Effectiveness of Pharmacotherapy for Depression after Adult Traumatic Brain Injury: an Umbrella Review.

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searching of online journals, Research Gate, Google Scholar and the TRIP Medical Database to identify published and unpublished systematic reviews and meta-analyses in English up to May 2020.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).

Pharmacotherapy for the Pseudobulbar Affect in Individuals Who Have Sustained a Traumatic Brain Injury: a Systematic Review.

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.

Alcohol Use, Mental Health, and Functional Capacity as Predictors of Workplace Disability in a Cohort With Manifest Huntington's Disease.

OBJECTIVE: Huntington's disease (HD) is an inherited neurodegenerative disease involving motor, cognitive, psychiatric, and behavioral impairments that eventually affect work-role functioning. There is limited research regarding predictors of workplace disability in HD. The authors examined predictors of work impairment and disability in a cross-sectional cohort of employed persons with symptomatic HD participating in the worldwide Enroll-HD study. METHODS: The study sample (N=316) comprised individuals with manifest HD and a CAG repeat length range between 39 and 60 and were currently engaged in paid full- or part-time employment. Univariate and multivariate logistic regression analyses identified predictors and the effect of all predictors in a fully adjusted model. RESULTS: Of the sample, 20.3% reported missing work due to HD, 60.1% reported experiencing impairment while working due to HD, 79.1% reported having work-related activity impairment due to HD, and 60.8% reported impairment in overall work productivity due to HD. Individuals had 25% higher odds of missing work time if they had a higher level of functional impairment (odds ratio=0.76, 95% CI=0.64, 0.91) and had three times greater odds of missing work if they were current alcohol drinkers, compared with nondrinkers (odds ratio=2.86, 95% CI=1.62, 5.03). Individuals with lower self-perceived mental health were also 5% more likely to experience impairment at work due to HD. Motor impairment was not a strong predictor of workplace disability. CONCLUSIONS: These findings provide important new knowledge that can inform the development of strategies or targeted intervention trials to support persons with symptomatic HD to maintain their work roles.

Suicidal ligature strangulation: a systematic review of the published literature.

To summarize the published forensic pathology evidence base in deaths concluded to be the result of suicidal ligature strangulation, an uncommon entity. Four electronic bibliographic databases Medline Ovid, Embase, Scopus, HEINonline were screened for relevant literature. No date restrictions were applied. All English language case reports or case series were included. Articles were evaluated and key data extracted according to predefined criteria. A total of 1554 references eventually yielded 24 papers with 31 eligible case reports. The location of the deaths and background circumstances and history mirror broadly those of suicide generally. The range of ligature types was diverse. 19/31 cases reported one or more knots present. In the remaining 12 cases, the ligatures did not lend themselves to knots. In only one case were laryngeal fractures reported, but the available material does not justify confidence in that report given the significance of the finding. This systematic review has identified and synthesized the evidence from 31 case reports of suicidal ligature strangulation. A forensic pathologist faced with a possible case can locate it within the spectrum of reported cases and therefore identify its common and distinguishing features. Inherent difficulties for research in forensic pathology mean that case reports are an important source of learning and evidence for the discipline. Opportunities for improvement exist especially in harmonizing terminology and standardizing techniques generally, and in reports of suicidal ligature strangulation in particular.

Klüver-Bucy Syndrome Following Traumatic Brain Injury: A Systematic Synthesis and Review of Pharmacological Treatment From Cases in Adolescents and Adults.

Klüver-Bucy syndrome (KBS) is a rare clinical presentation following traumatic brain injury (TBI). Symptoms include visual agnosia, placidity, hyperorality, sexual hyperactivity, changes in dietary behavior, and hypermetamorphosis. The purpose of this article was to identify and synthesize the available evidence from case reports and case series on the treatment profile of KBS among adolescents and adults after TBI. Four bibliographic databases (MEDLINE OVID, EMBASE, PsycINFO, and SCOPUS) were searched for relevant literature. No date or language restrictions were applied. All case reports containing original data on KBS following TBI among adolescents and adults were included. Articles were evaluated, and data were extracted according to predefined criteria. The literature search identified 24 case reports of KBS post-TBI published between 1968 and 2017. Most case subjects were male (70.1%), and the mean age at injury was 25.1 years (range, 13-67 years). Injury to one or both temporal lobes occurred in most cases. Inappropriate sexual hyperactivity was the most common KBS symptom, followed by a change in dietary behavior and hyperorality. Visual agnosia was the least reported. In 50% of cases, the patient fully recovered from KBS. One-half of all participants described pharmacological management; the most common medication prescribed was carbamazepine. Overall, there was a lack of data available on pharmacotherapy initiation and duration. The complex presentation of KBS presents challenges in terms of treatment options. Although overall individuals who were prescribed carbamazepine had positive outcomes, given the reliance on case reports, it is difficult to make a definitive recommendation to guide clinical practice.

Predictors of Workplace Disability in a Premanifest Huntington's Disease Cohort.

Huntington's disease (HD) is an inherited neurodegenerative disease involving motor, cognitive, and psychiatric/behavioral impairments that will eventually affect work role functioning. Few objective data exist regarding predictors of workplace disability in HD. The authors explored the predictors of work impairment and disability in a cross-sectional cohort of 656 employed, premanifest HD (preHD) individuals. In this cohort-the majority of whom were female, urban-dwelling, married/partnered, and working full-time, with minimal cognitive impairment, good function, minimal motor abnormality, and no indication of significant mental health issues-the number of participants who reported that they had missed work due to HD was low (2.4%). However, 12% of the study sample reported experiencing impairment while working due to preHD, 12.2% reported work-related activity impairment due to preHD, and 12.7% reported impairment in their overall work ability. Higher numbers of CAG repeats on the mutant allele and having more motor symptoms were associated with significantly higher odds of experiencing workplace impairment. Importantly, several modifiable factors were also found to predict workplace disability. Specifically, higher levels of anxiety symptoms were associated with significantly higher odds of experiencing workplace impairment. Good mental and physical health served as protective factors, where good physical health was associated with 6% lower odds of experiencing impairment or missing work time and good mental health was associated with of 10%-12% lower. The results provide important new knowledge for the development of future targeted intervention trials to support preHD individuals in maintaining their work roles as long as possible.

Benzodiazepines for psychosis-induced aggression or agitation.

BACKGROUND: Acute psychotic illness, especially when associated with agitated or violent behaviour, can require urgent pharmacological tranquillisation or sedation. In several countries, clinicians often use benzodiazepines (either alone or in combination with antipsychotics) for this outcome. OBJECTIVES: To examine whether benzodiazepines, alone or in combination with other pharmacological agents, is an effective treatment for psychosis-induced aggression or agitation when compared with placebo, other pharmacological agents (alone or in combination) or non-pharmacological approaches. SEARCH METHODS: We searched the Cochrane Schizophrenia Group's register (January 2012, 20 August 2015 and 3 August 2016), inspected reference lists of included and excluded studies, and contacted authors of relevant studies. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) comparing benzodiazepines alone or in combination with any antipsychotics, versus antipsychotics alone or in combination with any other antipsychotics, benzodiazepines or antihistamines, for people who were aggressive or agitated due to psychosis. DATA COLLECTION AND ANALYSIS: We reliably selected studies, quality assessed them and extracted data. For binary outcomes, we calculated standard estimates of risk ratio (RR) and their 95% confidence intervals (CI) using a fixed-effect model. For continuous outcomes, we calculated the mean difference (MD) between groups. If there was heterogeneity, this was explored using a random-effects model. We assessed risk of bias and created a 'Summary of findings' table using GRADE. MAIN RESULTS: Twenty trials including 695 participants are now included in the review. The trials compared benzodiazepines or benzodiazepines plus an antipsychotic with placebo, antipsychotics, antihistamines, or a combination of these. The quality of evidence for the main outcomes was low or very low due to very small sample size of included studies and serious risk of bias (randomisation, allocation concealment and blinding were not well conducted in the included trials, 30% of trials (six out of 20) were supported by pharmaceutical institutes). There was no clear effect for most outcomes.Benzodiazepines versus placeboOne trial compared benzodiazepines with placebo. There was no difference in the number of participants sedated at 24 hours (very low quality evidence). However, for the outcome of global state, clearly more people receiving placebo showed no improvement in the medium term (one to 48 hours) (n = 102, 1 RCT, RR 0.62, 95% CI 0.40 to 0.97, very low quality evidence). Benzodiazepines versus antipsychoticsWhen compared with haloperidol, there was no observed effect for benzodiazepines for sedation by 16 hours (n = 434, 8 RCTs, RR 1.13, 95% CI 0.83 to 1.54, low quality evidence). There was no difference in the number of participants who had not improved in the medium term (n = 188, 5 RCTs, RR 0.89, 95% CI 0.71 to 1.11, low quality evidence). However, one small study found fewer participants improved when receiving benzodiazepines compared with olanzapine (n = 150, 1 RCT, RR 1.84, 95% CI 1.06 to 3.18, very low quality evidence). People receiving benzodiazepines were less likely to experience extrapyramidal effects in the medium term compared to people receiving haloperidol (n = 233, 6 RCTs, RR 0.13, 95% CI 0.04 to 0.41, low quality evidence).Benzodiazepines versus combined antipsychotics/antihistaminesWhen benzodiazepine was compared with combined antipsychotics/antihistamines (haloperidol plus promethazine), there was a higher risk of no improvement in people receiving benzodiazepines in the medium term (n = 200, 1 RCT, RR 2.17, 95% CI 1.16 to 4.05, low quality evidence). However, for sedation, the results were controversial between two groups: lorazepam may lead to lower risk of sedation than combined antipsychotics/antihistamines (n = 200, 1 RCT, RR 0.91, 95% CI 0.84 to 0.98, low quality evidence); while, midazolam may lead to higher risk of sedation than combined antipsychotics/antihistamines (n = 200, 1 RCT, RR 1.13, 95% CI 1.04 to 1.23, low quality evidence).Other combinationsData comparing benzodiazepines plus antipsychotics versus benzodiazepines alone did not yield any results with clear differences; all were very low quality evidence. When comparing combined benzodiazepines/antipsychotics (all studies compared haloperidol) with the same antipsychotics alone (haloperidol), there was no difference between groups in improvement in the medium term (n = 185, 4 RCTs, RR 1.17, 95% CI 0.93 to 1.46, low quality evidence), but sedation was more likely in people who received the combination therapy (n = 172, 3 RCTs, RR 1.75, 95% CI 1.14 to 2.67,very low quality evidence). Only one study compared combined benzodiazepine/antipsychotics with antipsychotics; however, this study did not report our primary outcomes. One small study compared combined benzodiazepines/antipsychotics with combined antihistamines/antipsychotics. Results showed a higher risk of no clinical improvement (n = 60, 1 RCT, RR 25.00, 95% CI 1.55 to 403.99, very low quality evidence) and sedation status (n = 60, 1 RCT, RR 12.00, 95% CI 1.66 to 86.59, very low quality evidence) in the combined benzodiazepines/antipsychotics group. AUTHORS' CONCLUSIONS: The evidence from RCTs for the use of benzodiazepines alone is not good. There were relatively few good data. Most trials were too small to highlight differences in either positive or negative effects. Adding a benzodiazepine to other drugs does not seem to confer clear advantage and has potential for adding unnecessary adverse effects. Sole use of older antipsychotics unaccompanied by anticholinergic drugs seems difficult to justify. Much more high-quality research is still needed in this area.

Contextual Determinants of Childhood Injury: A Systematic Review of Studies With Multilevel Analytic Methods.

BACKGROUND: The definition of injury that underpins the contemporary approach to injury prevention is an etiological definition relating to bodily damage arising from transfer of energy to tissues of the body beyond the limits compatible with physiological function. Causal factors proximal to the energy transfer are nested within a more complex set of contextual determinants. For effective injury control, understanding of these determinants is critical. OBJECTIVES: The primary aims of this study were to describe the area-level determinants that have been included in multilevel analyses of childhood injury and to quantify the relationships between these area-level exposures and injury outcomes. SEARCH METHODS: We conducted a systematic review of peer-reviewed, English-language literature published in scientific journals between January 1997 and July 2014, reporting studies that employed multilevel analyses to quantify the eco-epidemiological causation of physical unintentional injuries to children aged 16 years and younger. We conducted and reported the review in accordance with the PRISMA guidelines. SELECTION CRITERIA: We included etiological studies of causal risk factors for unintentional traumatic injuries to children aged 0 to 16 years. Methodological inclusion criteria were as follows: Epidemiological studies quantifying the relationship between risk factors (at various levels) and injury occurrence in the individual; Studies that recognized individual exposure and at least 1 higher level of exposure with units at lower levels or microunits (e.g., individuals) nested within units at higher levels or macrounits (e.g., areas or neighborhoods); Injury outcomes (dependent variable) examined at the individual level; and Central analytic techniques belonging to the following categories: multilevel models, hierarchical models, random effects models, random coefficient models, covariance components models, variance components models, and mixed models. We combined criteria from the checklist described by the Cochrane Effective Practice and Organization of Care Review Group with factors in the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) statement, and we used several quality assessment items from other injury-related systematic reviews to create a quality assessment checklist for this review. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data and selected analysis features for the included studies by using preformatted tables. They extracted information as reported in the articles. We determined statistical significance of estimates and effects by using the conventional threshold, P < .05. Any differences in the information extracted were resolved by discussion between authors and by specifically rereading and rechecking the facts as reported in the relevant articles. We tabulated results from the final multilevel model(s) in each of the included articles with key aspects summarized in text. Interpretations of the results and identification of key issues raised by the collated material are reported in the Discussion section of this article. MAIN RESULTS: We identified 11,967 articles from the electronic search with only 14 being included in the review after a detailed screening and selection process. Nine of the 14 studies identified significant fixed effects at both the area and individual levels. The area-level variables most consistently associated with child injury rates related to poverty, education, employment, and access to services. There was some evidence that injury rates were lower in areas scoring well on area-level summary measures of neighborhood safety. There was marked variation in the methods used and in the mapping of measured variables onto the conceptual model of ecological causation. AUTHOR CONCLUSIONS: These results help establish the scope for the public policy approach to injury prevention. More consistent reporting of multilevel study results would aid future interpretation and translation of such findings.

How well do we report on compensation systems in studies of return to work: a systematic review.

PURPOSE: Occupational injury and work-related disability is a significant public health problem. For published research to provide a collective knowledge base for return to work (RTW) policy and practice, features of the compensation system relevant to the research must be described clearly. The level of the reporting on compensation system features is yet to be established. The aim of the present study was to synthesize the evidence for the reporting on compensation systems in prognostic studies of RTW following work-related injuries. METHODS: A systematic review of the literature was conducted. Ovid Medline and EMBASE were searched for studies published 1996-2011. Included studies were prognostic studies of RTW or work disability following work-related acute traumatic injuries. RESULTS: The initial search yielded 952 articles; 37 articles fulfilled the inclusion criteria. The majority of studies were based on clinical practice; eight studies were based on administrative data. Only two studies reported seven or more compensation features and two studies reported four to six. The majority of studies (19/37) did not report on any aspect of the compensation system that study participants were interacting with. The most common information reported was the extent of coverage at the population level (7/37) and the availability of wage replacement entitlements (7/37). The name of the compensation system was provided in 5 studies. CONCLUSIONS: Overall reporting on compensation systems in prognostic studies of RTW needs to be improved if research evidence is to inform policy and practice. Compensation system features that could be reported are provided.

Exploring the distribution and determinants of a change in recovery expectations following traumatic injury to Victorian workers.

PURPOSE: To examine the frequency, distribution and determinants of a change in recovery expectations following non-life threatening acute orthopaedic trauma to Victorian workers. It is proposed that interventions to modify recovery expectations may reduce the burden associated with injury. However, it is not known whether recovery expectations change over time or the factors that are associated with change. METHODS: A prospective inception cohort study was carried out in which participants were recruited following presentation to hospital for treatment of their injury and followed for 6 months post-injury. Baseline data was obtained by survey and medical record review. Binary logistic regression was used to examine factors associated with a change in recovery expectations between week 2 and week 12 post-injury. RESULTS: The cohort comprised injured workers (n = 145) who had sustained nonlife threatening acute orthopaedic trauma. Factors associated with an improvement in recovery expectations or recovery timeframe included more years of education and higher social functioning. Participants whose injury involved a perception of responsibility by a third party were 7.18 (95 % CI 1.86-27.68) times more likely to change their recovery expectations to more negative expectations and less likely to change to an earlier recovery timeframe. Participants with more severe injuries were more likely to change their recovery timeframe to a longer timeframe. CONCLUSION: Change in recovery expectations provide some information on injured workers who may benefit from targeted interventions to improve or maintain recovery expectations. The post-injury time-point at which recovery expectations are measured is important if recovery expectations are to inform long-term outcomes.

Epigenetic changes in response to tai chi practice: a pilot investigation of DNA methylation marks.

Tai chi exercise has been shown to improve physiological and psychosocial functions, well-being, quality of life, and disease conditions. The biological mechanisms by which tai chi exerts its holistic effects remain unknown. We investigated whether tai chi practice results in positive epigenetic changes at the molecular level. Design. The DNA methylation profiles of sixty CpG-dinucleotide marks in female tai chi practitioners (N = 237; 45-88 years old) who have been practising tai chi for three or more years were compared with those of age-matched control females (N = 263) who have never practised tai chi. Results. Six CpG marks originating from three different chromosomes reveal a significant difference (P < 0.05) between the two cohorts. Four marks show losses while two marks show gains in DNA methylation with age in the controls. In the tai chi cohort all six marks demonstrate significant slowing (by 5-70%) of the age-related methylation losses or gains observed in the controls, suggesting that tai chi practice may be associated with measurable beneficial epigenetic changes. Conclusions. The results implicate the potential use of DNA methylation as an epigenetic biomarker to better understand the biological mechanisms and the health and therapeutic efficacies of tai chi.

A systematic review of early prognostic factors for persisting pain following acute orthopedic trauma.

BACKGROUND: Acute orthopedic trauma contributes substantially to the global burden of disease. OBJECTIVES: The present systematic review aimed to summarize the current knowledge concerning prognostic factors for the presence of persistent pain, pain severity and pain-related disability following acute orthopedic trauma involving a spectrum of pathologies to working-age adults. METHODS: The Ovid MEDLINE and EMBASE databases were searched for level II prognostic studies published between January 1996 and October 2010. Studies that were longitudinal and reported results with multivariate analyses appropriate for prognostic studies were included. Studies that addressed two specific injury types that have been the subject of previous reviews, namely, injuries to the spinal column and amputations, were excluded. RESULTS: The searches yielded 992 studies; 10 studies met the inclusion criteria and were rated for methodological quality. Seventeen factors were considered in more than one cohort. There was strong evidence supporting the association of female sex, older age, high pain intensity, preinjury anxiety or depression, and fewer years of education with persistent pain outcomes. There was moderate evidence supporting the association between postinjury depression or anxiety with persistent pain, and that injury severity was not a risk factor for ongoing pain. CONCLUSION: Many individuals experience persistent pain following acute trauma. Due to the lack of studies, the use of different constructs to measure the same factor and the methodological limitations associated with many of the studies, the present review was only able to reliably identify a limited set of factors that predicted persistent pain. Recommendations for the conduct of future methodologically rigorous studies of persistent pain are provided.

Predictors of sustained return to work after work-related injury or disease: insights from workers' compensation claims records.

AIM: After work-related injury or disease, multiple spells of work absences and unsuccessful return to work (RTW) are common. The purpose of this study was to identify predictors of sustained RTW and work disability recurrences. METHODS: Australian WorkSafe Victoria claims containing income compensation payments starting between January 1st, 2001 and December 31st, 2004 (n = 59,526) were analysed over a 2-year observation window. Time until first RTW and final RTW, and 'recurrences' (cessations of payments of >7 days), were derived from claims payments data. Regression models were used relating demographic, occupational, workplace and injury characteristics to RTW outcomes. RESULTS: Although 94% of claimants had at least one RTW, only 79% achieved sustained RTW during follow-up. Median time until first RTW was 50 days; median time until final RTW was 91 days. Independent predictors of delayed final RTW were older age, afflictions involving the neck or multiple locations, and working in manufacturing. Of those who returned to work, 37% had at least one recurrence: risk factors were ages 35-55, female sex, working as a labourer, working in manufacturing, traumatic joint/ligament or muscle/tendon injury and musculoskeletal and connective tissue diseases, and afflictions involving the neck or multiple locations. CONCLUSIONS: Work disability recurrences are common and have considerable impact on sustained RTW outcomes. A policy focus on education about secondary prevention may help improve long-term RTW outcomes, particularly for persons with musculoskeletal disorders and those working in manufacturing.

The association of social functioning, social relationships and the receipt of compensation with time to return to work following unintentional injuries to Victorian workers.

PURPOSE: Understanding individual factors associated with return to work (RTW) post-injury is an important goal of compensation systems research. The aim of the present study was to determine factors associated with time to return to work following acute unintentional injuries. METHODS: A prospective cohort study was conducted in Victoria, Australia. The cohort comprised 133 persons who were employed at the time they were admitted to one of three study hospitals. Baseline health status data was obtained retrospectively at one-week post-injury and participants were further surveyed at 1, 6, 12, 26 and 52 weeks post-injury to measure recovery. Multivariate Cox proportional hazards regression analysis was used to examine the association between potential prognostic factors and time to RTW during the 12 month study. RESULTS: At the end of 12 months follow-up, 81.2% of the study cohort had returned to work. Older age, increased injury severity, self reported symptomatic pain and poor mental health at 1 week post-injury were associated with extended time to RTW. A significant statistical interaction between the receipt of compensation and high social functioning as measured by the SF-36 or strong social relationships as measured by the Assessment of Quality of Life was associated with earlier RTW. Participants reporting strong social relationships and high social functioning at 1 week post-injury and entitled to injury compensation returned to work 2.05 and 3.66 times earlier respectively, than similar participants with no entitlement to compensation. CONCLUSIONS: Both injury-related and psychosocial factors were associated with the duration of time to RTW following acute unintentional injuries. This study replicated previously reported findings on social functioning and compensation from an independent acute trauma sample. Programs or policies to improve social functioning early post-injury may provide opportunities to improve the duration of time to RTW following injury.

Reciprocal regulation of gastrointestinal homeostasis by SHP2 and STAT-mediated trefoil gene activation in gp130 mutant mice.

The intracellular signaling mechanisms that specify tissue-specific responses to the interleukin-6 (IL-6) family of cytokines are not well understood. Here, we evaluated the functions of the two major signaling pathways, the signal transducers and activators of transcription 1 and 3 (STAT1/3) and the Src-homology tyrosine phosphatase 2 (SHP2)-Ras-ERK, emanating from the common signal transducer, gp130, in the gastrointestinal tract. Gp130(757F) mice, with a 'knock-in' mutation abrogating SHP2-Ras-ERK signaling, developed gastric adenomas by three months of age. In contrast, mice harboring the reciprocal mutation ablating STAT1/3 signaling (gp130(Delta STAT)), or deficient in IL-6-mediated gp130 signaling (IL-6(-/-) mice), showed impaired colonic mucosal wound healing. These gastrointestinal phenotypes are highly similar to the phenotypes exhibited by mice deficient in trefoil factor 1 (pS2/TFF1) and intestinal trefoil factor (ITF)/TFF3, respectively, and corresponded closely with the capacity of the two pathways to stimulate transcription of the genes encoding pS2/TFF1 and ITF/TFF3. We propose a model whereby mucosal wound healing depends solely on activation of STAT1/3, whereas gastric hyperplasia ensues when the coordinated activation of the STAT1/3 and SHP2-Ras-ERK pathways is disrupted.

Effectiveness of pharmacotherapy for depression after traumatic brain injury in adults: an umbrella review protocol.

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.

Efficacy and Harms of Pharmacological Interventions for Anxiety after Traumatic Brain Injury: Systematic Review.

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.

Constitutive activation of the SRC family kinase Hck results in spontaneous pulmonary inflammation and an enhanced innate immune response.

To identify the physiological role of Hck, a functionally redundant member of the Src family of tyrosine kinases expressed in myelomonocytic cells, we generated Hck(F/F) "knock-in" mice which carry a targeted tyrosine (Y) to phenylalanine (F) substitution of the COOH-terminal, negative regulatory Y(499)-residue in the Hck protein. Unlike their Hck(-/-) "loss-of-function" counterparts, Hck(F/F) "gain-of-function" mice spontaneously acquired a lung pathology characterized by extensive eosinophilic and mononuclear cell infiltration within the lung parenchyma, alveolar airspaces, and around blood vessels, as well as marked epithelial mucus metaplasia in conducting airways. Lungs from Hck(F/F) mice showed areas of mild emphysema and pulmonary fibrosis, which together with inflammation resulted in altered lung function and respiratory distress in aging mice. When challenged transnasally with lipopolysaccharide (LPS), Hck(F/F) mice displayed an exaggerated pulmonary innate immune response, characterized by excessive release of matrix metalloproteinases and tumor necrosis factor (TNF)alpha. Similarly, Hck(F/F) mice were highly sensitive to endotoxemia after systemic administration of LPS, and macrophages and neutrophils derived from Hck(F/F) mice exhibited enhanced effector functions in vitro (e.g., nitric oxide and TNFalpha production, chemotaxis, and degranulation). Based on the demonstrated functional association of Hck with leukocyte integrins, we propose that constitutive activation of Hck may mimic adhesion-dependent priming of leukocytes. Thus, our observations collectively suggest an enhanced innate immune response in Hck(F/F) mice thereby skewing innate immunity from a reversible physiological host defense response to one causing irreversible tissue damage.

First return to work following injury: does it reflect a composite or a homogeneous outcome?

OBJECTIVE: To test whether return to work as a binary (yes/no) outcome that includes all persons who returned to work regardless of mode of return reflects a composite or a homogeneous outcome in a cohort of workers who have sustained acute orthopaedic trauma resulting in hospitalisation. METHODS: Prospective cohort study. One hundred and sixty-eight participants were recruited and followed for 6 months. The study achieved 89% follow-up. Baseline data were obtained at study recruitment and participants were further surveyed by phone at three timepoints during the study. Polytomous logistic regression was used to simultaneously examine the association between potential predictors and different modes of first return to work (RTW). A test of the equality of the ORs associated with the independent predictor variables was also undertaken. RESULTS: Of the 152 participants with full follow-up, 46 (30%) returned first to full duties, 58 (38%) returned first to modified work and 48 (32%) did not return to work during the study period. Significant determinants of the two modes of return to work were different. A test of the equality of ORs indicated that the relative ORs for the difference in the slope coefficients for five of the 10 independent factors in the two polytomous logistic regression sub-models corresponding to each mode of return to work were statistically significant. This raises the likelihood that first RTW reflects a composite rather than a homogeneous outcome. CONCLUSION: The study provides evidence that RTW may reflect a composite outcome when it includes different modes of first RTW. The identified predictive factors appear to exert different mechanisms of action depending on the mode of RTW. The findings suggest that the different modes of RTW may need to be considered independently. The results of the study have potentially important implications for research and insurance practice.

Bio-psychosocial determinants of time lost from work following non life threatening acute orthopaedic trauma.

BACKGROUND: To determine factors predicting the duration of time away from work following acute orthopaedic non life threatening trauma METHODS: Prospective cohort study conducted at four hospitals in Victoria, Australia. The cohort comprised 168 patients aged 18-64 years who were working prior to the injury and sustained a range of acute unintentional orthopaedic injuries resulting in hospitalization. Baseline data was obtained by survey and medical record review. Multivariate Cox proportional hazards regression analysis was used to examine the association between potential predictors and the duration of time away from work during the six month study. The study achieved 89% follow-up. RESULTS: Of the 168 participants recruited to the study, 68% returned to work during the six month study. Multivariate Cox proportional hazards regression analysis identified that blue collar work, negative pain attitudes with respect to work, high initial pain intensity, injury severity, older age, initial need for surgery, the presence of co-morbid health conditions at study entry and an orthopaedic injury to more than one region were associated with extended duration away from work following the injury. Participants in receipt of compensation who reported high social functioning at two weeks were 2.58 times more likely to have returned to work than similar participants reporting low social functioning. When only those who had returned to work were considered, the participant reported reason for return to work " to fill the day" was a significant predictor of earlier RTW [RR 2.41 (95% C.I 1.35-4.30)] whereas "financial security" and "because they felt able to" did not achieve significance. CONCLUSIONS: Many injury-related and psycho social factors affect the duration of time away from work following orthopaedic injury. Some of these are potentially modifiable and may be amenable to intervention. Further consideration of the reasons provided by participants for returning to work may provide important opportunities for social marketing approaches designed to alleviate the financial and social burden associated with work disability.