Angiopoietin-2 blockade suppresses growth of liver metastases from pancreatic neuroendocrine tumors by promoting T cell recruitment.

Improving the management of metastasis in pancreatic neuroendocrine tumors (PanNETs) is critical, as nearly half of patients with PanNETs present with liver metastases, and this accounts for the majority of patient mortality. We identified angiopoietin-2 (ANGPT2) as one of the most upregulated angiogenic factors in RNA-Seq data from human PanNET liver metastases and found that higher ANGPT2 expression correlated with poor survival rates. Immunohistochemical staining revealed that ANGPT2 was localized to the endothelial cells of blood vessels in PanNET liver metastases. We observed an association between the upregulation of endothelial ANGPT2 and liver metastatic progression in both patients and transgenic mouse models of PanNETs. In human and mouse PanNET liver metastases, ANGPT2 upregulation coincided with poor T cell infiltration, indicative of an immunosuppressive tumor microenvironment. Notably, both pharmacologic inhibition and genetic deletion of ANGPT2 in PanNET mouse models slowed the growth of PanNET liver metastases. Furthermore, pharmacologic inhibition of ANGPT2 promoted T cell infiltration and activation in liver metastases, improving the survival of mice with metastatic PanNETs. These changes were accompanied by reduced plasma leakage and improved vascular integrity in metastases. Together, these findings suggest that ANGPT2 blockade may be an effective strategy for promoting T cell infiltration and immunostimulatory reprogramming to reduce the growth of liver metastases in PanNETs.

"I've still got a job to go back to": the importance of early vocational rehabilitation after stroke.

PURPOSE: Returning to work is an important goal after stroke, not only as a recovery indicator but also for facilitating independent living and improved social identity. The aim of this study was to explore the lived experiences of vocational rehabilitation and the return to work pathway after stroke. METHOD: Qualitative data were collected through semi-structured interviews with purposively selected participants who had participated in a vocational rehabilitation trial. All participants were employed at the time of their stroke and were community-living. Interviews were undertaken by occupational therapists and were transcribed verbatim before data were thematically analysed using a framework approach. RESULTS: Sixteen participants were interviewed, seven received specialist vocational rehabilitation and nine received usual clinical rehabilitation. Three major themes were identified which highlighted the importance of tailored vocational rehabilitation to address the challenges that arise when returning to the workplace. Stroke survivors perceived the most beneficial components of the specialist vocational rehabilitation intervention to be employer liaison support, fatigue management, and support for cognition and executive processing skills. CONCLUSIONS: Vocational rehabilitation was perceived to provide an opportunity to influence working after stroke, although areas of unmet need were highlighted. Findings provide direction for the development of future stroke-specific vocational rehabilitation programs.

Psychosocial (emotional) and cognitive (memory and planning) changes along with post-stroke fatigue were perceived to be the greatest barriers faced on returning to work and should be key areas for intervention within a vocational rehabilitation program.Vocational rehabilitation interventions should be tailored to each participant, incorporating elements perceived to be important to stroke survivors, including workplace liaison, employer communication and psychological support.Workplaces may benefit from access to information about the range of physical, cognitive and language deficits associated with stroke, and the potential impact these may have on work skills.

Task-specific training versus usual care to improve upper limb function after stroke: the "Task-AT Home" randomised controlled trial protocol.

Background: Sixty percent of people have non-functional arms 6 months after stroke. More effective treatments are needed. Cochrane Reviews show low-quality evidence that task-specific training improves upper limb function. Our feasibility trial showed 56 h of task-specific training over 6 weeks resulted in an increase of a median 6 points on the Action Research Arm test (ARAT), demonstrating the need for more definitive evidence from a larger randomised controlled trial. Task-AT Home is a two-arm, assessor-blinded, multicentre randomised, controlled study, conducted in the home setting. Aim: The objective is to determine whether task-specific training is a more effective treatment than usual care, for improving upper limb function, amount of upper limb use, and health related quality of life at 6 weeks and 6 months after intervention commencement. Our primary hypothesis is that upper limb function will achieve a ≥ 5 point improvement on the ARAT in the task-specific training group compared to the usual care group, after 6 weeks of intervention. Methods: Participants living at home, with remaining upper limb deficit, are recruited at 3 months after stroke from sites in NSW and Victoria, Australia. Following baseline assessment, participants are randomised to 6 weeks of either task-specific or usual care intervention, stratified for upper limb function based on the ARAT score. The task-specific group receive 14 h of therapist-led task-specific training plus 42 h of guided self-practice. The primary outcome measure is the ARAT at 6 weeks. Secondary measures include the Motor Activity Log (MAL) at 6 weeks and the ARAT, MAL and EQ5D-5 L at 6 months. Assessments occur at baseline, after 6 weeks of intervention, and at 6 months after intervention commencement. Analysis will be intention to treat using a generalised linear mixed model to report estimated mean differences in scores between the two groups at each timepoint with 95% confidence interval and value of p. Discussion: If the task-specific home-based training programme is more effective than usual care in improving arm function, implementation of the programme into clinical practice would potentially lead to improvements in upper limb function and quality of life for people with stroke. Clinical Trial Registration: ANZCTR.org.au/ACTRN12617001631392p.aspx.

A Tailored Occupational Therapist-Led Vocational Intervention for People With Stroke: Protocol for a Pilot Randomized Controlled Trial.

BACKGROUND: Resuming work after stroke is a common goal of working-age adults, yet there are few vocational rehabilitation programs designed to address the unique challenges faced following stroke. The Work intervention was developed to address these gaps. OBJECTIVE: This paper presents a protocol that outlines the steps that will be undertaken to pilot both the intervention and trial processes for the Work trial. METHODS: The Work trial is a 2-arm, prospective, randomized, blinded-assessor study with intention-to-treat analysis. A total of 54 adults of working age who have experienced a stroke <4 months prior will be randomized 1:1 to either (1) an experimental group who will receive a 12-week early vocational intervention (Work intervention) plus usual clinical rehabilitation or (2) a control group who will receive only their usual clinical rehabilitation. RESULTS: Outcomes include study and intervention feasibility and intervention benefit. In addition to evaluating the feasibility of delivering vocational intervention early after stroke, benefit will be assessed by measuring rates of vocational participation and quality-of-life improvements at the 3- and 6-month follow-ups. Process evaluation using data collected during the study, as well as postintervention individual interviews with participants and surveys with trial therapists, will complement quantitative data. CONCLUSIONS: The results of the trial will provide details on the feasibility of delivering the Work intervention embedded within the clinical rehabilitation context and inform future trial processes. Pilot data will enable a future definitive trial to determine the clinical effectiveness of vocational rehabilitation when delivered in the early subacute phase of stroke recovery. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12619001164189; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=378112&isReview=true. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/40548.

Effect of occupational therapy home visit discharge planning on participation after stroke: protocol for the HOME Rehab trial.

INTRODUCTION: After first stroke, the transition from rehabilitation to home can be confronting and fraught with challenges. Although stroke clinical practice guidelines recommend predischarge occupational therapy home visits to ensure safe discharge and provision of appropriate equipment, there is currently limited evidence to support this recommendation. METHODS AND ANALYSIS: The HOME Rehab trial is a national, multicentre, phase III randomised controlled trial with concealed allocation, blinded assessment and intention-to-treat analysis being conducted in Australia. The trial aim is to determine the effect and potential cost-effectiveness of an enhanced occupational therapy discharge planning intervention that involves pre and postdischarge home visits, goal setting and occupational therapy in the home (the HOME programme) in comparison to an in-hospital predischarge planning intervention. Stroke survivors aged ≥45 years, admitted to a rehabilitation ward, expected to return to a community (private) dwelling after discharge, with no significant prestroke disability will be randomly allocated 1:1 to receive a standardised discharge planning intervention and the HOME programme or the standardised discharge planning intervention alone. The primary outcome is participation measured using the Nottingham Extended Activities of Daily Living. Secondary outcome areas include hospital readmission, disability, performance of instrumental activities of daily living, health-related quality of life, quality of care transition and carer burden. Resources used/costs will be collected for the cost-effectiveness analysis and hospital readmission. Recruitment commenced in 2019. Allowing for potential attrition, 360 participants will be recruited to detect a clinically important treatment difference with 80% power at a two-tailed significance level of 0.05. ETHICS AND DISSEMINATION: This study is approved by the Alfred Health Human Research Ethics Committee and site-specific ethics approval has been obtained at all participating sites. Results of the main trial and the secondary endpoint of cost-effectiveness will be submitted for publication in peer-reviewed journalsTrial registration numberACTRN12618001360202.

Cognitive Recovery After Stroke: A Meta-analysis and Metaregression of Intervention and Cohort Studies.

BACKGROUND: Cognition affects poststroke recovery, but meta-analyses of cognition have not yet provided a comparison of observational and intervention evidence. OBJECTIVE: To describe the trajectory of poststroke cognition and the factors that moderate it across intervention and observational cohorts. METHODS: Six databases were searched up to January 2020. Studies describing quantitative changes in cognition in adults poststroke were included. Interventions were classified into pharmacological, therapist-led, nonroutine/alternative, and usual care. Summary estimates were compared via hierarchical mixed-effects models. Age, recovery stage, stroke etiology, cognitive domain targeted in studies, and intervention types were investigated as moderators of cognition. Recovery stage and intervention were further analyzed in a multiplicative metaregression model. RESULTS: A total of 43 intervention trials and 79 observation cohorts involving 28 222 stroke participants were included. Heterogeneity was significant (τ2 = 0.09; CI = 0.01-0.21, P < .001) with no evidence of publication bias. Cognitive recovery was greater in intervention trials (g = 0.47; CI = 0.37-0.58) than observational cohorts (g = 0.28; CI = 0.20-0.36) across all moderators analyzed. Nonroutine/alternative and pharmacological trials achieved the best overall results (g = 0.57, CI = 0.42-0.73, and g = 0.52, CI = 0.30-0.74, respectively), followed by therapist-led (g = 0.46; CI = 0.17-0.74), and usual care (g = 0.28; CI = 0.11-0.45) interventions. Medium recovery effects (ie, g ≥ 0.5) were observed in examining first-ever stroke, executive function, visuo-perceptual, consciousness, and psychomotor skills, 61 to 180 days poststroke, in participants aged 65 to 70 years. CONCLUSION: Cognitive recovery is possible using different controlled interventions in all recovery stages, with smaller benefits ≥2 years poststroke. Longer-term studies are needed to determine the role of nonroutine/alternative therapies and the association between cognitive recovery and performance in everyday activities.

Designing an intervention process that embeds work-focussed interventions within inpatient rehabilitation: An intervention mapping approach.

INTRODUCTION: Returning to work is a goal for many people after brain injury. The failure to return to work after injury brings both economic and personal (quality of life) costs to those living with stroke or brain injury, their families, and society. This study explored the barriers to providing work-focused interventions during hospital-based rehabilitation and co-created solutions with rehabilitation providers to increase the provision of work-focused intervention during inpatient rehabilitation. METHODS: This study used an Intervention Mapping approach (a six-step protocol that guides the design of complex interventions) based on an action research methodology. Focus group data, in addition to best evidence from systematic reviews, practice guidelines and key articles were combined with theoretical models for changing behaviour and clinician experience. This was then systematically operationalised into an intervention process using consensus among clinicians. The process was further refined through piloting and feedback from key stakeholders, and group consensus on the final process. RESULTS: A detailed five phase return to work intervention process for inpatient rehabilitation was developed. The key features of the process include; having one key allied health clinician to coordinate the process, choosing assessments based on pre-injury work demands, emphasising the importance of core work skills and considering the most appropriate service for referral at the conclusion of rehabilitation. CONCLUSION: We used a systematic approach, guided by the intervention mapping approach and behaviour change theory to tailor existing workfocused interventions to the inpatient setting.

Effectiveness of health consumer representative involvement in implementation of interventions to change health professional behaviour.

BACKGROUND: The adoption of research evidence to improve client outcomes may be enhanced using the principles of implementation science. This systematic review aimed to understand the effect of involving consumers to change health professional behaviours and practices. The barriers and enablers to consumer engagement will also be examined. METHODS: We searched Medline, CINAHL, Embase, the Cochrane Central Register of Controlled Trials and PDQ-Evidence from 2004 to February 2019. Implementation studies involving consumers in at least one phase (development, intervention or facilitation) of an intervention that aimed to change health professional behaviour to align with evidence-based practice were included. Studies in the areas of paediatrics and primary care were excluded. Two review authors independently screened studies for inclusion, and one author extracted data and conducted quality assessments with review of a second author. Knowledge translation interventions were categorized using the Effective Practice and Organisation of Care taxonomy. The primary outcome was measures of change in health professional behaviour. RESULTS: Sixteen articles met the inclusion criteria. Meta-analysis of three studies found support for consumer involvement in changing healthcare professionals' behaviour (Hedges' g = 0.41, 95% CI [0.27, 0.57], P < 0.001). Most knowledge translation studies involved consumers during the development phase only (n = 12). Most studies (n = 9) included one type of knowledge translation intervention. Professional interventions (including education of health professionals, educational outreach, and audit and feedback) were described in 13 studies. CONCLUSIONS: Consumer involvement rarely moves beyond the design phase of knowledge translation research in healthcare settings. Further research of the barriers to and effect of increased consumer engagement across all stages of knowledge translation interventions is needed. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019119179.

A Systematic Scoping Review of Work Interventions for Hospitalised Adults with an Acquired Neurological Impairment.

Purpose Addressing return to work early after neurological impairment from stroke or moderate and severe traumatic brain injury may improve likelihood of returning to employment, yet little is known about how best to organize work interventions for delivery in the inpatient hospital setting. The purpose of this scoping review was to identify knowledge gaps and inform program development in hospital-based work interventions. Method We searched MEDLINE, CINAHL, OTSeeker and Embase for English-language articles published from database inception until March 2018. Citations were then manually searched using reference lists of included papers and Google Scholar. Articles were included if they described programs providing return to work intervention within a hospital to adults with newly acquired neurological conditions, such as traumatic brain injury or stroke. After identifying and selecting relevant studies, we charted the data and then synthesized the results. Results Twenty-eight articles explored work intervention in an inpatient hospital setting. Interventions targeted a diagnostically heterogeneous population, mostly including adults who had suffered either a traumatic brain injury or stroke. Most interventions included a structured process for assessment, highlighted the importance of collaboration, and aimed to improve performance of work skills that could be facilitated within a hospital setting only (as opposed to all work skills). Thematic analysis of included studies resulted in four themes: structure, collaboration, clinician training, and belief in future work capacity. Conclusion Return to work intervention appears to be an important component of neurological rehabilitation. While studies to date have identified enablers for the integration of work interventions into the inpatient hospital setting, there is limited description of specific components of programs, and a lack of studies evaluating program effectiveness.

Increased anticipatory but decreased consummatory brain responses to food in sisters of anorexia nervosa patients.

BACKGROUND: We have previously shown increased anticipatory and consummatory neural responses to rewarding and aversive food stimuli in women recovered from anorexia nervosa (AN). AIMS: To determine whether these differences are trait markers for AN, we examined the neural response in those with a familial history but no personal history of AN. METHOD: Thirty-six volunteers were recruited: 15 who had a sister with anorexia nervosa (family history) and 21 control participants. Using fMRI we examined the neural response during an anticipatory phase (food cues, rewarding and aversive), an effort phase and a consummatory phase (rewarding and aversive tastes). RESULTS: Family history (FH) volunteers showed increased activity in the caudate during the anticipation of both reward and aversive food and in the thalamus and amygdala during anticipation of aversive only. FH had decreased activity in the dorsal anterior cingulate cortex, the pallidum and the superior frontal gyrus during taste consumption. CONCLUSIONS: Increased neural anticipatory but decreased consummatory responses to food might be a biomarker for AN. Interventions that could normalise these differences may help to prevent disorder onset. DECLARATION OF INTEREST: C.M. has acted as a consultant to P1VITAL, Givaudan, GWPharma, the British Broadcasting Corporation (BBC) and Channel 4. COPYRIGHT AND USAGE: © The Royal College of Psychiatrists 2016. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) license.

Activity preferences and participation of school-age children living in urban and rural environments.

ABSTRACT It is important for therapists to be knowledgeable about the impact of the environment on children's participation patterns and activity preferences. This study investigated the activity preference and participation among school-age children living in urban and rural locations. The participation patterns and preferences for activities of 58 typically developing children (32 males and 26 females; response rate of 38.7%) aged 8-12 years were assessed across both urban (n = 24) and rural (n = 34) regions of southwest Victoria, Australia. The participation patterns and preferences for activities were assessed using the Children's Assessment of Participation and Enjoyment and Preferences for Activities of Children (CAPE/PAC). An independent samples t-test was used to determine whether significant differences existed for the CAPE/PAC scores for urban and rurally based children as well as boys and girls. Significant differences were found between the scores of children living in urban and rural areas on the following subscales: CAPE Diversity, CAPE Intensity, CAPE Whom, CAPE Where, PAC Physical Preference, and PAC Social Preference. A significant difference for rural and urban groups was found on the following CAPE activity types: Recreation Diversity, Recreation Intensity, Social Diversity, Social Intensity, Self-Improvement Diversity, and Self-Improvement Intensity. Rurally based children were engaged in a broader range of activities and did so more frequently than urban children. Differences in gender were identified with girls preferring to participate in social and skill-based activities and being more likely to participate with friends or people outside their home. However, there were no significant differences in the participation patterns of boys and girls. Physical, social, and structural aspects of the location where a child lives impact the frequency, type of activities, and whom a child participates with most frequently in out-of-school activities. The activity participation of boys and girls in Australia has become quite similar.