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searching of online journals, Research Gate, Google Scholar and the TRIP Medical Database to identify published and unpublished systematic reviews and meta-analyses in English up to May 2020.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

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.

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.

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.

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.

The Efficacy and Harms of Pharmacological Interventions for Aggression After Traumatic Brain Injury-Systematic Review.

Background: Aggression is a commonly reported problem following traumatic brain injury (TBI). It may present as verbal insults or outbursts, physical assaults, and/or property destruction. Aggressive behavior can fracture relationships and impede participation in treatment as well as a broad range of vocational and social activities, thereby reducing the individual's quality of life. Pharmacological intervention is frequently used to control aggression following TBI. The aim of this systematic review was to critically evaluate the evidence regarding efficacy of pharmacological interventions for aggression following TBI in adults. Methods: We reviewed studies in English, available before December 2018. 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 the severity of aggression and occurrence of harms. The secondary outcomes of interest were changes in quality of life, participation, psychological health (e.g., depression, anxiety), and cognitive function. Evidence quality was assessed using the Cochrane Risk of Bias tool and the Joanna Briggs Institute Critical Appraisal Instruments. Results: Ten studies were identified, including five randomized controlled trials (RCTs) and five case series. There were positive, albeit mixed, findings for the RCTs examining the use of amantadine in reducing irritability (n = 2) and aggression (n = 2). There were some positive findings favoring methylphenidate in reducing anger (n = 1). The evidence for propranolol was weak (n = 1). Individual analysis revealed differential drug response across individuals for both methylphenidate and propranolol. The less rigorous studies administered carbamazepine (n = 2), valproic acid (n = 1), quetiapine (n = 1), and sertraline (n = 1), and all reported reductions in aggression. However, given the lack of a control group, it is difficult to discern treatment effects from natural change over time. Conclusions: This review concludes that a recommendation for use of amantadine to treat aggression and irritability in adults following TBI is appropriate. However, there is a need for further well-designed, adequately powered and controlled studies of pharmacological interventions for aggression following TBI.

Prophylaxis Pharmacotherapy to Prevent the Onset of Post-Traumatic Brain Injury Depression: A Systematic Review.

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

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.

Pharmacotherapy for the pseudobulbar affect in individuals who have sustained a traumatic brain injury: a systematic review protocol.

REVIEW OBJECTIVE/QUESTION: The objective of this systematic review is to synthesize current evidence on the effectiveness of pharmacotherapy as compared to all comparators for the management of pseudobulbar affect in adults 16 years and over who have sustained a traumatic brain injury. The specific review question is: What is the effectiveness of pharmacotherapy for the management of pseudobulbar affect in adults 16 years and over who have sustained a traumatic brain injury?

Efficacy and Harms of Pharmacological Interventions for Neurobehavioral Symptoms in Post-Traumatic Amnesia after Traumatic Brain Injury: A Systematic Review.

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

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.

Efficacy and harms of pharmacological interventions for neurobehavioral symptoms in post traumatic amnesia after traumatic brain injury: a systematic review and meta-analysis protocol.

REVIEW OBJECTIVE/QUESTION: The objective of this systematic review is to synthesize the best available evidence on the effectiveness and harms of pharmacotherapy as compared to all types of comparators for the management of neurobehavioral symptoms in post-traumatic amnesia in adults aged 16 years and over who have sustained a traumatic brain injury. This review forms part of a larger project which aims to gather the evidence for the pharmacological treatment of neurobehavioral symptoms post traumatic brain injury as a prelude to the development of a clinical guideline.

Safety and effectiveness of pharmacotherapy for depression in adults who have sustained a traumatic brain injury: a systematic review protocol.

REVIEW OBJECTIVE/QUESTION: The objective of this systematic review is to synthesize the current evidence on the effectiveness and harms of pharmacotherapy in the management of depression in adults who have sustained a traumatic brain injury.

Ramucirumab for Treating Advanced Gastric Cancer or Gastro-Oesophageal Junction Adenocarcinoma Previously Treated with Chemotherapy: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

The National Institute for Health and Care Excellence (NICE) invited the company that manufactures ramucirumab (Cyramza®, Eli Lilly and Company) to submit evidence of the clinical and cost effectiveness of the drug administered alone (monotherapy) or with paclitaxel (combination therapy) for treating adults with advanced gastric cancer or gastro-oesophageal junction (GC/GOJ) adenocarcinoma that were previously treated with chemotherapy, as part of the Institute's single technology appraisal (STA) process. Kleijnen Systematic Reviews Ltd (KSR), in collaboration with Erasmus University Rotterdam, was commissioned to act as the Evidence Review Group (ERG). This paper describes the company's submission, the ERG review, and NICE's subsequent decisions. Clinical effectiveness evidence for ramucirumab monotherapy (RAM), compared with best supportive care (BSC), was based on data from the REGARD trial. Clinical effectiveness evidence for ramucirumab combination therapy (RAM + PAC), compared with paclitaxel monotherapy (PAC), was based on data from the RAINBOW trial. In addition, the company undertook a network meta-analysis (NMA) to compare RAM + PAC with BSC and docetaxel. Cost-effectiveness evidence of monotherapy and combination therapy relied on partitioned survival, cost-utility models. The base-case incremental cost-effectiveness ratio (ICER) of the company was £188,640 (vs BSC) per quality-adjusted life-year (QALY) gained for monotherapy and £118,209 (vs BSC) per QALY gained for combination therapy. The ERG assessment indicated that the modelling structure represented the course of the disease; however, a few errors were identified and some of the input parameters were challenged. The ERG provided a new base case, with ICERs (vs BSC) of £188,100 (monotherapy) per QALY gained and £129,400 (combination therapy) per QALY gained and conducted additional exploratory analyses. The NICE Appraisal Committee (AC), considered the company's decision problem was in line with the NICE scope, with the exception of the choice of comparators for the combination therapy model. The most plausible ICER for ramucirumab monotherapy compared with BSC was £188,100 per QALY gained. The Committee considered that the ERG's exploratory analysis in which RAM + PAC was compared with PAC by using the direct head-to-head data (including utilities) from the RAINBOW trial, provided the most plausible ICER (i.e. £408,200 per QALY gained) for ramucirumab combination therapy. The Committee concluded that end-of-life considerations cannot be applied for either case, since neither failed to offer an extension to life of at least 3 months. The company did not submit a patient access scheme (PAS). After consideration of the evidence, the Committee concluded that ramucirumab alone or with paclitaxel could not be considered a cost-effective use of National Health Service resources for treating advanced GC/GOJ patients that were previously treated with chemotherapy, and therefore its use could not be recommended. We might wonder if a complete STA process is necessary for treatments without a PAS, which are, according to the company's submission, already associated with ICERs far above the currently accepted threshold in all (base-case, sensitivity and scenario) analyses.

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.

Information interventions for recovery following vehicle-related trauma to persons of working age: a systematic review of the literature.

OBJECTIVES: Given the burden associated with vehicle-related trauma, there is interest in time and cost effective methods of providing information to assist recovery. This systematic review aims to address the question: "Do targeted early information interventions improve outcomes following vehicle--related injuries for persons of working age?" DATA SOURCES: Ovid Medline, EMBASE, PsychINFO and Cochrane databases were searched for studies published between 1990-April 2011. DATA SELECTION: Included studies were randomized or pseudo--randomized controlled trials of information interventions delivered to working age persons following vehicle-related injuries. Two reviewers independently selected and appraised the studies. DATA SYNTHESIS: Sixteen publications (13 primary studies) met the inclusion criteria and were assessed for bias. Hetero-geneity in terms of the information interventions and measured outcomes was encountered. In 4 of the included studies, the intervention was positively associated with at least one outcome reported. Methodological issues limited the conclusions that could be drawn. CONCLUSION: Following vehicle-related trauma, people often experience difficulties in ongoing functioning. The current evidence neither supports nor fails to support the effectiveness of information interventions in promoting injury recovery. There is a need for larger more methodologically and conceptually rigorous randomized controlled trials that better consider the type and timing of the intervention.

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.