United Kingdom Medical Research Council Research Articles

Modeling the relative influence of socio-demographic variables on post-acute COVID-19 quality of life.

Post-acute sequelae of SARS-CoV-2, referred to as "long COVID", are a globally pervasive threat. While their many clinical determinants are commonly considered, their plausible social correlates are often overlooked. Here, we use data from a multinational prospective cohort study to compare social and clinical predictors of differences in quality of life with long COVID. We further measure the extent to which clinical intermediates may explain relationships between social variables and quality of life with long COVID. Beyond age, neuropsychological and rheumatological comorbidities, educational attainment, employment status, and female sex were important predictors of long COVID-associated quality of life days (long COVID QALDs). Furthermore, most of their associations could not be attributed to key long COVID-predicting comorbidities. In Norway, 90% (95% CI: 77%, 100%) of the adjusted association between belonging to the top two quintiles of educational attainment and long COVID QALDs was not explained by these clinical intermediates. The same was true for 86% (73%, 100%) and 93% (80%,100%) of the adjusted association between full-time employment and long COVID QALDs in the United Kingdom (UK) and Russia. Additionally, 77% (46%,100%) and 73% (52%, 94%) of the adjusted associations between female sex and long COVID QALDs in Norway and the UK were unexplained by the clinical mediators. Our findings highlight that socio-economic proxies and sex are key predictors of long COVID QALDs and that other (non-clinical) mechanisms drive their observed relationships. Importantly, we outline a multi-method, adaptable causal approach for evaluating the isolated contributions of social disparities to experiences with long COVID. UK Foreign, Commonwealth and Development Office; Wellcome Trust; Bill & Melinda Gates Foundation; Oxford COVID-19 Research Response Funding; UK National Institute for Health and Care Research; UK Medical Research Council; Public Health England; Liverpool Experimental Cancer Medicine Centre; Research Council of Norway; Vivaldi Invest A/S; South Eastern Norway Health Authority.

Process evaluations for the scale-up of complex interventions – A scoping review

Background: Process evaluation (PE) is an essential part of testing and adapting complex health interventions (CHIs) and involves evaluating what is implemented (and how), mechanisms of change, and how context affects implementation and health outcomes. To address complex health needs, the focus is on developing new CHIs, rather than on adapting and scaling up existing interventions to promote stronger integration, increased population coverage, or comprehensiveness. Therefore, more attention is needed to process evaluations conducted during the scale-up process as they may have distinctive features, stakeholders, or objectives. We aim to describe the current practice of process evaluations conducted during the scale-up of CHIs.
 Who is it for? The results of this review are relevant to all stakeholders involved in the scale-up of CHI.
 Who did you involve and engage with? All authors of this review have been involved in the scale-up of integrated care across multiple contexts.
 What did you do? Eight primary data sources (PubMed, Embase, CENTRAL, Web of Science, CINAHL, Global Health, Scielo and African Index Medicus) and grey literature were searched. Studies were screened following gold standard review procedures. Study demographics, scale-up dimensions (i.e., integration, coverage, comprehensiveness), features of the complex intervention and PE were charted. Process evaluation was further assessed in terms of stakeholders involved and proposed objectives of the PE. For this review, the United Kingdom Medical Research Council’s (MRC) definition of PE was adjusted in terms of “scale-up” instead of “delivery and functioning.”
 What results did you get? We identified 10303 unique records of which 34 were included after abstract (n=223) and full-text (n=91) screening. Twenty of the 34 studies were conducted in one or more low-middle income countries (LMICs). Most CHIs studied looked at scale-up of interventions for patient empowerment through digital health, strengthening primary care, or person-centered care models. In the absence of a guiding framework for PEs in the context of scale-up, a variety of other frameworks were often used including the RE-AIM framework (n=5), Consolidated Framework for Implementation Research (n=3), or MRC framework for the PE of CHIs (n=1). Some of these frameworks were subsequently adapted to facilitate unexpected pathways to impact or interactions with contextual factors to emerge as well. Interestingly, in 12 out of 34 studies, beneficiaries (e.g., patients) were not stakeholders in the PE.
 What is the learning for the international audience? Process evaluations specific to the process of scaling up is advertently different from implementing a CHI. In the absence of a gold standard framework to guide PE during scale-up, the development of such guidance could be considered.
 What are the next steps? We plan to seek further engagement, including with those funded under the “Global Alliance of Chronic Disease” scale-up program, to determine the value and content of a process evaluation framework for scale-up.

Analyzing the value of IONM as a complex intervention: The gap between published evidence and clinical practice

ObjectiveIntraoperative neurophysiological monitoring (IONM) was investigated as a complex intervention (CI) as defined by the United Kingdom Medical Research Council (MRC) in published studies to identify challenges and solutions in estimating IONM’s effects on postoperative outcomes. MethodsA scoping review to April 2022 of the influence of setting on what was implemented as IONM and how it influenced postoperative outcomes was performed for studies that compared IONM to no IONM cohorts. IONM complexity was assessed with the iCAT_SR tool. Causal graphs were used to represent this complexity. ResultsIONM implementation depended on the surgical procedure, institution and/or surgeon. “How” IONM influenced neurologic outcomes was attributed to surgeon or institutional experience with the surgical procedure, surgeon or institutional experience with IONM, co-interventions in addition to IONM, models of IONM service delivery and individual characteristics of the IONM provider. Indirect effects of IONM mediated by extent of tumor resection, surgical approach, changes in operative procedure, shorter operative time, and duration of aneurysm clipping were also described. There were no quantitative estimates of the relative contribution of these indirect effects to total IONM effects on outcomes. ConclusionsIONM is a complex intervention whose evaluation is more challenging than that of a simple intervention. Its implementation and largely indirect effects depend on specific settings that are usefully represented in causal graphs. SignificanceIONM evaluation as a complex intervention aided by causal graphs and multivariable analysis could provide a valuable framework for future study design and assessments of IONM effectiveness in different settings.

Causal relationship between type 1 diabetes mellitus and six high-frequency infectious diseases: A two-sample mendelian randomization study.

Type 1 diabetes mellitus (T1DM) is associated with different types of infections; however, studies on the causal relationship between T1DM and infectious diseases are lacking. Therefore, our study aimed to explore the causalities between T1DM and six high-frequency infections using a Mendelian randomization (MR) approach. Two-sample MR studies were conducted to explore the causalities between T1DM and six high-frequency infections: sepsis, acute lower respiratory infections (ALRIs), intestinal infections (IIs), infections of the genitourinary tract (GUTIs) in pregnancy, infections of the skin and subcutaneous tissues (SSTIs), and urinary tract infections (UTIs). Data on summary statistics for T1DM and infections were obtained from the European Bioinformatics Institute database, the United Kingdom Biobank, FinnGen biobank, and Medical Research Council Integrative Epidemiology Unit. All data obtained for summary statistics were from European countries. The inverse-variance weighted (IVW) method was employed as the main analysis. Considering the multiple comparisons, statistical significance was set at p< 0.008. If univariate MR analyses found a significant causal association, multivariable MR (MVMR) analyses were performed to adjust body mass index (BMI) and glycated hemoglobin (HbA1c). MVMR-IVW was performed as the primary analysis, and the least absolute shrinkage and selection operator (LASSO) regression and MVMR-Robust were performed as complementary analyses. MR analysis showed that susceptibility to IIs increased in patients with T1DM by 6.09% using the IVW-fixed method [odds ratio (OR)=1.0609; 95% confidence interval (CI): 1.0281-1.0947, p=0.0002]. Results were still significant after multiple testing. Sensitivity analyses did not show any significant horizontal pleiotropy or heterogeneity. After adjusting for BMI and HbA1c, MVMR-IVW (OR=1.0942; 95% CI: 1.0666-1.1224, p<0.0001) showed significant outcomes that were consistent with those of LASSO regression and MVMR-Robust. However, no significant causal relationship was found between T1DM and sepsis susceptibility, ALRI susceptibility, GUTI susceptibility in pregnancy, SSTI susceptibility, and UTI susceptibility. Our MR analysis genetically predicted increased susceptibility to IIs in T1DM. However, no causality between T1DM and sepsis, ALRIs, GUTIs in pregnancy, SSTIs, or UTIs was found. Larger epidemiological and metagenomic studies are required to further investigate the observed associations between the susceptibility of certain infectious diseases with T1DM.

Development of a complex intervention (safe and secure) to support non-western migrant patients with palliative care needs and their families.

International evidence supports the benefits of early use of palliative care, although the best use of services is often under-utilised among Danish migrants. The study aims to develop a theoretically informed, evidence-based intervention to increase support in palliative care service provision among non-western migrant patients with a life-threatening disease and their families in Denmark. The overall approach was guided by the United Kingdom Medical Research Council framework for developing and evaluating complex interventions by involving stakeholders for example patients, family caregivers, and healthcare professionals. The intervention was developed iteratively by incorporating theory and evidence. Evidence was synthesized from a systematic review, semi-structured interviews, and group discussions with patients (n=8), family caregivers (n=11), healthcare professionals (n=10); and three workshops with migrants (n=5), social and healthcare professionals (n=6). The study took place in six different settings in two regions across Denmark. The safe and secure complex intervention is a healthcare professional (e.g. nurse, physiotherapist, or occupational therapist) led patient-centred palliative care intervention at the basic level. The final intervention consists of three components 1. Education and training sessions, 2. Consultations with the healthcare professional, and 3. Coordination of care. This study describes the development of a supportive palliative care intervention for non-western migrant patients with palliative care needs and their families, followed by a transparent and systematic reporting process. A palliative care intervention combining multiple components targeting different stakeholders, is expected that safe and secure is more suitable and well customized in increasing access and use of palliative care services for non-western migrant families in Denmark.

Participatory design application in obesity prevention targeting young adults and adolescents: a mixed-methods systematic scoping review protocol

BackgroundPrevention of obesity is economically and sociologically preferable to treatment, with early intervention key to preventing excess weight gain and obesity. The transition from adolescence to young adulthood is a critical intervention period. An expert-led, top-down model has dominated obesity prevention research and practice with limited success. Participatory design (PD) offers potential in transforming obesity prevention research and practice by delivering bottom-up solutions that young people value and may therefore voluntarily engage with over time. An evidence synthesis of PD application in obesity prevention targeting adolescents and young adults is currently lacking.ObjectivesReport the protocol for a mixed-methods systematic scoping review which aims to integrate and synthesise available evidence on PD application in obesity prevention targeting adolescents and young adults. Specifically, the review will address three research questions:RQ1: How is PD defined in obesity prevention interventions targeting adolescents and young adults?RQ2: To what extent is PD applied in obesity preventions interventions targeting adolescents and young adults?RQ3a: How is the utility of PD evaluated in obesity preventions interventions targeting adolescents and young adults?RQ3b: What is the utility of PD application in obesity prevention interventions targeting adolescents and young adults?MethodsThis mixed-methods systematic scoping review protocol adheres to the PRISMA-P guidelines and is informed by the PRISMA extension for scoping reviews (PRISMA-ScR). The search strategy and eligibility criteria are informed by the sample, phenomenon of interest, design, evaluation, and research type tool. Eligible studies will be peer-reviewed literature published in English, reporting on PD application in obesity prevention interventions (including intervention development, implementation, and/or evaluation) targeting adolescents and young adults (aged 10–35 years). Study designs will include qualitative, quantitative, and mixed methods. The review will comprise a systematic literature search, eligibility screening, data extraction, quality assessment using the Mixed-Methods Appraisal Tool (MMAT), and data analysis using an iterative narrative evidence synthesis approach. Evidence on PD application will be thematically integrated in terms of who was involved, when they were involved, and how and why they were involved. Further thematic analyses will be conducted according to the MATE taxonomy and the United Kingdom Medical Research Council (UK MRC’s) key functions of process evaluations. The MATE taxonomy classifies PD application in terms of methodology, agent of change, training, and engagement. The MRC describes three functions of process evaluations: implementation, mechanisms of impact, and context. Applying both in the evidence synthesis is intended to provide a more complete picture of PD application. Exploratory analyses will be conducted to assess any potential associations between PD application and effectiveness across key outcomes (weight, physical activity, sedentary time, nutrition and dietary habit, mental health, and sleep) reported within intervention evaluations.ConclusionsElucidating PD application is a prerequisite to establishing its utility. Through the location and synthesis of available evidence on PD application in obesity prevention targeting adolescents and young adults, this review will categorise and describe different methods of PD application and explore the utility of PD application including whether any differences may be observed between PD method applied and the effectiveness of obesity prevention interventions. Implications will be delineated from the narrative evidence synthesis to inform future research and advance practice in this context.Systematic review registrationPROSPERO CRD42021268240

Development of a Complex Intervention for Effective Management of Type 2 Diabetes in a Developing Country.

There has been little focus on designing tailored diabetes management strategies in developing countries. The aim of this study is to develop a theory-driven, tailored and context-specific complex intervention for the effective management of type 2 diabetes at a tertiary care setting of a developing country. We conducted interviews and focus groups with patients, health professionals, and policymakers and undertook thematic analysis to identify gaps in diabetes management. The results of our previously completed systematic review informed data collection. We used the United Kingdom Medical Research Council framework to guide the development of the intervention. Results comprised 48 interviews, two focus groups with 11 participants and three co-design panels with 24 participants. We identified a lack of structured type 2 diabetes education, counselling, and collaborative care of type 2 diabetes. Through triangulation of the evidence obtained from data collection, we developed an intervention called VICKY (patient-centred collaborative care and structured diabetes education and counselling) for effective management of type 2 diabetes. VICKY comprised five components: (1) patient-centred collaborative care; (2) referral system for patients across transitions of care between different health professionals of the diabetes care team; (3) tools for the provision of collaborative care and documentation of care; (4) diabetes education and counselling by trained diabetes educators; and (5) contextualised diabetes education curriculum, educational materials, and documentation tools for diabetes education and counselling. Implementation of the intervention may help to promote evidence-based, patient-centred, and contextualised diabetes care for improved patient outcomes in a developing country.

Mortality in HIV and tuberculosis patients following implementation of integrated HIV-TB treatment: Results from an open-label cluster-randomized trial.

SummaryBackgroundHIV-TB treatment integration reduces mortality. Operational implementation of integrated services is challenging. This study assessed the impact of quality improvement (QI) for HIV-TB integration on mortality within primary healthcare (PHC) clinics in South Africa.MethodsAn open-label cluster randomized controlled study was conducted between 2016 and 2018 in 40 rural clinics in South Africa. The study statistician randomized PHC nurse-supervisors 1:1 into 16 clusters (eight nurse-supervisors supporting 20 clinics per arm) to receive QI, supported HIV-TB integration intervention or standard of care (control). Nurse supervisors and clinics under their supervision, based in the study health districts were eligible for inclusion in this study. Nurse supervisors were excluded if their clinics were managed by municipal health (different resource allocation), did not offer co-located antiretroviral therapy (ART) and TB services, services were performed by a single nurse, did not receive non-governmental organisation (NGO) support, patient data was not available for > 50% of attendees. The analysis population consists of all patients newly diagnosed with (i) both TB and HIV (ii) HIV only (among patients previously treated for TB or those who never had TB before) and (iii) TB only (among patients already diagnosed with HIV or those who were never diagnosed with HIV) after QI implementation in the intervention arm, or enrolment in the control arm. Mortality rates was assessed 12 months post enrolment, using unpaired t-tests and cox-proportional hazards model. (Clinicaltrials.gov, NCT02654613, registered 01 June 2015, trial closed).FindingsOverall, 21 379 participants were enrolled between December 2016 and December 2018 in intervention and control arm clinics: 1329 and 841 HIV-TB co-infected (10·2%); 10 799 and 6 611 people living with Human Immunodeficiency Virus (HIV)/ acquired immunodeficiency syndrome (AIDS) (PLWHA) only (81·4%); 1 131 and 668 patients with TB only (8·4%), respectively. Average cluster sizes were 1657 (range 170–5782) and 1015 (range 33–2027) in intervention and control arms. By 12 months, 6529 (68·7%) and 4074 (70·4%) were alive and in care, 568 (6·0%) and 321 (5·6%) had completed TB treatment, 1078 (11·3%) and 694 (12·0%) were lost to follow-up, with 245 and 156 deaths occurring in intervention and control arms, respectively. Mortality rates overall [95% confidence interval (CI)] was 4·5 (3·4–5·9) in intervention arm, and 3·8 (2·6–5·4) per 100 person-years in control arm clusters [mortality rate ratio (MRR): 1·19 (95% CI 0·79–1·80)]. Mortality rates among HIV-TB co-infected patients was 10·1 (6·7–15·3) and 9·8 (5·0–18·9) per 100 person-years, [MRR: 1·04 (95% CI 0·51–2·10)], in intervention and control arm clusters, respectively.InterpretationHIV-TB integration supported by a QI intervention did not reduce mortality in HIV-TB co-infected patients. Demonstrating mortality benefit from health systems process improvements in real-world operational settings remains challenging. Despite the study being potentially underpowered to demonstrate the effect size, integration interventions were implemented using existing facility staff and infrastructure reflecting the real-world context where most patients in similar settings access care, thereby improving generalizability and scalability of study findings.FundingResearch reported in this publication was supported by South African Medical Research Council (SAMRC), and UK Government's Newton Fund through United Kingdom Medical Research Council (UKMRC).

ASHA-Led Community-Based Groups to Support Control of Hypertension in Rural India Are Feasible and Potentially Scalable.

Background: To improve the control of hypertension in low- and middle-income countries, we trialed a community-based group program co-designed with local policy makers to fit within the framework of India's health system. Trained accredited social health activists (ASHAs), delivered the program, in three economically and developmentally diverse settings in rural India. We evaluated the program's implementation and scalability.Methods: Our mixed methods process evaluation was guided by the United Kingdom Medical Research Council guidelines for complex interventions. Meeting attendance reports, as well as blood pressure and weight measures of attendees and adherence to meeting content and use of meeting tools were used to evaluate the implementation process. Thematic analysis of separate focus group discussions with participants and ASHAs as well as meeting reports and participant evaluation were used to investigate the mechanisms of impact.Results: Fifteen ASHAs led 32 community-based groups in three rural settings in the states of Kerala and Andhra Pradesh, Southern India. Overall, the fidelity of intervention delivery was high. Six meetings were delivered over a 3-month period to each of the intervention groups. The mean number of meetings attended by participants at each site varied significantly, with participants in Rishi Valley attending fewer meetings [mean (SD) = 2.83 (1.68)] than participants in West Godavari (Tukeys test, p = 0.009) and Trivandrum (Tukeys test, p < 0.001) and participants in West Godavari [mean (SD) = 3.48 (1.72)] attending significantly fewer meetings than participants in Trivandrum [mean (SD) = 4.29 (1.76), Tukeys test, p < 0.001]. Culturally appropriate intervention resources and the training of ASHAs, and supportive supervision of them during the program were critical enablers to program implementation. Although highly motivated during the implementation of the program ASHA reported historical issues with timely remuneration and lack of supportive supervision.Conclusions: Culturally appropriate community-based group programs run by trained and supported ASHAs are a successful and potentially scalable model for improving the control of hypertension in rural India. However, consideration of issues related to unreliable/insufficient remuneration for ASHAs, supportive supervision and their formal role in the wider health workforce in India will be important to address in future program scale up.Trial Registration: Clinical Trial Registry of India [CTRI/2016/02/006678, Registered prospectively].

Validation of Risk-Adapted Venous Thromboembolism Prediction in Multiple Myeloma Patients

Multiple myeloma (MM) is associated with an increased risk of venous thrombosis (VTE). In the United Kingdom Medical Research Council (MRC) XI study of patients treated with immunomodulatory therapy, the VTE rate was 11.8% despite 87.7% of the patients being on thromboprophylaxis at the time of thrombosis. In order to effectively prevent VTE events in MM patients, a better understanding of patient and disease risk factors that might predict thrombosis is required. We performed a retrospective cohort analysis of over 300 newly diagnosed MM patients at a tertiary referral centre to determine the VTE rate, predictive factors for VTE, value of the Khorana score for MM VTE events and long-term mortality outcomes. Fifty-four percent of the patients were receiving thromboprophylaxis at the time of the VTE event. The mortality odds ratio was 3.3 (95% CI, 2.4–4.5) in patients who developed VTE in comparison to age-matched controls with MM. A younger age at diagnosis and higher white cell count (WCC) were found to be predictive of VTE events. Our data suggest that standard thromboprophylaxis may not be effective in preventing VTE events in myeloma patients, and alternative strategies, which could include higher-intensity thromboprophylaxis in young patients with a high WCC, are necessary.

Protocol for a process evaluation of a cluster randomised controlled trial to improve psychosocial treatment of patients with psychotic spectrum disorders: the IMPULSE trial

Objective: This paper describes the protocol of a process evaluation of a cluster randomised controlled trial designed to evaluate the effectiveness, cost-effectiveness and implementation of a digital mental health intervention, called DIALOG+, in five low- and middle-income countries in Southeast Europe (Bosnia and Herzegovina, Kosovo1, Montenegro, North Macedonia and Serbia). The objectives of the process evaluation are: a) to explore attributes of context that might impact on the implementation of the DIALOG+ intervention; b) to assess intervention fidelity and c) to explore patients’ and clinicians’ retrospective (i.e. experienced) acceptability of the intervention.Materials and methods: This is a mixed-method process evaluation nested within the cluster randomised controlled trial. We adopted the guidance on process evaluations of complex interventions published by the United Kingdom Medical Research Council. Data collected during and after the trial, but prior to awareness of trial outcomes, include transcripts, questionnaire responses, routinely collected monitoring data and audio-recordings of intervention and control sessions. Data analysis is descriptive and involves triangulation methods to compare findings across countries, stakeholder groups (healthcare provider, patient) and data type (qualitative, quantitative).Results: This work is part of a larger study entitled ‘Implementation of an effective and cost-effective intervention for patients with psychotic disorders in low and middle-income countries in Southeast Europe’ (IMPULSE). The study is funded by the European Union’s Horizon 2020 research and innovation programme. The IMPULSE trial recruited 81 clinicians and 458 patients. The clinician clusters were randomised to the intervention (six sessions of DIALOG+ over 12 months) or treatment-as-usual arm. Process data collection began in parallel with the trial, starting in April 2019. Data collection and analysis will be completed before the main trial findings are known. Process evaluation findings will be used to interpret the trial results including assessing the effect of context on outcomes. Conclusion: This process evaluation will explore the context, intervention fidelity and acceptability to contextualise the trial results, help in optimising sustainability of the intervention and inform its future dissemination. The methods described here may also inform the development and implementation of other complex psychosocial interventions in low-resource settings.

Meeting Report: Psoriasis Stratification to Optimize Relevant Therapy Showcase

A stratified medicine approach for the treatment of psoriasis promises greater certainty of clinical decision making through prediction of response on the basis of clinical, pharmacological, and -omics data from an individual patient. As yet, there is no predictive model for treatment response in routine clinical use for psoriasis. The Psoriasis Stratification to Optimise Relevant Therapy (PSORT) Consortium is a United Kingdom Medical Research Council‒funded, academic‒industrial stratified medicine consortium established with the objective of discovering the predictors and stratifiers of response of psoriasis to biologic therapies. A showcase meeting was convened and attended by 80 stakeholders at the Royal College of Physicians, London, United Kingdom on 18 November 2019. The purpose was to disseminate the research findings from the PSORT consortium discovered thus far. This report summarizes the presentations made on the day and the significant advances made by PSORT toward a stratified medicine approach to the management of psoriasis.

The Landmark Series: Multimodal Therapy for Esophageal Cancer.

Esophagectomy is the mainstay of treatment for patients with resectable esophageal cancer, and chemotherapy and chemoradiation have become essential adjuncts to improve survival. Controversy remains regarding the optimal perioperative therapy. This review focuses on three landmark, randomized, controlled trials that have greatly influenced esophageal cancer management and established chemotherapy and chemoradiotherapy as standard of care: Medical Research Council Adjuvant Gastric Infusional Chemotherapy Trial (MAGIC); The United Kingdom Medical Research Council Esophageal Cancer Trial (OEO2); and Chemoradiotherapy for Oesophageal Cancer Followed by Surgery Study (CROSS). The findings from these landmark studies are reviewed and summarized. Chemotherapy regimens are heterogeneous but centered around platinum-based therapy and should be included in the management for all appropriate patients. Ongoing and future studies will further delineate the roles of various chemo- and chemoradiotherapy regimens and also will investigate the promising area of immunotherapy in the treatment of esophageal cancer.

Drawing on Dialogues in Arts-Based Dynamic Interpersonal Therapy (ADIT) for Complex Depression: A Complex Intervention Development Study Using the Medical Research Council (UK) Phased Guidance.

Aim: The aim of this paper is to present the development and evaluation of an art psychotherapy brief treatment method for complex depression for patients referred to mental health services.Background: Art Psychotherapy literature describes a range of processes of relational change through the use of arts focused and relationship focused interventions. Complex depression has a prevalence of 3% of the population in the West and it is recorded that in 2016 only 28% of that population were receiving psychological treatment. This study was developed to test the hypothesis of whether an accessible and acceptable approach to the treatment of complex depression could be developed in relation to existing evidence-based practice within mental health services.Method: The United Kingdom Medical Research Council phased guidance for complex intervention development was used (Phases I and II) to develop the intervention. The process included producing a literature overview, systematic description of clinical practice, including a logic model and a clinical protocol. The art psychotherapy protocol described an arts-based dynamic interpersonal therapy approach (ADIT), offered 1:1 over 24 sessions. Further to this the intervention was tested for referrer acceptability. The intervention is in the early stages of evaluation, using changes to the patient's depression and anxiety measured pre- and post-treatment with a follow-up measure at 3 months following completion of treatment.Results: Phase I of the study provided a good basis for developing a logic model and protocol. The authors found that there was good clinical consensus about the use of a structured clinical art psychotherapy method (ADIT) and the literature overview was used to support specific examples of good practice. The verification of clinical coherence was represented by a logic model and clinical protocol for delivering the intervention. The acceptability study demonstrated very high levels of acceptability for referrers reporting that (i) ADIT was acceptable for patients with complex/major depression, (ii) that they were likely to refer to ADIT in the future (iii) that the use of arts was likely to improve accessibility (iv) the use of arts was likely to improve outcomes and (v) that offering ADIT was an effective use of mental health resources.Discussion: Phase I of this intervention development study (following MRC guidance) demonstrated theoretical and practice coherence resulting in a clinical protocol and logic model. Whilst Phase II of this study showed promising results, Phase II would need to be sufficiently scaled up to a full trial to further test the intervention and protocol.

Outcomes in Relation to Early Parenteral Nutrition Use in Preterm Neonates Born between 30 and 33 Weeks Gestation: A Propensity Score Matched Observational Study

Importance: Preterm neonates are among the highest users of parenteral nutrition (PN). Randomised trials in critically ill older children show that harms, such as nosocomial infection, outweigh benefits of early PN administration; there is a paucity of similar randomised trial data in neonates. Objective: To evaluate whether in preterm neonates born between 30+0 and 32+6 weeks+days, PN use in the first seven postnatal days, compared with no PN use, is associated with differences in survival and other important morbidities. Design: Retrospective cohort study using propensity matching including 35 maternal, infant and organisational factors to minimise bias and confounding. Routinely recorded clinical data obtained from the UK National Neonatal Research Database. Setting: National population-level data from all National Health Service neonatal units in England and Wales. Participants: 35,362 neonates born over the period January 2012 to December 2017 and admitted to a neonatal unit; 16,292 neonates were compared in propensity score matched analyses. Exposure: The exposure was PN administered in the first seven days of postnatal life; the comparator was no PN in the first seven days. Main Outcome and Measure: The primary outcome was survival to discharge from neonatal care. Secondary outcomes comprised the neonatal core outcome set (including necrotising enterocolitis, bronchopulmonary dysplasia and late-onset sepsis). Results: Compared with matched neonates not given PN in the first postnatal week, neonates who received PN had higher survival to discharge (absolute rate increase 0.91%; 95% CI 0.53% to 1.30%), but higher rates of necrotising enterocolitis (absolute rate increase 4.6%; 95% CI 3.9% to 5.3%), bronchopulmonary dysplasia (absolute rate increase 3.9%; 95% CI 3.2% to 4.7%), late-onset sepsis (absolute rate increase 1.5%; 95% CI 1.1% to 1.8%) and need for surgical procedures (absolute rate increase 0.92%; 95% CI 0.57% to 1.3%). Conclusions and Relevance: In neonates born between 30+0 and 32+6 weeks gestation, those given PN in the first postnatal week had higher rates of survival but higher rates of important neonatal morbidities. Prospective, randomised trials powered for important outcomes are needed to identify in which neonates the benefits of early PN use outweigh the harms. Trial Registration: ClinicalTrials.gov: NCT03767634, Prospectively Registered: 06/12/2018. Funding Statement: The NNRD is funded and maintained from awards to NM. These include costs for data transfer, storage, cleaning, merging, administration and regulatory approvals. The extraction of study data from the NNRD and analysis for this study was funded through a Mason Medical Research Fellowship awarded to JW. CG was funded by the United Kingdom Medical Research Council (MRC) through a Clinician Scientist Fellowship award. Declaration of Interests: JW has received support from Chiesi Pharmaceuticals to attend an educational conference and has received a research grant from Mason Medical Research Foundation. SU has received funding from the National Institute of Health Research, the Department of Health and Prolacta Life Sciences. SU has been on the Advisory Board of Fresenius Kabi and received honoraria and travel expenses for speaking at study days organised by Fresenius Kabi. SU is a member of the National Institute for Health and Care Excellence Parenteral Nutrition Guideline Development Committee. NM is the Chief Investigator for the National Neonatal Research Database and Director of the Neonatal Data Analysis Unit at Imperial College London. In the last five years NM has served on the Board of Trustees of the Royal College of Paediatrics and Child Health, David Harvey Trust, Medical Women’s Federation and Medact; and is a member of the Nestle Scientific Advisory Board. NM has received research grants from the British Heart Foundation, Medical Research Council, National Institute of Health Research, Westminster Research Fund, Collaboration for Leadership in Applied Health and Care Northwest London, Healthcare Quality Improvement Partnership, Bliss, Prolacta Life Sciences, Chiesi, Shire and HCA International; travel and accommodation expenses from, Nutricia, Prolacta, Nestle and Chiesi; honoraria from Ferring Pharmaceuticals and Alexion Pharmaceuticals for contributions to expert advisory boards, and Chiesi for contributing to a lecture programme. CG is part of an international team developing reporting guidance (a CONSORT extension) for clinical trials using cohorts and routinely collected health data. He has received support from Chiesi Pharmaceuticals to attend an educational conference; in the past 5 years he been investigator on received research grants from Medical Research Council, National Institute of Health Research, Canadian Institute of Health Research, Department of Health in England, Mason Medical Research Foundation, Westminster Medical School Research Trust and Chiesi Pharmaceuticals, and has been an unremunerated member of the Neonatal Data Analysis Unit Board, which oversees the NNRD. The authors declare no other competing interests. Ethics Approval Statement: Obtained study-specific research ethics committee, Health Research Authority and Health and Care Research Wales approval (18/NI/0214).

Clinically Relevant Vulnerabilities of Deep Machine Learning Systems for Skin Cancer Diagnosis

Clinically Relevant Vulnerabilities of Deep Machine Learning Systems for Skin Cancer Diagnosis

Detection of &lt;i&gt;M. tuberculosis&lt;/i&gt; DNA in CD34-Positive Peripheral Blood Mononuclear Cells of Asymptomatic TB Contacts

Background: Haematopoietic stem cells expressing the CD34 surface marker have been posited as a niche for M. tuberculosis complex (MTBC) bacilli during latent tuberculosis infection (LTBI). Methods: We conducted a cross-sectional study in Ethiopia to determine whether MTBC DNA was detectable in peripheral blood mononuclear cells (PBMC) isolated from 100 ml blood taken from 197 asymptomatic adults with a history of recent household TB contact and/or HIV infection, using digital polymerase chain reaction (dPCR). A nested prospective study was conducted in a sub-set of 43 HIV-infected individuals to evaluate whether administration of isoniazid preventive therapy (IPT) was effective in clearing MTBC DNA from PBMC. Results: MTBC DNA was detected in PBMC of 156/197 participants (79.2%; 95% CI 73.5% to 84.9%). Where present, it was found more frequently in CD34-positive vs. CD34-negative PBMC (154/155 [99.4%] vs. 46/155 [29.7%], P<0.001). Prevalence of dPCR-detected MTBC DNA did not differ between QuantiFERON-negative vs. QuantiFERON-positive participants (77/99 [77.8%] vs. 79/98 [80.6%], P=0.73), but it was higher in HIV-infected vs. HIV-uninfected participants (67/75 [89.3%] vs. 89/122 [73.0%], P=0.006). By contrast, the proportion of QuantiFERON-positive participants was lower in HIV-infected vs. HIV-uninfected participants (25/75 [33.3%] vs. 73/122 [59.8%], P<0.001). Administration of IPT reduced prevalence of dPCR-detected MTBC DNA from 41/43 (95.3%) at baseline to 23/43 (53.5%) post-treatment (P<0.001), but it did not influence prevalence of QuantiFERON-positivity (17/43 [39.5%] at baseline vs. 13/43 [30.2%] post-treatment; P=0.13). Conclusions: We report a novel molecular microbiological biomarker of LTBI with properties that are distinct from those of a commercial interferon-gamma release assay. Our findings implicate the bone marrow as a niche for M. tuberculosis in latently infected individuals. Detection of MTBC DNA in PBMC has potential applications in the diagnosis of LTBI, in monitoring response to chemoprophylaxis and as an outcome measure in clinical trials of interventions to prevent or treat LTBI. Funding Statement: This work was supported by a grant from the United Kingdom Medical Research Council (Reference Number MR/P024548/1, to ARM). SF and STR acknowledge support from the Cambridge NIMR BRC antibiotic resistance theme. JM acknowledges support from the DELTAS Africa Initiative (ref DEL-15-011, via THRiVE-2). JFH, GJ and DMO’S acknowledge support from the UK government Department for Business, Energy & Industrial Strategy (BEIS). Declaration of Interests: STR has a pending patent that is relevant to the work. All other authors have no competing interests to declare. Ethics Approval Statement: The study was approved by the Ethiopian National Research Ethics Review Committee, Addis Ababa, Ethiopia (ref 310/253/2017). Written informed consent was obtained from all participants.

A Mathematical Model Impact Analysis of a Pre-Exposure Prophylaxis and Treatment-As-Prevention Study Among Female Sex Workers in Cotonou, Benin

Background: Daily pre-exposure prophylaxis (PrEP) and treatment-as-prevention (TasP) reduce HIV acquisition and transmission risk, respectively. With a 2015 HIV prevalence of 17%, female sex workers (FSW) are a key group for HIV prevention in Cotonou, Benin. A demonstration study (2015-2017) assessed the feasibility of TasP and PrEP among FSW. We aimed to assess the population-level impact of the study and various extended and scaled-up PrEP and TasP interventions. Methods: We developed a dynamic HIV transmission model, featuring PrEP, and ART among FSW, clients and the low-risk population, parameterised with the demonstration study data and historical demographic, behavioural, epidemiological and intervention data from Cotonou. The model was calibrated to HIV prevalence, ART coverage, and demonstration study data, reflecting observed lower PrEP uptake, adherence and retention compared to TasP. We modelled the two-year study and several twenty-year intervention scenarios, varying coverage and adherence. We estimated the median (2.5th-97.5th percentile uncertainty interval (95%UI)) percentage and number of incident HIV infections averted comparing the intervention and counterfactual (2017 coverages: 0% PrEP, 49% ART) scenarios. Findings: The two-year study (2017 coverages: 9% PrEP, 83% ART) prevented an estimated 8% (95%UI 6-11) and 5% (2-9) infections among FSW over two and twenty years, respectively, compared to 16% (9-28) and 7% (3-12) among clients, and 6% (3-11) and 4% (2-8) overall. Twenty-year PrEP and TasP scale-ups (2035 coverages: 47% PrEP, 88% ART) prevented 23% (18-28) and 15% (9-23) infections among FSW respectively, and 5% (3-9) and 14% (8-25) overall. Compared to TasP scale-up alone, scaling up PrEP and TasP together prevented 107% and 29% more infections among FSW and overall, respectively. PrEP impact doubled when assuming perfect adherence. Interpretation: The demonstration study had a modest impact, mostly due to TasP. Increasing PrEP adherence and coverage improves impact substantially among FSW, but little in the overall population. TasP should be offered in future prevention packages. Funding Statement: This study was funded by the Bill and Melinda Gates Foundation (grant no. OPP1098973). Complementary funding was provided by the Canadian Institutes of Health Research (grant numbers ROH-115205 and FDN-143218). Truvada for pre-exposure prophylaxis was provided free of charge by Gilead Sciences, Inc. Studentship funding was provided by the United Kingdom Medical Research Council. KM and MCB acknowledge partial funding from the HPTN modelling centre, which is funded by the U.S. National Institutes of Health (NIH UM1 AI068617) through HPTN. Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: The authors received approval from the Imperial College Research Ethics Committee (ICREC reference: 18IC4641) to carry out our analysis.

The CHIRPY DRAGON intervention in preventing obesity in Chinese primary-school--aged children: Acluster-randomised controlled trial.

BackgroundIn countries undergoing rapid economic transition such as China, rates of increase in childhood obesity exceed that in the West. However, prevention trials in these countries are inadequate in both quantity and methodological quality. In high-income countries, recent reviews have demonstrated that school-based prevention interventions are moderately effective but have some methodological limitations. To address these issues, this study evaluated clinical- and cost- effectiveness of the Chinese Primary School Children Physical Activity and Dietary Behaviour Changes Intervention (CHIRPY DRAGON) developed using the United Kingdom Medical Research Council complex intervention framework to prevent obesity in Chinese primary-school–aged children.Methods and findingsIn this cluster-randomised controlled trial, we recruited 40 state-funded primary schools from urban districts of Guangzhou, China. A total of 1,641 year-one children with parent/guardian consent took part in baseline assessments prior to stratified randomisation of schools (intervention arm, 20 schools, n = 832, mean age = 6.15 years, 55.6% boys; control arm n = 809, mean age = 6.14 years, 53.3% boys). The 12-month intervention programme included 4 school- and family-based components delivered by 5 dedicated project staff. We promoted physical activity and healthy eating behaviours through educational and practical workshops, family activities, and supporting the school to improve physical activity and food provision. The primary outcome, assessed blind to allocation, was between-arm difference in body mass index (BMI) z score at completion of the intervention. A range of prespecified, secondary anthropometric, behavioural, and psychosocial outcomes were also measured. We estimated cost effectiveness based on quality-adjusted life years (QALYs), taking a public sector perspective. Attrition was low with 55 children lost to follow up (3.4%) and no school dropout. Implementation adherence was high. Using intention to treat analysis, the mean difference (MD) in BMI z scores (intervention − control) was −0.13 (−0.26 to 0.00, p = 0.048), with the effect being greater in girls (MD = −0.18, −0.32 to −0.05, p = 0.007, p for interaction = 0.015) and in children with overweight or obesity at baseline (MD = −0.49, −0.73 to −0.25, p < 0.001, p for interaction < 0.001). Significant beneficial intervention effects were also observed on consumption of fruit and vegetables, sugar-sweetened beverages and unhealthy snacks, screen-based sedentary behaviour, and physical activity in the intervention group. Cost effectiveness was estimated at £1,760 per QALY, with the probability of the intervention being cost effective compared with usual care being at least 95% at a willingness to pay threshold of £20,000 to 30,000 per QALY. There was no evidence of adverse effects or harms. The main limitations of this study were the use of dietary assessment tools not yet validated for Chinese children and the use of the UK value set to estimate QALYS.ConclusionsThis school- and family-based obesity prevention programme was effective and highly cost effective in reducing BMI z scores in primary-school–aged children in China. Future research should identify strategies to enhance beneficial effects among boys and investigate the transferability of the intervention to other provinces in China and countries that share the same language and cultures.Trial registrationISRCTN Identifier ISRCTN11867516.

Integrating quantitative and qualitative data and findings when undertaking randomised controlled trials

It is common to undertake qualitative research alongside randomised controlled trials (RCTs) when evaluating complex interventions. Researchers tend to analyse these datasets one by one and then consider their findings...