Evaluating the feasibility of complex interventions in mental health services: standardised measure and reporting guidelines

Aims: To develop a) an empirically-based standardised measure of the feasibility of complex interventions for use within mental health services and b) reporting guidelines to facilitate feasibility assessment. Method: A focussed narrative review of studies assessing implementation blocks and enablers was conducted with thematic analysis and vote counting used to determine candidate items for the measure. Twenty purposively sampled studies (15 trial reports, 5 protocols) were included in the psychometric evaluation, spanning different interventions types. Cohen’s Kappa was calculated for inter-rater reliability and test-retest reliability. Results: 95 influences on implementation were identified from 299 reviewed references. The final measure - Structured Assessment of Feasibility (SAFE) - comprises 16 items rated on a Likert scale. SAFE demonstrated excellent inter-rater (kappa 0.84, 95% CI 0.79 - 0.89) and test re-test reliability (kappa 0.89, 95% CI 0.85 - 0.93). Cost information and training time were the two influences least likely to be reported in intervention papers. SAFE Reporting Guidelines include 16 items organised into 3 categories (Intervention, Resource consequences, Evaluation). Conclusion: SAFE is a novel approach to evaluating interventions, and supplements efficacy and health economic evidence. SAFE Reporting Guidelines will allow feasibility of an intervention to be systematically assessed

VprBP/DCAF1 Regulates the Degradation and Nonproteolytic Activation of the Cell Cycle Transcription Factor FoxM1

The oncogenic transcription factor FoxM1 plays a vital role in cell cycle progression, is activated in numerous human malignancies, and is linked to chromosome instability. We characterize here a cullin 4-based E3 ubiquitin ligase and its substrate receptor, VprBP/DCAF1 (CRL4VprBP), which we show regulate FoxM1 ubiquitylation and degradation. Paradoxically, we also found that the substrate receptor VprBP is a potent FoxM1 activator. VprBP depletion reduces expression of FoxM1 target genes and impairs mitotic entry, whereas ectopic VprBP expression strongly activates a FoxM1 transcriptional reporter. VprBP binding to CRL4 is reduced during mitosis, and our data suggest that VprBP activation of FoxM1 is ligase independent. This implies a nonproteolytic activation mechanism that is reminiscent of, yet distinct from, the ubiquitin-dependent transactivation of the oncoprotein Myc by other E3s. Significantly, VprBP protein levels were upregulated in high-grade serous ovarian patient tumors, where the FoxM1 signature is amplified. These data suggest that FoxM1 abundance and activity are controlled by VprBP and highlight the functional repurposing of E3 ligase substrate receptors independent of the ubiquitin system

Engineering hemoglobin to enable homogenous PEGylation without modifying protein functionality

In order to infuse hemoglobin into the vasculature as an oxygen therapeutic or blood substitute, it is necessary to increase the size of the molecule to enhance vascular retention. This aim can be achieved by PEGylation. However, using non-specific conjugation methods creates heterogenous mixtures and alters protein function. Site-specific PEGylation at the naturally reactive thiol on human hemoglobin (βCys93) alters hemoglobin oxygen binding affinity and increases its autooxidation rate. In order to avoid this issue, new reactive thiol residues were therefore engineered at sites distant to the heme group and the α/β dimer/dimer interface. The two mutants were βCys93Ala/αAla19Cys and βCys93Ala/βAla13Cys. Gel electrophoresis, size exclusion chromatography and mass spectrometry revealed efficient PEGylation at both αAla19Cys and βAla13Cys, with over 80% of the thiols PEGylated in the case of αAla19Cys. For both mutants there was no significant effect on the oxygen affinity or the cooperativity of oxygen binding. PEGylation at αAla19Cys had the additional benefit of decreasing the rates of autoxidation and heme release, properties that have been considered contributory factors to the adverse clinical side effects exhibited by previous hemoglobin based oxygen carriers. PEGylation at αAla19Cys may therefore be a useful component of future clinical products

Non-randomised feasibility study testing a primary care intervention to promote engagement in an online health community for adults with troublesome asthma: protocol

Introduction: In the UK, approximately 4.3 million adults have asthma, with one-third experiencing poor asthma control, affecting their quality of life, and increasing their healthcare use. Interventions promoting emotional/behavioural self-management can improve asthma control and reduce comorbidities and mortality. Integration of online peer support into primary care services to foster self-management is a novel strategy. We aim to co-design and evaluate an intervention for primary care clinicians to promote engagement with an asthma online health community (OHC). Our protocol describes a ‘survey leading to a trial’ design as part of a mixed-methods, non-randomised feasibility study to test the feasibility and acceptability of the intervention. Methods and analysis: Adults on the asthma registers of six London general practices (~3000 patients) will be invited to an online survey, via text messages. The survey will collect data on attitudes towards seeking online peer support, asthma control, anxiety, depression, quality of life, information on the network of people providing support with asthma and demographics. Regression analyses of the survey data will identify correlates/predictors of attitudes/receptiveness towards online peer support. Patients with troublesome asthma, who (in the survey) expressed interest in online peer support, will be invited to receive the intervention, aiming to reach a recruitment target of 50 patients. Intervention will involve a one-off, face-to-face consultation with a practice clinician to introduce online peer support, sign patients up to an established asthma OHC, and encourage OHC engagement. Outcome measures will be collected at baseline and 3 months post intervention and analysed with primary care and OHC engagement data. Recruitment, intervention uptake, retention, collection of outcomes, and OHC engagement will be assessed. Interviews with clinicians and patients will explore experiences of the intervention. Ethics and dissemination: Ethical approval was obtained from a National Health Service Research Ethics Committee (reference: 22/NE/0182). Written consent will be obtained before intervention receipt and interview participation. Findings will be shared via dissemination to general practices, conference presentations and peer-reviewed publications. Trial registration number: NCT05829265

Isolation of Angola-like Marburg virus from Egyptian rousette bats from West Africa.

Marburg virus (MARV) causes sporadic outbreaks of severe Marburg virus disease (MVD). Most MVD outbreaks originated in East Africa and field studies in East Africa, South Africa, Zambia, and Gabon identified the Egyptian rousette bat (ERB; Rousettus aegyptiacus) as a natural reservoir. However, the largest recorded MVD outbreak with the highest case-fatality ratio happened in 2005 in Angola, where direct spillover from bats was not  shown. Here, collaborative studies by the Centers for Disease Control and Prevention, Njala University, University of California, Davis USAID-PREDICT, and the University of Makeni identify MARV circulating in ERBs in Sierra Leone. PCR, antibody and virus isolation data from 1755 bats of 42 species shows active MARV infection in approximately 2.5% of ERBs. Phylogenetic analysis identifies MARVs that are similar to the Angola strain. These results provide evidence of MARV circulation in West Africa and demonstrate the value of pathogen surveillance to identify previously undetected threats

Service user experiences of REFOCUS: a process evaluation of a pro-recovery complex intervention

Purpose: Policy is increasingly focused on implementing a recovery-orientation within mental health services, yet the subjective experience of individuals receiving a pro-recovery intervention is under-studied. The aim of this study was to explore the service user experience of receiving a complex, pro-recovery intervention (REFOCUS), which aimed to encourage the use of recovery-supporting tools and support recovery-promoting relationships. Methods: Interviews (n=24) and two focus groups (n=13) were conducted as part of a process evaluation and included purposive sample of service users who received the complex, pro-recovery intervention within the REFOCUS randomised controlled trial (ISRCTN02507940). Thematic analysis was used to analyse the data. Results: Participants reported that the intervention supported the development of an open and collaborative relationship with staff, with new conversations around values, strengths and goals. This was experienced as hope-inspiring and empowering. However, others described how the recovery tools were used without context, meaning participants were unclear of their purpose and did not see their benefit. During the interviews, some individuals struggled to report any new tasks or conversations occurring during the intervention. Conclusion: Recovery-supporting tools can support the development of a recovery-promoting relationship, which can contribute to positive outcomes for individuals. The tools should be used, in a collaborative and flexible manner. Information exchanged around values, strengths and goals should be used in care-planning. As some service users struggled to report their experience of the intervention, alternative evaluation approaches need to be considered if the service user experience is to be fully captured

Case identification of depression in patients with chronic physical health problems: a diagnostic accuracy meta-analysis of 113 studies.

Depression is more likely in patients with chronic physical illness, and is associated with increased rates of disability and mortality. Effective treatment of depression may reduce morbidity and mortality. The use of two stem questions for case finding in diabetes and coronary heart disease is advocated in the Quality and Outcomes Framework, and has become normalised into primary care

Possibilities for the future of global mental health: a scenario planning approach.

BACKGROUND: Global mental health is a widely used term describing initiatives in policies, research and practice to improve the mental health of people worldwide. It has been gaining momentum over the last 10 years, reflected in increasing funding opportunities, training programmes, and publications. In light of the rising importance of global mental health and the various uncertainties about its future directions, this paper explores what the future may hold for global mental health in 30 years' time. METHOD: A scenario planning method was used, involving a workshop with experts from four continents and a range of backgrounds, including clinical and academic psychiatry, psychology, art and music therapy, service user advisory role, funder of global health research and post-graduate students. RESULTS: Six distinct scenarios that describe potential future situations were developed: universal standards for care; worldwide coordination of research; making use of diversity; focus on social factors; globalised care through technology; mental health as a currency in global politics. CONCLUSIONS: These scenarios consider different social, economic, scientific and technological drivers and focus on distinct aspects. Some reflect a global application of possible trends in mental health, whilst others apply general global developments to mental health care. They are not fixed forecasts, but instead may help to promote discussion and debate about further developments and decisions

Staff understanding of recovery-orientated mental health practice: a systematic review and narrative synthesis

Background: Mental health policy is for staff to transform their practice towards a recovery orientation. Staff understanding of recovery-orientated practice will influence the implementation of this policy. The aim of this study was to conduct a systematic review and narrative synthesis of empirical studies identifying clinician and manager conceptualisations of recovery-orientated practice. Methods: A systematic review of empirical primary research was conducted. Data sources were online databases (n = 8), journal table of contents (n = 5), internet, expert consultation (n = 13), reference lists of included studies and references to included studies. Narrative synthesis was used to integrate the findings. Results: A total of 10,125 studies were screened, 245 full papers were retrieved, and 22 were included (participants, n = 1163). The following three conceptualisations of recovery-orientated practice were identified: clinical recovery, personal recovery and service-defined recovery. Service-defined recovery is a new conceptualisation which translates recovery into practice according to the goals and financial needs of the organisation. Conclusions: Organisational priorities influence staff understanding of recovery support. This influence is leading to the emergence of an additional meaning of recovery. The impact of service-led approaches to operationalising recovery-orientated practice has not been evaluated. Trial Registration: The protocol for the review was pre-registered (PROSPERO 2013: CRD42013005942)

Genome-Wide Divergence of DNA Methylation Marks in Cerebral and Cerebellar Cortices

Emerging evidence suggests that DNA methylation plays an expansive role in the central nervous system (CNS). Large-scale whole genome DNA methylation profiling of the normal human brain offers tremendous potential in understanding the role of DNA methylation in brain development and function.Using methylation-sensitive SNP chip analysis (MSNP), we performed whole genome DNA methylation profiling of the prefrontal, occipital, and temporal regions of cerebral cortex, as well as cerebellum. These data provide an unbiased representation of CpG sites comprising 377,509 CpG dinucleotides within both the genic and intergenic euchromatic region of the genome. Our large-scale genome DNA methylation profiling reveals that the prefrontal, occipital, and temporal regions of the cerebral cortex compared to cerebellum have markedly different DNA methylation signatures, with the cerebral cortex being hypermethylated and cerebellum being hypomethylated. Such differences were observed in distinct genomic regions, including genes involved in CNS function. The MSNP data were validated for a subset of these genes, by performing bisulfite cloning and sequencing and confirming that prefrontal, occipital, and temporal cortices are significantly more methylated as compared to the cerebellum.These findings are consistent with known developmental differences in nucleosome repeat lengths in cerebral and cerebellar cortices, with cerebrum exhibiting shorter repeat lengths than cerebellum. Our observed differences in DNA methylation profiles in these regions underscores the potential role of DNA methylation in chromatin structure and organization in CNS, reflecting functional specialization within cortical regions