challenging behaviour post-ABI. This paper introduces PBS + PLUS: a multi-component and flexible PBS intervention using a person-driven collaborative approach to build a meaningful life and self-regulate behaviour after ABI. PBS + PLUS is currently being examined in a randomized controlled trial (RCT). Three detailed pilot case studies illustrate the highly individualized implementation of the programme, delivered to the individuals with ABI and carers over 12 months by a transdisciplinary team including neuropsychologists, occupational therapists, and psychiatrists. Objective behavioural outcomes are reported for participants using the Overt Behaviour Scale at baseline and four-monthly intervals for two years. Goal attainment scaling was used to measure personally meaningful goals. The qualitative appraisals of the intervention by participants, families and carers, and 12-month follow-up outcomes are described. The advantages and challenges of programme delivery are discussed. These case studies will assist clinicians and service providers to implement PBS + PLUS in anticipation of the results of the RCT.

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.

Although care of patients with heart failure (HF) has improved in the past decade, important disparities in HF outcomes persist based on race/ethnicity. Age-adjusted HF-related cardiovascular disease death rates are higher for Black patients, particularly among young Black men and women whose rates of death are 2.6- and 2.97-fold higher, respectively, than White men and women. Similarly, the rate of HF hospitalization for Black men and women is nearly 2.5-fold higher when compared with Whites, with costs that are significantly higher in the first year after HF hospitalization. While the relative rate of HF hospitalization has improved for other race/ethnic minorities, the disparity in HF hospitalization between Black and White patients has not decreased during the last decade. Although access to care and socioeconomic status have been traditional explanations for the observed racial disparities in HF outcomes, contemporary data suggest that novel factors including genetic susceptibility as well as social determinants of health and implicit bias may play a larger role in health outcomes than previously appreciated. The purpose of this review is to describe the complex interplay of factors that influence racial disparities in HF incidence, prevalence, and disease severity, with a highlight on evolving knowledge that will impact the clinical care and address future research needs to improve HF disparities in Blacks.

Background: Agitation is common in the early stages of recovery from traumatic brain injury (TBI), when patients are in post-traumatic amnesia (PTA). Agitation is associated with risk of harm to patients and caregivers. Recent guidelines recommend that agitation during PTA is managed using environmental modifications. Agitation is also frequently treated pharmacologically, with the use of atypical antipsychotics such as olanzapine among the most common. This is despite a lack of well-designed studies to support the use of antipsychotics within this context. This study will be a double-blind, placebo-controlled randomised controlled trial. We will examine the efficacy, safety, cost-effectiveness and outcomes associated with the use of olanzapine for reducing agitation in patients in PTA following TBI over and above recommended environmental management., Methods: Fifty-eight TBI rehabilitation inpatients who are in PTA and are agitated will receive olanzapine or placebo for the duration of PTA. All participants will additionally receive optimal environmental management for agitation. Measures of agitation, PTA and health will be undertaken at baseline. Treatment administration will begin at a dose of 5 mg daily and may be escalated to a maximum dose of 20 mg per day. Throughout the treatment period, agitation and PTA will be measured daily, and adverse events monitored weekly. Efficacy will be assessed by treatment group comparison of average Agitated Behaviour Scale scores during PTA. Participants will cease treatment upon emergence from PTA. Agitation levels will continue to be monitored for a further 2 weeks, post-treatment measures of health will be undertaken and cognitive and functional status will be assessed. Level of agitation and functional health will be assessed at hospital discharge. At 3 months post-discharge, functional outcomes and health service utilisation will be measured., Discussion: This trial will provide crucial evidence to inform the management of agitation in patients in PTA following TBI. It will provide guidance as to whether olanzapine reduces agitation over and above recommended environmental management or conversely whether it increases or prolongs agitation and PTA, increases length of inpatient hospitalisation and impacts longer term cognitive and functional outcomes. It will also speak to the safety and cost-effectiveness of olanzapine use in this population., Trial Registration: ANZCTR ACTRN12619000284167 . Registered on 25 February 2019.

Pseudobulbar affect is a debilitating condition that significantly reduces quality of life for many individuals following traumatic brain injury (TBI). It is characterized by embarrassing and often uncontrollable episodes of crying or laughter. The aim of this systematic review was to evaluate the effectiveness of pharmacotherapy as compared to all other comparators for the management of pseudobulbar affect in adults who have sustained TBI. Six databases were searched, with additional hand searching of journals, clinical trials registries and international drug regulators to identify published and unpublished studies in English up to June 2018. Studies were eligible for this review if they included adults who had sustained a medically confirmed TBI and presented with pseudobulbar affect. All pharmacotherapy and comparator interventions were considered for inclusion, and study design was not limited to randomised controlled trials. Evidence quality was assessed using Joanna Briggs Institute Critical Appraisal Instruments. Two quasi-experimental studies examining the effectiveness of dextrometamorphan/quinidine (DM/Q) were identified. These studies reported that DM/Q was effective in reducing symptoms of pseudobulbar affect and had a positive safety profile, over follow-up periods of 3 months (n = 87) and 12 months (n = 23). However, both studies were limited by lack of a control group and a high dropout rate. The findings of twelve case reports examining the effectiveness of DM/Q (n = 6) and anti-depressants (n = 6) are also discussed. Further research is required to determine which pharmacological interventions provide the best outcomes for individuals with pseudobulbar affect following TBI, with consideration given to side effect profiles and financial costs.