School-based interventions TO Prevent Dating and Relationship Violence and Gender-Based Violence: STOP-DRV-GBV systematic review.

Background: Schools have a duty of care to prevent violence between students but a significant amount of dating and relationship violence and gender-based violence occurs in schools. These are important public health issues with important longitudinal consequences for young people. Objectives: To understand functioning and effectiveness of school-based interventions for the prevention of dating and relationship violence and gender-based violence. Review methods: We undertook a mixed-methods systematic review to synthesise different types of evidence relating to school-based interventions for the prevention of dating and relationship violence and gender-based violence to understand if, how and in what ways these interventions are effective. We searched 21 databases and 2 trial registers and undertook forwards and backwards citation chasing, author contact and other supplementary search methods. Searches identified all literature published to June 2021. All screening was undertaken in duplicate and independently, and we quality appraised all included studies. Results: We included 247 reports (68 outcome evaluations, 137 process evaluations). Synthesis of intervention components produced an intervention typology: single-component, curricular, multicomponent, and multilevel programmes. Synthesis of intervention theories suggested that interventions aiming to increase students' sense of school belonging and sense of safety in the school building could encourage increased learning of prosocial skills and increased prosocial peer norms, and so potentially reducing dating and relationship violence and gender-based violence. Synthesis of factors affecting delivery highlighted school organisation and leaders who believed in the importance of addressing dating and relationship violence/gender-based violence, along with time and resources to deliver the interventions. The ease with which the intervention could be delivered and modified was also important. Meta-analysis found stronger evidence for intervention effectiveness in reducing dating and relationship violence than for gender-based violence, with significant long-term impacts on dating and relationship violence victimisation and perpetration, and some evidence that interventions in high-income countries could be effective for reducing victimisation and perpetration of gender-based violence in the long-term. Impacts on knowledge and attitudes were primarily short-term. Network meta-analysis did not suggest superiority of any intervention type. Moderation evidence suggested interventions reduced dating and relationship violence perpetration in boys more than girls, but reduced gender-based violence perpetration more in girls. Metaregression by intervention component did not explain heterogeneity in effectiveness, but qualitative comparative analysis suggested that reducing perpetration was important to reducing victimisation, and that perpetration could be reduced via focus on interpersonal skills, guided practice and (for gender-based violence) implementation of social structural components. Limitations: Despite an exhaustive search, trials may have been missed and risk of publication bias was high for several analyses. Conclusions: This is the most comprehensive systematic review of school-based interventions for dating and relationship violence and gender-based violence to date. It is clear that the prevention of dating and relationship violence and gender-based violence in schools will require longer-term investment to show benefit. Future work: Future research is needed to understand why intervention effectiveness appears stronger for dating and relationship violence than gender-based violence. Study registration: The study is registered as PROSPERO CRD42020190463. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Public Health Research programme (NIHR award ref: NIHR130144) and is published in full in Public Health Research; Vol. 12, No. 3. See the NIHR Funding and Awards website for further award information.

Schools are places where dating and relationship violence and gender-based violence occur. Therefore, interventions conducted within schools are ideally placed to prevent and reduce dating and relationship violence and gender-based violence. We reviewed existing research on these interventions, exploring how they were expected to work, what factors affected their implementation in practice, how they had an impact on dating and relationship violence and gender-based violence, and what specific parts of the interventions were most effective and in what contexts. We defined what sort of evidence to include in the review, carried out a comprehensive search and found 247 reports on school-based interventions to prevent dating and relationship violence or gender-based violence, most of which were conducted in North America. Most interventions aimed to provide students with the knowledge, attitudes and skills needed to prevent perpetration and victimisation. They varied in complexity; some had one activity, others had multiple activities, some were integrated into the existing school curricula and others were complex in that they sought to change how schools as a whole respond to dating and relationship violence or gender-based violence. We theorised that complex interventions would bring about greater and more sustainable change, but this was not supported by our findings. The implementation of interventions was affected by factors such as school organisation and leaders who believed in the importance of addressing dating and relationship violence/gender-based violence, along with time and resources to deliver the interventions. The ease with which the intervention could be delivered and modified was also important. There was stronger evidence for intervention effectiveness in reducing dating and relationship violence than for gender-based violence, with significant long-term impacts on dating and relationship violence victimisation and perpetration. There was some evidence that interventions in high-income countries could be effective for reducing victimisation and perpetration of gender-based violence in the long-term. More complicated interventions were not more effective, and interventions tended to reduce dating and relationship violence perpetration in boys more than in girls. We have also been able to identify where there are gaps in available evidence, which may provide avenues for future research.

An Analysis of Uncertainties and Data Collection Agreements in the Cancer Drugs Fund.

BACKGROUND: Managed Access Agreements (MAAs) are a commercial arrangement that provide patients earlier access to innovative health technologies while uncertainties in the evidence base are resolved through data collection. In the UK, data collection agreements (DCAs) outline the evidence that will be collected during the MAA period and are intended to resolve uncertainties in the clinical- and cost-effectiveness of a technology sufficient for the National Institute of Health and Care Excellence (NICE) committee to make a final decision on reimbursement. OBJECTIVE: The aim of this study was to identify the primary uncertainties leading to a recommendation for entry to the Cancer Drugs Fund (CDF) and evaluate how the corresponding DCAs attempt to address these. METHODS: A database of MAAs agreed within the CDF was compiled with coverage between July 2016 and December 2020 (the time during which evidence generation was routinely collected within the CDF up until the time of analysis). Uncertainties in the evidence base for technologies entering the CDF were analysed alongside the outcomes planned for data collection during the MAA. These data provide an overview of the key uncertainties surrounding health technologies in the CDF on entry and the types of evidence targeted by DCAs. RESULTS: In the assessment of 39 Cancer Drugs Fund (CDF) cases, NICE committees identified a total of 108 key uncertainties in cost-effectiveness estimates. Overall survival was the most commonly identified uncertainty, followed by generalisability of the evidence to the target population. DCAs specified a range of outcomes relevant to understanding the clinical effectiveness of the technology, though fewer than half (43.6%) of the DCAs addressed all the key uncertainties identified by the NICE committee. CONCLUSION: The analysis indicated that data collection within the CDF is not sufficient to resolve all the uncertainties identified by the NICE committee, meaning that other approaches will be needed at re-appraisal to ensure that the NICE committee can reach a final decision on reimbursement.

Early access schemes for innovative health technologies: the views of international stakeholders.

OBJECTIVES: Early access schemes (EASs) are approaches used by payers to balance and facilitate earlier patient access to innovative health technologies while evidence generation is ongoing. Schemes require investment from payers and are associated with significant risk since not all technologies will be routinely reimbursed. The purpose of this study was to gain the perspectives of policy experts about the key challenges for EASs and potential solutions for their optimal design and implementation. METHODS: Two virtual workshops were convened including (i) UK-based policy experts (England, Wales, and Scotland) and (ii) representatives from multiple healthcare systems (England, France, Sweden, Canada, Poland, and Norway). Participants were encouraged to share their experiences with EASs in their healthcare system and highlight key challenges for policy makers. Discussions were transcribed and analyzed using framework analysis. RESULTS: Participants agreed that EASs have value when targeted toward innovative technologies with the potential for significant clinical benefit in an area of high unmet need. Participants discussed potential solutions to the challenges faced by payers implementing EASs, including defining eligibility criteria, supporting evidence generation, and approaches to reimbursement. CONCLUSIONS: Participants agreed that EASs are one possible solution for their healthcare systems and have the potential to deliver significant clinical value to patients. However, widespread adoption of EASs is limited due to concerns about the risks for patients and healthcare budgets, further solutions are needed to deliver EASs for targeted therapies.

An evaluation of managed access agreements in England based on stakeholder experience.

OBJECTIVES: The objective of this research was to evaluate managed access policy in England, drawing upon the expertise of a range of stakeholders involved in its implementation. METHODS: Seven focus groups were conducted with payer and health technology assessment representatives, clinicians, and representatives from industry and patient/carer organizations within England. Transcripts were analyzed using framework analysis to identify stakeholders' views on the successes and challenges of managed access policy. RESULTS: Stakeholders discussed the many aims of managed access within the National Health Service in England, and how competing aims had affected decision making. While stakeholders highlighted a number of priorities within eligibility criteria for managed access agreements (MAAs), stakeholders agreed that strict eligibility criteria would be challenging to implement due to the highly variable nature of innovative technologies and their indications. Participants highlighted challenges faced with implementing MAAs, including evidence generation, supporting patients during and after the end of MAAs, and agreeing and reinforcing contractual agreements with industry. CONCLUSIONS: Managed access is one strategy that can be used by payers to resolve uncertainty for innovative technologies that present challenges for reimbursement and can also deliver earlier access to promising technologies for patients. However, participants cautioned that managed access is not a "silver bullet," and there is a need for greater clarity about the aims of managed access and how these should be prioritized in decision making. Discussions between key stakeholders involved in managed access identified challenges with implementing MAAs and these experiences should be used to inform future managed access policy.

Re-orientating systematic reviews to rigorously examine what works, for whom and how: Example of a realist systematic review of school-based prevention of dating and gender violence.

Conventional systematic reviews offer few insights into for whom and how interventions work. 'Realist reviews' examine such questions via examining 'context-mechanism-outcome configurations' (CMOCs) but are insufficiently rigorous in how evidence is identified, assessed and synthesised. We developed 'realist systematic reviews', addressing similar questions to realist reviews but using rigorous methods. We applied this to synthesising evidence on school-based prevention of dating and relationship violence (DRV) and gender-based violence (GBV). This paper reflects on overall methods and findings, drawing on papers reporting each analysis. Drawing on intervention descriptions, theories of change and process evaluations, we developed initial CMOC hypotheses: interventions triggering 'school-transformation' mechanisms (preventing violence by changing school environments) will achieve larger effects than those triggering 'basic-safety' (stopping violence by emphasising its unacceptability) or 'positive-development' (developing students' broader skills and relationships) mechanisms; however, school transformation would only work in schools with high organisational capacity. We used various innovative analyses, some of which aimed to test these hypotheses and some of which were inductive, drawing on available findings to augment and refine the CMOCs. Overall, interventions were effective in reducing long-term DRV but not GBV or short-term DRV. DRV prevention occurred most effectively via the 'basic-safety' mechanism. 'School-transformation' mechanisms were more effective in preventing GBV but only in high-income countries. Impacts on long-term DRV victimisation were greater when working with a critical mass of participating girls. Impacts on long-term DRV perpetration were greater for boys. Interventions were more effective when focusing on skills, attitudes and relationships, or lacking parental involvement or victim stories. Our method provided novel insights and should be useful to policy-makers seeking the best interventions for their contexts and the most information to inform implementation.

Are school-based interventions to prevent dating and relationship violence and gender-based violence equally effective for all students? Systematic review and equity analysis of moderation analyses in randomised trials.

School-based interventions for the prevention of dating and relationship violence (DRV) and gender-based violence (GBV) take advantage of universal opportunities for intervention. Information on differential effectiveness of interventions is important to assess if they ameliorate or worsen social gradients in specific outcomes. This is especially important in DRV and GBV prevention given the gendered context of these behaviours and their common aetiologies in patriarchal gender norms, and social acceptance in school contexts of sexual harassment, such as catcalling or unwanted groping. We undertook a systematic review of moderation analyses in randomised trials of school-based interventions for DRV and GBV prevention. We searched 21 databases and used supplementary search methods without regard to publication type, language or year of publication, and synthesised moderation tests relating to equity-relevant characteristics (principally sex and prior history of the outcome) for DRV and GBV perpetration and victimisation. Across 23 included outcome evaluations, programme effects on DRV victimisation were not moderated by gender or prior experience of DRV victimisation, but DRV perpetration outcomes were greater for boys, particularly for emotional and physical DRV perpetration. Findings for GBV outcomes were counterintuitive. Our findings suggest that practitioners should carefully monitor local intervention effectiveness and equity to ensure that interventions are working as intended. However, one of the most surprising findings from our analysis-with clear relevance for uncertainties in practice-was that differential impacts by sexuality or sexual minority status were not frequently evaluated.

School-Based Interventions to Prevent Dating and Relationship Violence and Gender-Based Violence: Systematic Review and Network Meta-Analysis.

Background. Schools are sites of dating and relationship violence (DRV) and of gender-based violence (GBV) victimization and perpetration. School-based interventions can reach a broad range of students, targeting both individual and group processes that may underpin DRV and GBV. Considering DRV and GBV jointly is important because of their shared etiologies. Comparing the effectiveness of interventions using network meta-analysis (NMA) can support decision-making on optimal resource use. Objectives. To evaluate the comparative effectiveness of school-based interventions for children aged 5 to 18 years on DRV and GBV victimization, perpetration, and related mediators. Search Methods. We searched 21 databases in July 2020 and June 2021, alongside extensive supplementary search methods, including gray literature searches, forward and backward citation chasing, and searches on first and last author names. Selection Criteria. We included randomized-controlled trials of interventions for children of compulsory school age implemented within the school setting, and either partially or wholly aimed at changing DRV or GBV outcomes. Data Collection and Analysis. Pairwise meta-analyses using random-effects robust variance estimation considered intervention effectiveness on DRV and GBV victimization and perpetration using odds ratios, and on mediators (e.g., knowledge and attitudes) using standardized mean differences. Effects were divided into short-term (< 12 months postbaseline) and long-term (≥ 12 months postbaseline). NMAs on victimization and perpetration outcomes compared interventions categorized by breadth of mechanism and complexity of delivery and implementation. Meta-regression tested sensitivity to percentage of girls in the trial sample and country context. Main Results. Our analysis included 68 trials. Evidence was stronger overall for effects on DRV than for GBV, with significant long-term impacts on DRV victimization (odds ratio [OR] = 0.82; 95% confidence interval [CI] = 0.68, 0.99) and DRV perpetration (OR = 0.78; 95% CI = 0.64, 0.94). Knowledge and attitudinal effects were predominantly short-term (e.g., for DRV-related violence acceptance, d = 0.16; 95% CI = 0.08, 0.24). NMAs did not suggest the superiority of any intervention type; however, most analyses for GBV outcomes were inconsistent. A higher proportion of girls in the sample was associated with increased effectiveness on long-term victimization outcomes. Author's Conclusions. Evidence is stronger for DRV than for GBV, despite considerable heterogeneity. Certainty of findings was low or very low overall. Public Health Implications. Violence reductions may require more than 1 school year to become apparent. More extensive interventions may not be more effective. A possible reason for stronger effectiveness for DRV is that whereas GBV is ingrained in school cultures and practices, DRV is potentially more open to change via addressing individual knowledge and attitudes. (Am J Public Health. 2023;113(3):320-330. https://doi.org/10.2105/10.2105/AJPH.2022.307153).

Systematic Review of the Economics of School-Based Interventions for Dating Violence and Gender-Based Violence.

Dating and relationship violence (DRV) and gender-based violence (GBV) among children and young people incur a high cost to individuals and society. School-based interventions present an opportunity to prevent DRV and GBV early in individuals' lives. However, with school resources under pressure, policymakers require guidance on the economics of implementing interventions. As part of a large systematic review funded by the National Institute for Health and Care Research (NIHR), we searched for economic evaluations and costing studies of school-based interventions for DRV and GBV. No formal economic evaluations were identified. Seven studies reporting costs, cost savings, or resource use for eight interventions were identified. The largest costs of implementing interventions were related to staff training and salaries but savings could be made by implementing interventions on a large scale. The potential cost savings of avoided DRV and GBV far outweighed the costs of implementation.

Exploring the Activities and Target Audiences of School-Based Violence Prevention Programs: Systematic Review and Intervention Component Analysis.

Adolescents are at an increased risk for experiencing dating and relationship violence (DRV) and gender-based violence (GBV). School-based interventions remain an important and frequently used method for DRV/GBV prevention. A clear understanding and description of the different components of school-based interventions specific to DRV/GBV is needed to organize and advance the array of prevention efforts being utilized in school settings. We conducted an intervention component analysis to create a taxonomy for school-based interventions addressing DRV and GBV. We searched 21 databases in July 2020 and updated searches in June 2021, alongside extensive supplementary search methods. We included randomized controlled trials (RCTs) in adolescents of compulsory school-age that were implemented within the school setting which partially or wholly focused on DRV and GBV topics. Our analysis included 68 studies describing 76 different school-based interventions. Through an iterative coding process we identified 40 intervention components organized within 13 activity categories, including both student-directed components and non-student-directed components such as activities for school personnel and family members of students. We also identified components addressing higher levels of the social-ecological model including structural-social and structural-environmental aspects of DRV/GBV which prior reviews have not considered. This taxonomy of components and synthesis of intervention efficacy for DRV/GBV school-based interventions provides a framework for comparing past intervention evaluations and constructing new interventions to address these issues at multiple levels within a community.

School-based interventions for preventing dating and relationship violence and gender-based violence: A systematic review and synthesis of theories of change.

School-based interventions for preventing dating and relationship violence (DRV) and gender-based violence (GBV) are an important way of attempting to prevent and reduce the significant amount of DRV and GBV that occurs in schools. A theoretical understanding of how these interventions are likely to cause change is essential for developing and evaluating effectiveness, so developing an overarching theory of change for school-based interventions to prevent DRV and GBV was the first step in our systematic review. Theoretical data were synthesised from 68 outcome evaluations using methods common to qualitative synthesis. Specifically, we used a meta-ethnographic approach to develop a line-of-argument for an overarching theory of change and Markham and Aveyard's (2003, Social Science & Medicine, 56, 1209) theory of human functioning and school organisation as a framework for structuring the concepts. The overall theory of change generated was that by strengthening relationships between and among staff and students, between the classroom and the wider school, and between schools and communities, and by increasing students' sense of belonging with student-centred learning opportunities, schools would encourage student commitment to the school and its values, prosocial behaviour and avoidance of violence and aggression. The theory of human functioning informed our understanding of the mechanisms of action but from our analysis we found that it required refinement to address the importance of context and student agency.

Voretigene Neparvovec for Treating Inherited Retinal Dystrophies Caused by RPE65 Gene Mutations: An Evidence Review Group Perspective of a NICE Highly Specialised Technology Appraisal.

The UK National Institute for Health and Care Excellence (NICE) considered evidence for voretigene neparvovec (VN; Luxturna®) for the treatment of RPE65-mediated inherited retinal dystrophies (IRD) within its highly specialised technology programme. This paper summarises the evidence provided by the company; the appraisal of the evidence by the Peninsula Technology Appraisal Group, who were commissioned to act as the independent evidence review group (ERG); and the development of the NICE guidance by the appraisal committee. The evidence presented by the company highlighted the significant lifelong burden of IRD for patients and carers. Evidence to support the effectiveness of VN was lacking, but the available evidence showed a modest, sustained improvement across a variety of vision-related outcomes. While patients would remain visually impaired, the committee considered that VN would prevent further deterioration in vision. The modelling approach used by the company had a number of limitations and relied heavily upon a large volume of clinical expert input to produce cost-effectiveness estimates with large uncertainty around long-term effectiveness. The ERG's main concerns revolved around these long-term outcomes and the plausibility of utility values. The NICE committee were convinced that the clinical benefits of VN were important and an appropriate use of national health service resources within a specialised service. The committee concluded that a high unmet need existed in patients with RPE65-mediated IRD and that VN represents a step change in the management of this condition.

Clinical effectiveness and safety of erythropoietin-stimulating agents for the treatment of low- and intermediate-1-risk myelodysplastic syndrome: a systematic literature review.

Many patients with lower-risk myelodysplastic syndrome (MDS) experience anaemia, which has negative consequences. Erythropoiesis-stimulating agents (ESAs) and their biosimilars are used to treat anaemia in MDS and, currently, epoetin alfa and darbepoetin alfa are commonly used and recommended by clinical guidelines. To better understand the evidence available on the use of ESAs for anaemia in lower-risk MDS, we conducted a systematic literature review to identify randomized and nonrandomized prospective studies reporting on clinical efficacy/effectiveness, patient-reported quality of life (QoL), and safety. We extended our review to include retrospective studies for darbepoetin alfa specifically and to ascertain the feasibility of completing an indirect network meta-analysis comparing epoetin and darbepoetin alfa. Overall, 53 articles reporting on 35 studies were included. The studies indicated a clinical benefit of ESAs, with benefits observed across key clinical outcomes. ESAs showed consistent improvement in erythroid response rates (ESA-naïve, 45-73%; previous ESA exposure, 25-75%) and duration of response. Comparative studies demonstrated similar progression to acute myeloid leukaemia and several showed improved overall survival and QoL. Limited safety concerns were identified. This analysis confirmed ESA therapy should be the foremost first-line treatment of anaemia in most patients with lower-risk MDS who lack the 5q deletion.

Systematic literature review and assessment of patient-reported outcome instruments in sickle cell disease.

BACKGROUND: Sickle cell disease (SCD) is a chronic condition associated with high mortality and morbidity. It is characterized by acute clinical symptoms such as painful vaso-occlusive crises, which can impair health-related quality of life (HRQL). This study was conducted to identify validated patient-reported outcome (PRO) instruments for use in future trials of potential treatments for SCD. METHODS: A systematic literature review (SLR) was performed using MEDLINE and EMBASE to identify United States (US)-based studies published in English between 1997 and 2017 that reported on validated PRO instruments used in randomized controlled trials and real-world settings. The COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist was used to assess the quality of PRO instruments. RESULTS: The SLR included 21 studies assessing the psychometric properties of 24 PRO instruments. Fifteen of those instruments were developed and validated for adults and 10 for children (one instrument was used in both children and young adults aged up to 21 years). Only five of the 15 adult instruments and three of the 10 pediatric instruments were developed specifically for SCD. For most instruments, there were few or no data on validation conducted in SCD development cohorts. Of the 24 PRO instruments identified, 16 had strong internal reliability (Cronbach's α ≥0.80). There was often insufficient information to assess the content validity, construct validity, responsiveness, or test-retest reliability of the instruments identified for both child and adult populations. No validated PRO instruments measuring caregiver burden in SCD were identified. CONCLUSIONS: The evidence on the psychometric properties of PRO instruments was limited. However, the results of this SLR provide key information on such tools to help inform the design of future clinical trials for patients with SCD in the US.

Activation of Nigrostriatal Dopamine Neurons during Fear Extinction Prevents the Renewal of Fear.

Manipulations that increase dopamine (DA) signaling can enhance fear extinction, but the circuits involved remain unknown. DA neurons originating in the substantia nigra (SN) projecting to the dorsal striatum (DS) are traditionally viewed in the context of motor behavior, but growing data implicate this nigrostriatal circuit in emotion. Here we investigated the role of nigrostriatal DA in fear extinction. Activation of SN DA neurons with designer Gq-coupled receptors exclusively activated by designer drugs (Gq-DREADD) during fear extinction had no effect on fear extinction acquisition, but enhanced fear extinction memory and blocked the renewal of fear in a novel context; a pattern of data paralleled by cFos expression in the central amygdala. D1 receptors in the DS are a likely target mediating the effects of SN DA activation. D1-expressing neurons in the medial DS (DMS) were recruited during fear extinction, and Gq-DREADD-induced DA potentiated activity of D1-expressing neurons in both the DMS and the lateral DS (DLS). Pharmacological activation of D1 receptors in the DS did not impact fear extinction acquisition or memory, but blocked fear renewal in a novel context. These data suggest that activation of SN DA neurons and DS D1 receptors during fear extinction render fear extinction memory resistant to the disrupting effects of changes in contextual contingencies, perhaps by recruiting habitual learning strategies involving the DLS. Nigrostriatal DA thus represents a novel target to enhance long-term efficacy of extinction-based therapies for anxiety and trauma-related disorders.

Acute exercise enhances the consolidation of fear extinction memory and reduces conditioned fear relapse in a sex-dependent manner.

Fear extinction-based exposure therapy is the most common behavioral therapy for anxiety and trauma-related disorders, but fear extinction memories are labile and fear tends to return even after successful extinction. The relapse of fear contributes to the poor long-term efficacy of exposure therapy. A single session of voluntary exercise can enhance the acquisition and consolidation of fear extinction in male rats, but the effects of exercise on relapse of fear after extinction are not well understood. Here, we characterized the effects of 2 h of voluntary exercise during the consolidation phase of contextual or auditory fear extinction learning on long-term fear extinction memory and renewal in adult, male and female, Long-Evans rats. Results indicate that exercise enhances consolidation of fear extinction memory and reduces fear relapse after extinction in a sex-dependent manner. These data suggest that brief bouts of exercise could be used as an augmentation strategy for exposure therapy, even in previously sedentary subjects. Fear memories of discrete cues, rather than of contextual ones, may be most susceptible to exercise-augmented extinction, especially in males. Additionally, exercise seems to have the biggest impact on fear relapse phenomena, even if fear extinction memories themselves are only minimally enhanced.

Exercise increases mTOR signaling in brain regions involved in cognition and emotional behavior.

Exercise can enhance learning and memory and produce resistance against stress-related psychiatric disorders such as depression and anxiety. In rats, these beneficial effects of exercise occur regardless of exercise controllability: both voluntary and forced wheel running produce stress-protective effects. The mechanisms underlying these beneficial effects of exercise remain unknown. The mammalian target of rapamycin (mTOR) is a translation regulator important for cell growth, proliferation, and survival. mTOR has been implicated in enhancing learning and memory as well as antidepressant effects. Moreover, mTOR is sensitive to exercise signals such as metabolic factors. The effects of exercise on mTOR signaling, however, remain unknown. The goal of the present study was to test the hypothesis that exercise, regardless of controllability, increases levels of phosphorylated mTOR (p-mTOR) in brain regions important for learning and emotional behavior. Rats were exposed to 6 weeks of either sedentary (locked wheel), voluntary, or forced wheel running conditions. At 6 weeks, rats were sacrificed during peak running and levels of p-mTOR were measured using immunohistochemistry. Overall, both voluntary and forced exercise increased p-mTOR-positive neurons in the medial prefrontal cortex, striatum, hippocampus, hypothalamus, and amygdala compared to locked wheel controls. Exercise, regardless of controllability, also increased numbers of p-mTOR-positive glia in the striatum, hippocampus, and amygdala. For both neurons and glia, the largest increase in p-mTOR positive cells was observed after voluntary running, with forced exercise causing a more modest increase. Interestingly, voluntary exercise preferentially increased p-mTOR in astrocytes (GFAP+), while forced running increased p-mTOR in microglia (CD11+) in the inferior dentate gyrus. Results suggest that mTOR signaling is sensitive to exercise, but subtle differences exist depending on exercise controllability. Increases in mTOR signaling could contribute to the beneficial effects of exercise on cognitive function and mental health.

'I am not a depressed person': how identity conflict affects help-seeking rates for major depressive disorder.

BACKGROUND: There is a significant treatment gap for patients with depression. A third of sufferers never seek help, and the vast majority of those who do only do so after considerable delay. Little is understood regarding poor help-seeking rates amongst people with depression, with existing research mainly focussed on the impact of barriers to treatment. The current study explored psychological factors affecting help-seeking behaviour in clinically depressed individuals. METHODS: Semi-structured interviews were conducted with 20 current or previously clinically depressed participants who either had or had not sought professional help. Thematic analysis was used to analyse results. RESULTS: The onset of depressive symptoms created conflict with participants' identity and personal goals. Delays in seeking help were primarily attributed to the desire to protect identity and goals from the threat of depressive symptoms. Participants used avoidance strategies to reduce the perceived threat of depressive symptoms on identity. These strategies interfered with help-seeking. Help-seeking was only undertaken once participants reached a point of acceptance and began to make concessions in their identity and goals, at which time they reduced their use of avoidance. CONCLUSIONS: Difficulties resolving conflict between identity and depressive symptoms may account for significant delays in seeking help for depression. The results have implications for predicting health behaviour and improving treatment uptake for depression, and may inform existing help-seeking models.