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Introduction The Children and Young People’s Health Partnership (CYPHP) Evelina London Model of Care is a new approach to integrated care delivery for children and young people (CYP) with common health complaints and chronic conditions. CYPHP includes population health management (services shaped by data-driven understanding of population and individual needs, applied in this case to enable proactive case finding and tailored biopsychosocial care), specialist clinics with multidisciplinary health teams and training resources for professionals working with CYP. This complex health system strengthening programme has been implemented in South London since April 2018 and will be evaluated using a cluster randomised controlled trial with an embedded process evaluation. This protocol describes the within-trial and beyond-trial economic evaluation of CYPHP.Methods and analysis The economic evaluation will identify, measure and value resources and health outcome impacts of CYPHP compared with enhanced usual care from a National Health Service/Personal Social Service and a broader societal perspective. The study population includes 90 000 CYP under 16 years of age in 23 clusters (groups of general practitioner (GP) practices) to assess health service use and costs, with more detailed cost-effectiveness analysis of a targeted sample of 2138 CYP with asthma, eczema or constipation (tracer conditions). For the cost-effectiveness analysis, health outcomes will be measured using the Paediatric Quality of Life Inventory and quality-adjusted life years (QALYs) using the Child Health Utility 9 Dimensions (CHU-9D) measure. To account for changes in parental well-being, the Warwick-Edinburg Mental Well-being Scale will be integrated with QALYs in a cost–benefit analysis. The within-trial economic evaluation will be complemented by a novel long-term model that expands the analytical horizon to 10 years. Analyses will adhere to good practice guidelines and National Institute for Health and Care Excellence public health reference case.Ethics and dissemination The study has received ethical approval from South West-Cornwall and Plymouth Research Ethics Committee (REC Reference: 17/SW/0275). Results will be submitted for publication in peer-reviewed journals, made available in briefing papers for local decision-makers, and provided to the local community through website and public events. Findings will be generalisable to community-based models of care, especially in urban settings.Trial registration number NCT03461848.

Rationale COPD and smoking are characterised by pulmonary inflammation. 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) imaging may improve knowledge of pulmonary inflammation in COPD patients and aid early development of novel therapies as an imaging biomarker. Objectives To evaluate pulmonary inflammation, assessed by FDG uptake, in whole and regional lung in “usual” (smoking-related) COPD patients, alpha-1 antitrypsin deficiency (α1ATD) COPD patients, smokers without COPD and never-smokers using FDG PET/CT. Secondly, to explore cross-sectional associations between FDG PET/CT and systemic inflammatory markers in COPD patients and repeatability of the technique in COPD patients. Methods Data from two imaging studies were evaluated. Pulmonary FDG uptake (normalised Ki; nKi) was measured by Patlak graphical analysis in four subject groups: 84 COPD patients, 11 α1ATD-COPD patients, 12 smokers and 10 never-smokers. Within the COPD group, associations between nKi and systemic markers of inflammation were assessed. Repeatability was evaluated in 32 COPD patients comparing nKi values at baseline and at 4-month follow-up. Results COPD patients, α1ATD-COPD patients and smokers had increased whole lung FDG uptake (nKi) compared with never-smokers (0.0037±0.001, 0.0040±0.001, 0.0040±0.001 versus 0.0028±0.001 mL·cm−3·min−1, respectively, p

Abstract Background Chronic obstructive pulmonary disease (COPD) is a complex inflammatory condition in which an important extra-pulmonary manifestation is cardiovascular disease. We hypothesized that COPD patients would have increased aortic inflammation and stiffness, as candidate mechanisms mediating increased cardiovascular risk, compared to two negative control groups: healthy never-smokers and smokers without COPD. We also studied patients with COPD due to alpha− 1 antitrypsin deficiency (α1ATD) as a comparator lung disease group. Methods Participants underwent 18F-Fluorodeoxyglucose (FDG) positron emission tomography imaging to quantify aortic inflammation as the tissue-to-blood-ratio (TBR) of FDG uptake. Aortic stiffness was measured by carotid-femoral aortic pulse wave velocity (aPWV). Results Eighty-five usual COPD (COPD due to smoking), 12 α1ATD-COPD patients and 12 each smokers and never-smokers were studied. There was no difference in pack years smoked between COPD patients and smokers (45 ± 25 vs 37 ± 19, p = 0.36), but α1ATD patients smoked significantly less (19 ± 11, p

Background: Chronic, non-communicable disease, accounts for the vast majority of all disability adjusted life years lost (DALYS), among children and young people in high income countries. Our current model of hospital‐centred paediatric care was developed to deliver acute inpatient and high intensity specialist services rather than high quality care for children and young people (CYP) with long-term conditions. The CYPHP Evelina London model was developed with key stakeholders including CYP, carers, front line practitioners and health service commissioners in response to these evolving health care needs. The CYPHP Evelina London model is an innovative approach to reshaping everyday healthcare services, expanding on the principles of integrated care. CYPHP brings together physical and mental healthcare, addresses the social context of families, integrates primary and secondary healthcare, and links healthcare with local government efforts to improve the wider determinants of health. A major focus of the CYPHP Evelina London model is improving front line care for all CYP. Methods: The CYPHP model will be rolled out in phases, allowing an opportunistic evaluation using a cluster Randomised Controlled Trial (cRCT) design involving 90,000 children and young people in 23 clusters. The evaluation has four component parts: 1- Pseudonymised population-based evaluation for all children and young people in participating GP practices to assess health service use; 2- An evaluation of consented children with asthma, eczema, and constipation to assess impact on health-related quality of life, parental-reported disease severity, prevalence and severity of mental health difficulties, and mental wellbeing among parents, using validated questionnaires. 3- A mixed-methods process evaluation to understand the barriers and facilitators to implementing the model of care; 4- Economic evaluation. Results: Initial baseline results from the first 219 Health Checks showed poorly controlled symptoms for asthma, eczema and constipation in between 60 and 76% of young people. In total, 28% of CYP scored ‘High’/’Very High’ on Strengths & Difficulties Questionnaire for mental health difficulties. Over a quarter of families reported problems paying bills and 12% of parents expressed concerns regarding their own mental health. Discussion: The ongoing CYPHP evaluation is the largest population based evaluation of a pediatrics integrated care model to date in the UK. We will discuss the need for robust evaluation in the space of health transformation using CYPHP as an exemplar. Conclusions: Initial results show high levels of unmet physical, psychological and social needs in children and young people with common and chronic illness. Clinical academic partnerships are key to robust evaluation of health service models at scale. Lessons learned: The difficulties, of carrying out a large randomised controlled trial of a health systems transformation programme across two London Boroughs including partnership working, funding models, ethics approval and recruitment will be discussed. Limitations: Though final results are not available, initial results show high levels of unmet need in our population which the CYPHP model of care is meeting. Suggestions for future research: Robust evaluation using experimental designs is possible and needed in the health systems space. These evaluations at scale will inform new health system design.

Background: Children and young people’s (CYP) health and healthcare outcomes are often poor. Demand for urgent healthcare is rising. The current model of care is primarily reactive and acute rather than proactive and preventative; leading to increased use and reliance on secondary healthcare services. Over the past 5 years there has been increases in non-elective admissions and attendances and outpatient appointments (1.7%, 3% and 3.2%). At a population level, these small increases incur increasing financial cost and burden on services already at capacity. The clinical-academic Children and Young People’s Health Partnership (CYPHP) is delivers new care models to improve CYP health; with evaluation using robust designs to determine the extent the new model of care is curbing rising healthcare use. Methods: CYPHP is a partnership between 3 large NHS Trusts, including mental health and children’s, 2 Clinical Commissioning Groups and Local Authorities, and a University. Model design included analysis of segmented population need, systematic literature reviews, and extensive engagement with CYP, parents, health professionals, providers, and commissioners. An evidence-based implementation plan was agreed to roll out services to a child population of 120,000. We are opportunistically evaluating the service using a cluster randomised control trial (cRCT) design. Results: We are implementing and evaluating an evidence-based comprehensive new child and family-centred integrated cycle of care including individual and population health promotion; proactive case-finding and triage for ongoing conditions at a population-level; biopsychosocial assessment and self-referral via a patient portal; holistic tailored care, specialist clinics and increased education and training for professionals working with CYP. Services are delivered by multidisciplinary health teams to increase coordination across primary, community, and hospital settings and to better integrate physical and mental healthcare for CYP’s social context. The cRCT evaluation design, with nested process evaluation and qualitative studies, will provide high quality evidence of the impact of the CYPHP model on outcomes including CYP health and wellbeing, healthcare quality, and health service and system measures. Implications: CYPHP is implementing and evaluating a new model of care to improve health, heathcare quality, and outcomes for local CYP, contribute generalizable evidence about children’s health services and systems, and shape child health policy.

Introduction: New models of healthcare have largely focussed on adults, with increasing policy and practice interest in integrated care across many high-income countries. Integrated care models have been identified as a promising solution by children and young people (CYP), and by policy-makers, to target the gaps in healthcare delivery for CYP with on-going conditions. However, there has been limited work on developing and evaluating integrated models of child healthcare, so there is an evidence gap in this important area of policy. This systematic review and meta-analysis assessed the effects of integrated care interventions on child health, health service use, and healthcare quality for CYP with on-going conditions. Methods: Articles were eligible for the review if they 1) reported randomised controlled trials (RCTs), published between 1996 and September 2018; 2) evaluated an integrated healthcare intervention designed to improve child health; 3) included CYP (0-18 years) with an on-going health condition; 4) included at least one health-related outcome. Descriptive data on a range of outcomes was synthesised for all included papers, and data homogeneity allowed further meta-analyses to explore the effects of integrated care interventions compared with usual care, on health-related quality of life (QOL) and number of emergency department visits. Results: Twenty-three randomised controlled trials were identified, describing 18 interventions. Studies had medium risk of bias, as assessed by the Cochrane Risk of Bias tool. Improvements were found for quality of care (87% of interventions found a positive effect for intervention) and child health (39% found a positive effect for intervention). The meta-analyses found that integrated care interventions have a positive effect in improving QOL over usual care (n=5 trials; SMD = 0.24; 95% CI = 0.03, 0.44; P=0.02), but no significant difference across groups for emergency department contacts (n=5 trials; OR=0.82; 95% CI = 0.53, 1.26; p=0.37). Conclusion and Discussion: Integrated care interventions for CYP with on-going conditions may deliver improved quality of life for children, health, and quality of care. However, no conclusions can be made about the direction or magnitude of the effect for integrated care interventions on emergency department contacts in CYP with on-going conditions. However, only 23 RCTs were included in this review, which were of moderate quality, highlighting the need for more robust trials to inform current health service delivery in this area and fully establish the effectiveness of integrated healthcare interventions on CYP outcomes. In collaboration with NHS Trusts, local councils, CYP and families, the findings from this review have been used to inform a fully integrated healthcare model for CYP that will be implemented at scale, and rigorously evaluated using an RCT design.

Background: Children and young people’s (CYP) health outcomes in England are variable and often poor. Health systems throughout high income countries are struggling to adapt to epidemiological transitions, social change, rising demand, and budget cuts. There was a 58% rise in CYP attending EDs between 2007 and 2016, projected to rise 50-60% more by 2030. CYP from the most deprived backgrounds are 60-70% more likely to go to A&E than the least deprived. The majority of ED attendances by CYP are manageable in primary care or integrated models, yet 85% of ED attendances are for minor illnesses, increasing 5% annually. The Children and Young People’s Health Partnership (CYPHP) is a health system strengthening initiative implementing and evaluating a new model of care. Methods: Health system strengthening using the WHO building blocks model included service design by analysis of population need, systematic literature reviews, and extensive patient and public involvement. An evidence-based implementation plan was agreed for a child population of 90,000 in London, and we are evaluating using a cluster randomised control trial (cRCT) design with nested process evaluation and qualitative studies to assess CYP health and wellbeing, healthcare quality, patterns of healthcare use, and cost effectiveness. Results: CYPHP’s comprehensive care includes health promotion and supported self-management, proactive case-finding, biopsychosocial assessment and self-referral via a patient portal, with care delivered by a multidisciplinary team. Services are integrated vertically and horizontally incorporating physical and mental healthcare. Implementation has taken two years longer than anticipated due to technical and cultural challenges of health system strengthening. Early results indicate a reduction of 72 ED contacts per 100 children with asthma, 30 for children with epilepsy, and 15 for children with constipation. We estimate cost savings per 100 asthma patients to be over £15,000, for epilepsy over £6,000, and for constipation over £3,000. Of the first 200 patients, most were from socially deprived areas and 68% were from black and minority ethnic groups. Families report more confidence in managing their child’s condition. Discussion: As a clinical academic partnership, CYPHP combines pragmatic quality improvement and rigorous health services research. CYPHP demonstrates that health system strengthening in high income countries is feasible and effective for implementing and testing new models of care to improve child health. Conclusions: Early results suggest encouraging impact on patterns of healthcare use and potential cost savings. CYPHP’s population health approach provides care for those with greatest health and social need. Lessons learned: Rigorous health services and systems research is feasible in large scale system change in the NHS. Health system strengthening is a new concept in high income countries. It is slow and difficult, but important for effective implementation of new models of care. Fully integrated comprehensive models of care for children may improve health and healthcare outcomes. Limitations: Results are preliminary and reflect early implementation. Suggestions for future research: Rigorously designed health services research for ongoing large-scale health systems changes are an important source of new knowledge. There are few examples of such opportunistic research, representing new avenues for opportunity.

BackgroundCardiovascular disease is a major cause of morbidity and mortality in COPD patients. Systemic inflammation associated with COPD, is often hypothesised as a causal factor. p38 mitogen-activated protein kinases play a key role in the inflammatory pathogenesis of COPD and atherosclerosis.ObjectivesThis study sought to evaluate the effects of losmapimod, a p38 mitogen-activated protein kinase (MAPK) inhibitor, on vascular inflammation and endothelial function in chronic obstructive pulmonary disease (COPD) patients with systemic inflammation (defined by plasma fibrinogen >2·8g/l).MethodsThis was a randomised, double-blind, placebo-controlled, Phase II trial that recruited COPD patients with plasma fibrinogen >2.8g/l. Participants were randomly assigned by an online program to losmapimod 7·5mg or placebo tablets twice daily for 16 weeks. Pre- and post-dose 18F-Fluorodeoxyglucose positron emission tomography co-registered with computed tomography (FDG PET/CT) imaging of the aorta and carotid arteries was performed to quantify arterial inflammation, defined by the tissue-to-blood ratio (TBR) from scan images. Endothelial function was assessed by brachial artery flow-mediated dilatation (FMD).ResultsWe screened 160 patients, of whom, 36 and 37 were randomised to losmapimod or placebo. The treatment effect of losmapimod compared to placebo was not significant, at -0·05 for TBR (95% CI: -0·17, 0·07), p = 0·42, and +0·40% for FMD (95% CI: -1·66, 2·47), p = 0·70. The frequency of adverse events reported was similar in both treatment groups.ConclusionsIn this plasma fibrinogen-enriched study, losmapimod had no effect on arterial inflammation and endothelial function at 16 weeks of treatment, although it was well tolerated with no significant safety concerns. These findings do not support the concept that losmapimod is an effective treatment for the adverse cardiovascular manifestations of COPD.

The VoxTox research programme has applied expertise from the physical sciences to the problem of radiotherapy toxicity, bringing together expertise from engineering, mathematics, high energy physics (including the Large Hadron Collider), medical physics and radiation oncology. In our initial cohort of 109 men treated with curative radiotherapy for prostate cancer, daily image guidance computed tomography (CT) scans have been used to calculate delivered dose to the rectum, as distinct from planned dose, using an automated approach. Clinical toxicity data have been collected, allowing us to address the hypothesis that delivered dose provides a better predictor of toxicity than planned dose.

Background: COPD is independently associated with increased cardiovascular events. Arterial stiffening and systemic inflammation are postulated aetiological factors. We hypothesised that vascular inflammation links systemic inflammation with vascular stiffening and sought to test this in a cohort of COPD subjects undergoing baseline FDG PET/CT either as part of the EVOLVE observational study or EVOLUTION trial (NCT 01541852). Methods: 85 COPD subjects underwent assessments including spirometry, arterial stiffness (aortic pulse wave velocity (aPWV)), inflammatory biomarkers (fibrinogen and hsCRP) and FDG PET/CT imaging (lungs, aorta and carotids) to evaluate inflammation and aortic calcification. Results: 66% of the cohort were male, median age was 68 (IQR 63–73) years, 87% were ex-smokers. Mean aPWV was 9.9 (SEM 0.2) m/s, aortic calcification volume 7156 (1461) mm3, hsCRP 5.2 (0.8) mg/dl, fibrinogen 3.4 (0.08) g/l. Log hsCRP correlated only with carotid FDG uptake (R=0.23, p=0.04) and log fibrinogen did not correlate with FDG uptake in any vascular region. Systemic inflammatory markers were positively associated with aortic inflammation but only weakly. The estimated change in FDG uptake was 0.2 (95% CI 0.11–0.29) and 0.07 (0.06–0.08), for each log unit change in fibrinogen and hsCRP respectively. Aortic inflammation was not a significant determinant of aPWV, but aortic calcification was, adjusted for age, supine HR, MAP and years smoked (p=0.02, β=0.26). Conclusion: HsCRP and fibrinogen are weak predictors of vascular inflammation and therefore likely unsuitable stratification biomarkers of vascular inflammation in COPD. Calcification rather than inflammation appears to be the dominant pathophysiological mechanism underlying arterial stiffness in COPD.

Introduction: COPD is associated with increased cardiovascular risk, independent of established risk factors. Arterial stiffness is a surrogate of cardiovascular risk and we sought to determine its relationship with COPD severity and prognosis in the ERICA (Evaluation of role of inflammation in airways disease) multi-site UK study: the largest cohort study focusing on cardiovascular manifestations in COPD. Methods: Spirometry and haemodynamic measures (aortic pulse wave velocity (aPWV), augmentation index (AIx)) were performed in 729 COPD subjects aged ≥40 years. COPD severity was classified by BODE Index [BMI (low BMI worse prognosis), Obstruction (FEV1), Dyspnoea (mMRC score), Exercise tolerance (6-minute walk distance) high BODE index: worse outcome], a validated score based on clinical variables and an independent predictor of mortality in COPD. Results: Mean aPWV was 10.3 (SD 2.6) m/s, AIx 27 (10)%. BODE correlated with aPWV (R = 0.2, p = 0.0001) and this was maintained when adjusted for study site, age, supine HR and MAP, years smoked and cardiovascular comorbidities (MI, stroke, diabetes, peripheral vascular disease), (β = 0.2, p = 0.0001). BODE was also a determinant of AIx when adjusted for site, age, seated HR and MAP, years smoked and cardiovascular comorbidities (β = 0.1, p = 0.02). Conclusions: BODE is associated with arterial stiffness in COPD, independent of traditional risk factors. Its composite variables are not on the causal pathway for vascular stiffness, so its association likely reflects patient susceptibility to smoke injury in the lungs and vasculature. BODE may also enhance cardiovascular risk stratification in COPD, since its relationship with stiffness was independent of self-reported cardiovascular comorbidities.