Detection of risk for future depression among adolescents: Stakeholder views of acceptability and feasibility in the United Kingdom.

AIM: Depression is one of the most common mental illnesses globally and a leading cause of disability. It is often established by late adolescence and thus identifying which adolescents are most at risk is crucial to enable early intervention to prevent depression onset. We have previously developed a risk calculator to stratify which adolescents are at high risk of developing depression and in this study explore the views of stakeholders to ascertain the acceptability and feasibility of implementing such a tool in the UK. METHODS: Semi-structured interviews were conducted with 60 UK-based stakeholders (12 healthcare workers, 12 social workers, 12 school workers, 12 policymakers and 12 parents). Interviews were audio-recorded and transcribed verbatim. Transcripts were analysed drawing on framework analysis techniques in NVivo 12. RESULTS: Six overarching themes were identified: facilitators of acceptability; barriers to acceptability; role of stakeholders in implementing risk screening; feasibility of delivering the risk calculator in practice; barriers to implementation; and policy and system implications of using it in the current UK health and social care climate. The implementation of a depression risk calculator in the UK was seen as largely acceptable and feasible by most respondents. There was a strong emphasis on the utility of schools to implement this risk calculator, although it was recognized that training and support would be essential. CONCLUSIONS: Stakeholders were generally positive about utilizing a tool to screen for risk of future depression among adolescents in the UK but raised important concerns which should be taken into account before implementation.

Headspace for parents: qualitative report investigating the use of a mindfulness-based app for managing parents' stress during COVID-19.

BACKGROUND: Stress can compromise parental well-being and may contribute to harsh and critical parenting styles, which are in turn associated with children's conduct problems. Coronavirus disease 2019 (COVID-19)-related restrictions are likely to have exacerbated parental stress as, for many, UK-based family life was altered considerably. Mindfulness has been demonstrated to improve stress management and emotion regulation when delivered to parents in person, however, more accessible online interventions are under-researched. AIMS: To provide preliminary data on family well-being and parent-child relationships as well as the acceptability and usability of the Headspace app - a self-delivered mindfulness-based intervention - for parents in low-risk families during the early days of the COVID-19 pandemic. METHOD: We provided 12 parents with access to Headspace, and collected qualitative data (semi-structured interviews and 5 minute speech samples) immediately following the initial COVID-19 lockdown in the UK. The resulting transcripts were thematically analysed. RESULTS: Most parents reported Headspace to be acceptable and useful - improvements in parents' own sleep were particularly noted - and there was high adherence to the intervention. However, difficulties related to family well-being and parent-child relationships following the lockdown were also reported. CONCLUSIONS: As a result of the confounding impact of COVID-19 restrictions, and varied access to app content, we were unable to determine any outcomes to be a result of practising mindfulness specifically. However, COVID-19 has had a profound impact on many UK-based families, including those previously at low risk, and our results demonstrate that Headspace may have beneficial effects for parents. There is a need to more rigorously test this tool with a broader range of families.

Oncogenic Truncations of ASXL1 Enhance a Motif for BRD4 ET-Domain Binding.

Proper regulation of gene-expression relies on specific protein-protein interactions between a myriad of epigenetic regulators. As such, mutation of genes encoding epigenetic regulators often drive cancer and developmental disorders. Additional sex combs-like protein 1 (ASXL1) is a key example, where mutations frequently drive haematological cancers and can cause developmental disorders. It has been reported that nonsense mutations in ASXL1 promote an interaction with BRD4, another central epigenetic regulator. Here we provide a molecular mechanism for the BRD4-ASXL1 interaction, demonstrating that a motif near to common truncation breakpoints of ASXL1 contains an epitope that binds the ET domain within BRD4. Binding-studies show that this interaction is analogous to common ET-binding modes of BRD4-interactors, and that all three ASX-like protein orthologs (ASXL1-3) contain a functional ET domain-binding epitope. Crucially, we observe that BRD4-ASXL1 binding is markedly increased in the prevalent ASXL1Y591X truncation that maintains the BRD4-binding epitope, relative to full-length ASXL1 or truncated proteins that delete the epitope. Together, these results show that ASXL1 truncation enhances BRD4 recruitment to transcriptional complexes via its ET domain, which could misdirect regulatory activity of either BRD4 or ASXL1 and may inform potential therapeutic interventions.

Molecular Regulation of the Polycomb Repressive-Deubiquitinase.

Post-translational modification of histone proteins plays a major role in histone-DNA packaging and ultimately gene expression. Attachment of ubiquitin to the C-terminal tail of histone H2A (H2AK119Ub in mammals) is particularly relevant to the repression of gene transcription, and is removed by the Polycomb Repressive-Deubiquitinase (PR-DUB) complex. Here, we outline recent advances in the understanding of PR-DUB regulation, which have come through structural studies of the Drosophila melanogaster PR-DUB, biochemical investigation of the human PR-DUB, and functional studies of proteins that associate with the PR-DUB. In humans, mutations in components of the PR-DUB frequently give rise to malignant mesothelioma, melanomas, and renal cell carcinoma, and increase disease risk from carcinogens. Diverse mechanisms may underlie disruption of the PR-DUB across this spectrum of disease. Comparing and contrasting the PR-DUB in mammals and Drosophila reiterates the importance of H2AK119Ub through evolution, provides clues as to how the PR-DUB is dysregulated in disease, and may enable new treatment approaches in cancers where the PR-DUB is disrupted.

Detection of risk for depression among adolescents in diverse global settings: protocol for the IDEA qualitative study in Brazil, Nepal, Nigeria and the UK.

INTRODUCTION: Globally, depression is a leading cause of disability among adolescents, and suicide rates are increasing among youth. Treatment alone is insufficient to address the issue. Early identification and prevention efforts are necessary to reduce morbidity and mortality. The Identifying Depression Early in Adolescence (IDEA) consortium is developing risk detection strategies that incorporate biological, psychological and social factors that can be evaluated in diverse global populations. In addition to epidemiological and neuroscience research, the IDEA consortium is conducting a qualitative study to explore three domains of inquiry: (1) cultural heterogeneity of biopsychosocial risk factors and lived experience of adolescent depression in low-income and middle-income countries (LMIC); (2) the feasibility, acceptability and ethics of a risk calculator tool for adolescent depression that can be used in LMIC and high-income countries and (3) capacity for biological research into biomarkers for depression risk among adolescents in LMIC. This is a multisite qualitative study being conducted in Brazil, Nepal, Nigeria and the UK. METHODS AND ANALYSIS: A systematic set of qualitative methods will be used in this study. The Delphi method, Theory of Change (ToC) workshops, key-informant interviews and focus group discussions will be used to elicit perspectives on the study topics from a broad range of stakeholders (adolescents, parents, policy-makers, teachers, health service providers, social workers and experts). Delphi panellists will participate in three survey rounds to generate consensus through facilitated feedback. Stakeholders will create ToC models via facilitated workshops in the LMIC sites. The framework approach will be used to analyse data from the study. ETHICS AND DISSEMINATION: Ethical approvals were received from the Ethics Review Board of George Washington University and from site-specific institutions in Brazil, Nepal, Nigeria and the UK. The findings generated from this study will be reported in highly accessed, peer-reviewed, scientific and health policy journals.

Structure-based mechanism of preferential complex formation by apoptosis signal-regulating kinases.

Apoptosis signal-regulating kinases (ASK1, ASK2, and ASK3) are activators of the p38 and c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) pathways. ASK1-3 form oligomeric complexes known as ASK signalosomes that initiate signaling cascades in response to diverse stress stimuli. Here, we demonstrated that oligomerization of ASK proteins is driven by previously uncharacterized sterile-alpha motif (SAM) domains that reside at the carboxy-terminus of each ASK protein. SAM domains from ASK1-3 exhibited distinct behaviors, with the SAM domain of ASK1 forming unstable oligomers, that of ASK2 remaining predominantly monomeric, and that of ASK3 forming a stable oligomer even at a low concentration. In contrast to their behavior in isolation, the ASK1 and ASK2 SAM domains preferentially formed a stable heterocomplex. The crystal structure of the ASK3 SAM domain, small-angle x-ray scattering, and mutagenesis suggested that ASK3 oligomers and ASK1-ASK2 complexes formed discrete, quasi-helical rings through interactions between the mid-loop of one molecule and the end helix of another molecule. Preferential ASK1-ASK2 binding was consistent with mass spectrometry showing that full-length ASK1 formed hetero-oligomeric complexes incorporating large amounts of ASK2. Accordingly, disrupting the association between SAM domains impaired ASK activity in the context of electrophilic stress induced by 4-hydroxy-2-nonenal (HNE). These findings provide a structural template for how ASK proteins assemble foci that drive inflammatory signaling and reinforce the notion that strategies to target ASK proteins should consider the concerted actions of multiple ASK family members.

Substrate binding allosterically relieves autoinhibition of the pseudokinase TRIB1.

The Tribbles family of pseudokinases recruits substrates to the ubiquitin ligase COP1 to facilitate ubiquitylation. CCAAT/enhancer-binding protein (C/EBP) family transcription factors are crucial Tribbles substrates in adipocyte and myeloid cell development. We found that the TRIB1 pseudokinase was able to recruit various C/EBP family members and that the binding of C/EBPß was attenuated by phosphorylation. To explain the mechanism of C/EBP recruitment, we solved the crystal structure of TRIB1 in complex with C/EBPα, which revealed that TRIB1 underwent a substantial conformational change relative to its substrate-free structure and bound C/EBPα in a pseudosubstrate-like manner. Crystallographic analysis and molecular dynamics and subsequent biochemical assays showed that C/EBP binding triggered allosteric changes that link substrate recruitment to COP1 binding. These findings offer a view of pseudokinase regulation with striking parallels to bona fide kinase regulation-by means of the activation loop and αC helix-and raise the possibility of small molecules targeting either the activation "loop-in" or "loop-out" conformations of Tribbles pseudokinases.

A bidentate Polycomb Repressive-Deubiquitinase complex is required for efficient activity on nucleosomes.

Attachment of ubiquitin to lysine 119 of Histone 2A (H2AK119Ub) is an epigenetic mark characteristic of repressed developmental genes, which is removed by the Polycomb Repressive-Deubiquitinase (PR-DUB) complex. Here we report the crystal structure of the Drosophila PR-DUB, revealing that the deubiquitinase Calypso and its activating partner ASX form a 2:2 complex. The bidentate Calypso-ASX complex is generated by dimerisation of two activated Calypso proteins through their coiled-coil regions. Disrupting the Calypso dimer interface does not affect inherent catalytic activity, but inhibits removal of H2AK119Ub as a consequence of impaired recruitment to nucleosomes. Mutating the equivalent surface on the human counterpart, BAP1, also compromises activity on nucleosomes. Together, this suggests that high local concentrations drive assembly of bidentate PR-DUB complexes on chromatin-providing a mechanistic basis for enhanced PR-DUB activity at specific genomic foci, and the impact of distinct classes of PR-DUB mutations in tumorigenesis.

What is the relationship between increased access to HAART, relationship status and fertility decisions amongst HIV-positive women? A literature review and meta-analysis.

AIMS AND OBJECTIVES: To investigate the relationship between fertility decisions, to have already had a child or to desire to have one in the future, and the prognostic factors; access to antiretrovirals, the time since these became widely available (year of the study); and relationship status. BACKGROUND: There have been significant advances in the treatment of human immunodeficiency virus with the advent of antiretroviral therapy which has been used to successfully reduce the rate of mother to child transmission; leading researchers to hypothesise that human immunodeficiency virus-positive women may desire to have children more so now than in the past. However, this topic is often not discussed in healthcare consultations. DESIGN & METHODS: A systematic search was conducted on Cumulative Index of Nursing and Allied Health Literature and Medline, using the key terms 'fertility decisions' and 'human immunodeficiency virus positive'. A meta-analysis of proportions and a meta-regression were conducted using a random-effects model and a logit transformation to normalise the data. Heterogeneity was assessed using Q, I2 and R2 values, and p-values were produced for each regressed variable. RESULTS: There was no statistically significant relationship between a desire to have children in the future and any of the prognostic variables. However, there were statistically significant relationships between already having had at least one child; being on antiretroviral therapy; wanting a child in the future; and being in a cohabiting partnership or marriage. CONCLUSION: There are no reliable prognostic variables which can be used to predict fertility intentions in human immunodeficiency virus-positive women. There is, however, a significant proportion of women who wish to have children or who have already had children and are in need of reproductive counselling from their healthcare providers. RELEVANCE TO CLINICAL PRACTICE: A greater knowledge of factors which may influence reproductive decisions amongst human immunodeficiency virus-positive position will allow healthcare professionals to individualise the care they provide.

A socially inclusive approach to user participation in higher education.

AIM: This paper is a report of a study to evaluate the development of an innovative Service User Academic post in mental health nursing in relation to student learning and good employment practice in terms of social inclusion. BACKGROUND: Institutions providing professional mental health education are usually expected to demonstrate user involvement in the design, delivery and evaluation of their educational programmes to ensure that user voices are central to the development of clinical practice. Involvement can take many forms but not everyone values user knowledge as equal to other sources of knowledge. This can lead to users feeling exploited, rather than fully integrated in healthcare professional education processes. Development of the post discussed in this paper was stimulated and informed by an innovative example from Australia. METHOD: An observational case study of the development and practice of a Service User Academic post was undertaken in 2005. Participants were purposively sampled and included the User Academic, six members of a user and carer reference group, 10 educators and 35 students. Data were collected by group discussions and interviews. Data analysis was based on the framework approach. FINDINGS: The evaluation revealed tangible benefits for the students and the wider academic community. Most important was the powerful role model the Service User Academic provided for students. The post proved an effective method to promote service user participation and began to integrate service user perspectives within the educational process. However, the attempts to achieve socially inclusive practices were inhibited by organizational factors. The expectations of the role and unintended discriminatory behaviours had an impact on achieving full integration of the role. Furthermore, shortcomings in the support arrangements were revealed. CONCLUSIONS: The search for an optimum model of involvement may prove elusive, but the need to research and debate different strategies, to avoid tokenism and exploitation, remains.

Experiences of service user and carer participation in health care education.

The agenda of involving service users and their carers more meaningfully in the development, delivery and evaluation of professional education in health is gaining in importance. The paper reports on a symposium which presented three diverse initiatives, established within a school of nursing and midwifery in the United Kingdom. These represent different approaches and attempts to engage service users and in some instances carers more fully in professional education aimed at developing mental health practitioners. Each is presented as achieving movement on a continuum of participation from service users as passive recipients to service users as collaborators and co-researchers. The paper concludes with a discussion of the lessons to be learnt which will hopefully stimulate service user involvement on a wider basis.

The introduction of integrated out-of-hours arrangements in England: a discrete choice experiment of public preferences for alternative models of care.

OBJECTIVE: To establish which generic attributes of general practice out-of-hours health services are important to the public. METHODS: A discrete choice experiment postal survey conducted in three English general practitioner (GP) co-operatives. A total of 871 individuals aged 20-70 years registered with a GP. Outcomes were preferences for, and trade-offs between: time to making initial contact, time waiting for advice/treatment, informed of expected waiting time, type of contact, professional providing advice, chance contact relieves anxiety, and utility estimates for valuing current models of care. RESULTS: Response rate was 37%. Respondents valued out-of-hours contact for services for reducing anxiety but this was not the only attribute of importance. They had preferences for the way in which services were organized and valued information about expected waiting time, supporting findings from elsewhere. Participants were most willing to make trade-offs between waiting time and professional person. Of the predicted utility for three models of care utility was higher for fully integrated call management. CONCLUSIONS: Greater utility might be achieved if existing services are re-configured more in line with the government's fully integrated call management model. Because the attributes were described in generic terms, the findings can be applied more generally to the plethora of models that exist (and many that might exist in the future). The approach used is important for achieving greater public involvement in how health services develop. Few experiments have elicited public preferences for health services in the UK to date. This study showed valid preferences were expressed but there were problems obtaining representative views from the public.

Experiences of service user and carer participation in health care education.

The agenda of involving service users and their carers more meaningfully in the development, delivery and evaluation of professional education in health is gaining in importance. The paper reports on a symposium which presented three diverse initiatives, established within a school of nursing and midwifery in the United Kingdom. These represent different approaches and attempts to engage service users and in some instances carers more fully in professional education aimed at developing mental health practitioners. Each is presented as achieving movement on a continuum of participation from service users as passive recipients to service users as collaborators and co-researchers. The paper concludes with a discussion of the lessons to be learnt which will hopefully stimulate service user involvement on a wider basis.

Effect of introduction of integrated out of hours care in England: observational study.

OBJECTIVES: To quantify service integration achieved in the national exemplar programme for single call access to out of hours care through NHS Direct, and its effect on the wider health system. DESIGN: Observational before and after study of demand, activity, and trends in the use of other health services. PARTICIPANTS: 34 general practice cooperatives with NHS Direct partners (exemplars): four were case exemplars; 10 control cooperatives. SETTING: England. MAIN OUTCOME MEASURES: Extent of integration; changes in demand, activity, and trends in emergency ambulance transports; attendances at emergency departments, minor injuries units, and NHS walk-in centres; and emergency admissions to hospital in the first year. RESULTS: Of 31 distinct exemplars, 21 (68%) integrated all out of hours call management. Nine (29%) achieved single call access for all patients. In the only case exemplar where direct comparison was possible, a higher proportion of telephone calls were handled by cooperative nurses before integration than by NHS Direct afterwards (2622/6687 (39%) v 2092/7086 (30%): P < 0.0001). Other case exemplars did not achieve 30%. A small but significant downturn in overall demand for care seen in two case exemplars was also seen in the control cooperatives. The number of emergency ambulance transports increased in three of the four case exemplars after integration, reaching statistical significance in two (5%, -0.02% to 10%, P = 0.06; 6%, 1% to 12%, P = 0.02; 7%, 3% to 12%, P = 0.001). This was always accompanied by a significant reduction in the number of calls to the integrated service. CONCLUSION: Most exemplars achieved integration of call management but not single call access for patients. Most patients made at least two telephone calls to contact NHS Direct, and then waited for a nurse to call back. Evidence for transfer of demand from case exemplars to 999 ambulance services may be amenable to change, but NHS Direct may not have sufficient capacity to support national implementation of the programme.