Neil Walker

Background: Long-term (previously termed chronic) depression is associated with significant personal, social and economic consequences often resulting in a poor quality of life for individuals. Effective treatments that improve quality of life for individuals with chronic depression remain limited. DIALOG+, a solution-focused and person-centred intervention, guided by a tablet-based application, was developed to address these challenges. Initially proven to be effective in handling psychotic disorders, this study adapted and evaluated DIALOG+ for individuals with chronic depression. Objectives: The research aimed to adapt and assess the feasibility, clinical and cost-effectiveness of DIALOG+ for improving quality of life, reducing depression severity and enhancing treatment satisfaction among individuals with chronic depression. Setting: The study was conducted across nine National Health Service sites in England, encompassing both urban and rural settings. Participants were recruited from outpatient Community Mental Health Teams, including primary care services, such as increasing access to psychological therapies, ensuring diverse sociodemographic characteristics and clinical contexts. Clinicians from varied professional backgrounds, including mental health nurses, psychiatrists and social workers, were trained to deliver the intervention. Design: The study comprised multiple interlinked work packages: Systematic review: existing recruitment and retention strategies for trials with individuals with depression. Focus groups and pilot study: to adapt the intervention. Small-scale cluster randomised controlled trial: testing feasibility of the intervention and trial processes. Large multisite pragmatic cluster randomised controlled trial: including a nested qualitative process evaluation and economic evaluation. Training and implementation study: evaluating feasibility and applicability within different clinical services. A total of 366 participants with chronic depression were included. Patients were clustered by clinician and clusters randomised 1 : 1 to receive DIALOG+ or an active control (treatment as usual with DIALOG scale completion). Participants were assessed at baseline, 3, 6 and 12 months. The primary outcome was subjective quality of life, measured by the Manchester Short Assessment of Quality of Life at 12 months. Secondary outcomes included depression severity (Montgomery–Åsberg Depression Rating Scale, Beck Depression Inventory-II), treatment satisfaction (Client Satisfaction Questionnaire-8) and health-related quality of life (EuroQol-5 Dimensions, five-level version). Economic evaluation was conducted from National Health Service and Personal Social Services perspectives. Process evaluation involved implementation data and interviews with participants and clinicians to assess intervention experience. Results: The systematic review highlighted the overall poor quality of reporting for existing trials of psychosocial intervention, with many trials failing to outline information on recruitment and retention. It was demonstrated that the intervention was feasible and acceptable to individuals with chronic depression during the feasibility and pilot work. Although the intervention remained unchanged, feedback from the initial phases of the project, alongside lived experience input led to changes in intervention training, which included the addition of case vignettes specific to long-term depression. Within the cluster randomised controlled trial, at 12 months, the DIALOG+ group exhibited a borderline significant improvement in Manchester Short Assessment of Quality of Life scores compared to the control group (adjusted mean difference: 0.18, p = 0.05). This equated to an average improvement of 1 point on 2 of the 12 Manchester Short Assessment of Quality of Life domains. There were no significant differences in any other outcome at 6 and 12 months. However, longitudinal analysis demonstrated significant reductions in Montgomery–Åsberg Depression Rating Scale and Beck Depression Inventory-II scores in the DIALOG+ group at 12 months ( p < 0.01), and participants reported better coping strategies and resilience in managing depressive symptoms. The intervention was associated with an incremental cost-effectiveness ratio of £4749 per quality-adjusted life-year gained. Probabilities of cost-effectiveness were 79.8% at a willingness-to-pay threshold of £20,000/quality-adjusted life-year and 87% at £30,000/quality-adjusted life-year. Despite high retention rates (73% at 12 months), challenges included attrition due to COVID-19 disruptions, with whole clusters lost during early lockdown phases. Fidelity to the intervention protocol varied, with just under a third of participants receiving fewer than three sessions (the minimum recommended dose). Nonetheless, the observed treatment effects were robust across varying levels of engagement. Findings from the process evaluation were increased satisfaction with care, improved therapeutic relationships and a greater sense of empowerment. However, some participants noted challenges with the structured nature of the intervention and the use of technology. This was mirrored by the clinician experience, which found DIALOG+ easy to integrate into routine care and appreciated its structured, patient-centred approach. Barriers included variability in implementation fidelity and technological challenges, particularly during remote delivery. Limitations: Key challenges across the programme included: (1) disruption from the COVID-19 pandemic, leading to adaptations in delivery methods and pauses in recruitment; (2) implementation variability, with some clinicians requiring additional training to maintain fidelity within the cluster randomised controlled trial; and (3) attrition and missing data, particularly in measures for economic evaluation, which necessitated the use of multiple imputation for some analyses. Conclusions: The DIALOG+ demonstrated small but clinically meaningful improvements in quality of life and reductions in depression severity for individuals with chronic depression. While the improvement in Manchester Short Assessment of Quality of Life scores was very modest, it represents a potential gain for a population with long-term difficulties and low baseline quality of life. The probabilities of the intervention being cost-effective in comparison to active control at the National Institute for Health and Care Excellence recommended willingness-to-pay thresholds were high. The intervention was also associated with high patient and clinician satisfaction. These findings support the wider implementation of DIALOG+ in routine mental health care, with adaptations for remote delivery and ongoing support for clinicians. Future directions: Further research is needed to explore the long-term impacts of DIALOG+ on quality of life and depression severity. Peer-delivered models and strategies to enhance engagement with the intervention may strengthen its effectiveness and scalability. Trial registration: This trial is registered as ISRCTN16864442. The definitive cRCT was registered as ISRCTN11301686. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research Programme (NIHR award ref: RP-PG-0615-20010) and is published in full in Programme Grants for Applied Research ; Vol. 14, No. 20. See the NIHR Funding and Awards website for further award information.

Background: FLO-ELA is a multi-centre, parallel-group, open-label, randomised controlled trial (RCT) looking at the effect of minimally invasive cardiac output monitoring in the management of patients aged 50 years and above undergoing emergency gastrointestinal surgery. The primary outcome is days alive and out of hospital within 90 days of randomisation (DAOH-90). This article describes the statistical analysis plan (SAP) for this trial. The estimand and analytical approach presented here may be appropriate for clinical trials in a similar setting (critical care surgery). Methods and design: FLO-ELA is a superiority trial, incorporating an early-stage pilot phase, conducted at 63 UK hospitals. Participants are randomised on a 1:1 basis to the intervention or control group using a minimisation algorithm which balances on the following two factors (i) age, split into 3 groups, and (ii) American Society of Anesthesiologists (ASA) category, 5 categories on an ordinal scale reflecting participants’ baseline co-morbidities. In this SAP, we define the estimands and strategies for handling intercurrent events for each study outcome, then give a detailed description of planned analyses including general analytical principles, analytical framework for primary, secondary and process measure outcomes, approach to missing data and supplementary analyses looking at heterogeneity in treatment effect between key subgroups and potential differences in outcomes pre and post onset of Covid pandemic in the UK. Trial registration: ISRCTN 14729158. Registered on 02 May 2017.

Background: Following vitamin D₃ oral administration, attained serum concentrations of its metabolite 25-hydroxyvitamin D₃ (25(OH)D₃) are variable among children. Methods: We developed physiologically based pharmacokinetic (PBPK) modelling using annually measured serum 25(OH)D₃ concentrations in 77 Cape Town schoolchildren aged 6–11 years who received weekly oral doses of 10,000 IU vitamin D₃ for 3 years during a clinical trial (Δ25(OH)D = 32.2 nmol/L, 95% CI: [−3.2, 65.8] nmol/L). Simulations were performed to test the model on 463 other participants in the same trial, and in a cohort of 1756 Mongolian schoolchildren aged 6–11 years who received weekly oral doses of 14,000 IU vitamin D₃ for 3 years in another trial. Results: The best model attributed most of the variability in post-supplementation 25(OH)D₃ concentrations to hepatic clearance and covariates including weight (ΔAIC = −21) and ZBMI (body mass index Z-score, ΔAIC = −34). For 463 other children from the Cape Town trial (Δ25(OH)D = 25.8 nmol/L, 95% CI: [8.3, 47.2] nmol/L), mean estimation error was 5.3 nmol/L, and 76.7% of observations were within the 95% prediction intervals. Our simulation supported the previous proposal that serum 25(OH)D₃ should exceed 50 nmol/L among 97.5% of European children at 24.4 μg/day vitamin D₃ dosing. At a higher weekly dose (14,000 IU), the Mongolian children demonstrated a higher average increase in serum 25(OH)D₃ (40.6 [−2.9, 88.9] nmol/L) but were overestimated by the model. Conclusion: We developed the first PBPK model to successfully predict the long-term serum 25(OH)D₃ increases in healthy schoolchildren in Cape Town who received orally administered vitamin D₃ and exhibited higher relative increases than Mongolian children.

Background: Following vitamin D3 oral administration, attained serum concentrations of its metabolite 25-hydroxyvitamin D3 (25(OH)D3) are variable among children. Methods: We developed physiologically-based pharmacokinetic (PBPK) modelling using annually measured serum 25(OH)D3 concentrations in 77 Cape Town schoolchildren aged 6-11 years who received weekly oral doses of 10,000 IU vitamin D3 for 3 years during a clinical trial. Simulations were performed to test the model on 463 other participants in the same trial, and in a cohort of 1871 Mongolian schoolchildren aged 6-14 years who received weekly oral doses of 14,000 IU vitamin D3 for 3 years in another trial. Results: The best model attributed most of the variability in post-supplementation 25(OH)D3 concentrations to hepatic clearance and covariates including weight (ΔAIC=-21) and ZBMI (body mass index Z-score, ΔAIC=-34). For 463 other children from the same Cape Town trial (mean 25.8 nmol/L, 95% CI: [8.3-47.2] nmol/L), the mean estimation error was 5.3 nmol/L, and 76.7% of observations were within the 95% prediction intervals. Our simulation supported the previous proposal that serum 25(OH)D3 should exceed 50 nmol/L among 97.5% of European children at 24.4 μg/day vitamin D3 dosing. Despite a higher weekly dose (14,000 IU), the Mongolian children demonstrated a smaller average increase in serum 25(OH)D3 (23.3 [-24.5, 83.1] nmol/L), and were overestimated by the model. Conclusion: We developed the first PBPK model to successfully predict the long-term serum 25(OH)D3 increases in healthy schoolchildren in Cape Town who received orally administered vitamin D3 and exhibited higher increases than Mongolian children.

Randomized controlled trials (RCTs) to determine the influence of vitamin D on BMC and fracture risk in children of Black African ancestry are lacking. We conducted a sub-study (n = 450) nested within a phase 3 RCT of weekly oral supplementation with 10 000 IU vitamin D₃ vs placebo for 3 yr in HIV-uninfected Cape Town schoolchildren aged 6–11 yr. Outcomes were BMC at the whole body less head (WBLH) and LS and serum 25-hydroxyvitamin D₃ (25(OH)D₃), PTH, alkaline phosphatase, C-terminal telopeptide, and PINP. Incidence of fractures was a secondary outcome of the main trial (n = 1682). At baseline, mean serum 25(OH)D₃ concentration was 70.0 nmol/L (SD 13.5), and 5.8% of participants had serum 25(OH)D₃ concentrations 3 concentrations were higher for participants allocated to vitamin D vs placebo (adjusted mean difference [aMD] 39.9 nmol/L, 95% CI, 36.1 to 43.6) and serum PTH concentrations were lower (aMD −0.55 pmol/L, 95% CI, −0.94 to −0.17). However, no interarm differences were seen for WBLH BMC (aMD −8.0 g, 95% CI, −30.7 to 14.7) or LS BMC (aMD −0.3 g, 95% CI, −1.3 to 0.8) or serum concentrations of bone turnover markers. Fractures were rare among participants in the main trial randomized to vitamin D vs placebo (7/755 vs 10/758 attending at least 1 follow-up; adjusted odds ratio 0.70, 95% CI, 0.27 to 1.85). In conclusion, a 3-yr course of weekly oral vitamin D supplementation elevated serum 25(OH)D₃ concentrations and suppressed serum PTH concentrations in HIV-uninfected South African schoolchildren of Black African ancestry but did not influence BMC or serum concentrations of bone turnover markers. Fracture incidence was low, limiting power to detect an effect of vitamin D on this outcome. Vitamin D—the “sunshine vitamin”—is essential for helping the body to absorb calcium from the diet, which is laid down in bone to improve its strength. There is a lack of clinical trials testing whether vitamin D supplements can improve bone content of calcium and other minerals, or reduce risk of bone fractures (broken bones) in children of Black African ancestry. We therefore conducted such a study, recruiting 1682 schoolchildren aged 6–11 yr living in Cape Town, South Africa. We found that a weekly dose of 10 000 international units (250 micrograms) of vitamin D₃, given by mouth for 3 yr, was effective in boosting vitamin D levels in trial participants who received it. However, this did not have any effect on bone content of calcium and other minerals. Relatively few children experienced a broken bone during the study, so we were unable to say with confidence whether or not vitamin D supplements might affect this outcome.

Promoting online peer support beyond the informal sector to statutory health services requires ethical considerations and evidence-based knowledge about its impact on patients, health care professionals, and the wider health care system. Evidence on the effectiveness of digital interventions in primary care is sparse, and definitive guidance is lacking on the ethical concerns arising from the use of social media as a means for health-related interventions and research. Existing literature examining ethical issues with digital interventions in health care mainly focuses on apps, electronic health records, wearables, and telephone or video consultations, without necessarily covering digital social interventions, and does not always account for primary care settings specifically. Here we address the ethical and information governance aspects of undertaking research on the promotion of online peer support to patients by primary care clinicians, related to medical and public health ethics.

Introduction: Postoperative morbidity and mortality in patients undergoing major emergency gastrointestinal surgery are a major burden on healthcare systems. Optimal management of perioperative intravenous fluids may reduce mortality rates and improve outcomes from surgery. Previous small trials of cardiac-output guided haemodynamic therapy algorithms in patients undergoing gastrointestinal surgery have suggested this intervention results in reduced complications and a modest reduction in mortality. However, this existing evidence is based mainly on elective (planned) surgery, with little evaluation in the emergency setting. There are fundamental clinical and pathophysiological differences between the planned and emergency surgical setting which may influence the effects of this intervention. A large definitive trial in emergency surgery is needed to confirm or refute the potential benefits observed in elective surgery and to inform widespread clinical practice. Methods: The FLO-ELA trial is a multi-centre, parallel-group, open, randomised controlled trial. 3138 patients aged 50 and over undergoing major emergency gastrointestinal surgery will be randomly allocated in a 1:1 ratio using minimisation to minimally invasive cardiac output monitoring to guide protocolised administration of intra-venous fluid, or usual care without cardiac output monitoring. The trial intervention will be carried out during surgery and for up to 6 h postoperatively. The trial is funded through an efficient design call by the National Institute for Health and Care Research Health Technology Assessment (NIHR HTA) programme and uses existing routinely collected datasets for the majority of data collection. The primary outcome is the number of days alive and out of hospital within 90 days of randomisation. Participants and those delivering the intervention will not be blinded to treatment allocation. Participant recruitment started in September 2017 with a 1-year internal pilot phase and is ongoing at the time of publication. Discussion: This will be the largest contemporary randomised trial examining the effectiveness of perioperative cardiac output-guided haemodynamic therapy in patients undergoing major emergency gastrointestinal surgery. The multi-centre design and broad inclusion criteria support the external validity of the trial. Although the clinical teams delivering the trial interventions will not be blinded, significant trial outcome measures are objective and not subject to detection bias. Trial registration: ISRCTN 14729158. Registered on 02 May 2017.

UNSTRUCTURED Promoting online peer support beyond the informal sector to statutory health services requires ethical considerations and evidence-based knowledge about its impact on patients, health care professionals, and the wider health care system. Evidence on the effectiveness of digital interventions in primary care is sparse, and definitive guidance is lacking on the ethical concerns arising from the use of social media as a means for health-related interventions and research. Existing literature examining ethical issues with digital interventions in health care mainly focuses on apps, electronic health records, wearables, and telephone or video consultations, without necessarily covering digital social interventions, and does not always account for primary care settings specifically. Here we address the ethical and information governance aspects of undertaking research on the promotion of online peer support to patients by primary care clinicians, related to medical and public health ethics.

Background: Many with an acute depressive disorder go on to develop chronic depression, despite ongoing care. There are few specifically designed interventions to treat chronic depression. DIALOG+, a technology-assisted intervention based on the principles of solution-focused therapy, may be beneficial. It has been shown to be effective as a treatment for patients with psychotic disorders, especially in regards to increasing quality of life. DIALOG+ was designed to be flexibly applied and not diagnosis-specific, aiming to structure communication and generate a personally-tailored care plan. This cluster randomised controlled trial (RCT) is part of a programme of research to adapt and test DIALOG+ for patients with chronic depression. Methods: Patients will be eligible for the trial, if they have exhibited symptoms of depression or non-psychotic low mood for at least 2 years, have regular contact with a clinician and have a low subjective quality of life and moderate depressive symptoms. Clinicians, who routinely see eligible patients, will be recruited from a number of sites across NHS England. Clusters will have between 1 and 6 patients per clinician and will be randomised in a 1:1 ratio to either the intervention (DIALOG+) or active control group (treatment as usual + DIALOG scale). Clinicians in the intervention group are trained and asked to deliver the intervention regularly for 12 months. Active control participants receive treatment as usual and are asked to rate their satisfaction with areas of life and treatment on the DIALOG scale at the end of the clinical session. Approximately 112 clinician clusters will be recruited to reach a total patient sample size of 376. Clinical and social outcomes including costs are assessed at baseline and 3, 6 and 12 months post randomisation. The primary outcome will be subjective quality of life at 12 months. Discussion: This definitive multi-site, cluster RCT aims to evaluate the clinical- and cost-effectiveness of DIALOG+ for people with chronic depression. If shown to be effective for this patient population it could be used to improve outcomes of mental health care on a larger scale, ensuring that patients with complex and co-morbid diagnoses can benefit. Trial registration: ISRCTN11301686. Registered on 13 Jun 2019.

Vitamin D deficiency (25-hydroxyvitamin D[25(OH)D] p < 0.001). However, no association between participants with hyperparathyroidism (PTH >6.9 pmol/L) and vitamin D deficiency was seen (p = 0.42). In conclusion, we report that season is the major determinant of vitamin D status among Cape Town primary schoolchildren, with prevalence of vitamin D deficiency ranging from 1.4% in January–March to 22.8% in July–September.