Cost-effectiveness of the children and young People's health partnership (CYPHP) model of integrated care versus enhanced usual care: analysis of a pragmatic cluster randomised controlled trial in South London.

Background: Integration of paediatric health services across primary and secondary care holds great promise for the management of chronic conditions, yet limited evidence exists on its cost-effectiveness. This paper reports the results of the economic evaluation of the Children and Young People's Health Partnership (CYPHP) aimed at integrating care for children with common chronic conditions (asthma, eczema, and constipation). Methods: Cost-effectiveness, cost-utility and cost-benefit analyses were conducted alongside a pragmatic cluster randomised controlled trial involving 97,970 children in 70 general practices in South London, including 1,731 participants with asthma, eczema and or constipation with self-reported health-related quality of life measures. Analyses considered the National Health Service (NHS)/Personal Social Service (PSS) and societal perspectives, and time horizons of 6 and 12-months. Costs included intervention delivery, health service use (primary and secondary care), referrals to social services, and time lost from work and school. Health outcomes were measured through the Paediatric Quality of Life Inventory, the Child Health Utility 9-Dimensions, and monetarised benefit combining Quality-Adjusted Life Years (QALYs) for children and parental mental well-being. Results present incremental cost-effectiveness ratios (ICERs), compared to a willingness to pay threshold (WTP) of £20,000-30,000/QALY, and net monetary benefit (NMB), with deterministic sensitivity analyses. Findings: At 6 months, from the NHS/PSS perspective, CYPHP is not cost-effective (ICER = £721,000/QALY), and this result holds at 12 months (ICER = £45,586/QALY). However, under the societal perspective CYPHP falls within WTP thresholds (ICER = £22,966/QALY), with a probability of being cost-effective between 0.4 and 0.6 at £20,000/QALY and £30,000/QALY, respectively. The cost-benefit analysis yields a positive NMB of CYPHP at 12 months £109 under the societal perspective, with similar probabilistic results. Interpretation: CYPHP was not cost-effective at 6 months or under the NHS/PSS perspective. Trends towards cost-effectiveness are observed once a longer time horizon and a more inclusive perspective on effects is considered. Further research beyond 12 months is needed as the model becomes firmly embedded into the paediatric healthcare delivery system. Funding: This research was funded by Guy's and St Thomas' Charity, Lambeth and Southwark Clinical Commissioning Groups. The funders had no role in the writing of the manuscript, decision to submit it for publication, or any other process involved in the research.

Changing contexts of child health: an assessment of unmet physical, psychological and social needs of children with common chronic childhood illness.

BACKGROUND: We assessed the biopsychosocial needs and key health drivers among children living with a common chronic illness, as baseline for a cluster randomised controlled trial of a child health system strengthening intervention. METHODS: Cross-sectional data were analysed from a large population sample of children from South London with asthma, eczema or constipation, as exemplar tracer conditions of a new integrated care service. Descriptive and regression analyses, accounting for sociodemographic factors, investigated social needs, psychosocial outcomes and quality of life associated with poor symptom control. RESULTS: Among 7779 children, 4371 children (56%) had at least one uncontrolled physical health condition. Across the three domains of physical health, mental health and social needs, 77.5% of children (n=4304 of 5554) aged 4-15 years had at least one unmet need, while 16.3% of children had three unmet needs. Children from the most socioeconomically disadvantaged quintile had a 20% increased risk of at least one poorly controlled physical condition (risk ratio (RR)=1.20, 95% CI: 1.11 to 1.31, p<0.001) compared with those from the least disadvantaged quintile. There was an 85% increased risk of clinically important mental health needs among children with uncontrolled asthma (RR=1.85, 95% CI: 1.65 to 2.07, p<0.001), 57% for active constipation (RR=1.57, 95% CI: 1.12 to 2.20, p<0.01) and 39% for uncontrolled eczema (RR=1.39, 95% CI: 1.24 to 1.56, p<0.001). Health-related quality of life was associated with poor symptom control. CONCLUSIONS: There is a large burden of unmet biopsychosocial needs among children with chronic illness, signalling an urgent need for prevention, early intervention and integrated biopsychosocial care.

"They had clothes on their back and they had food in their stomach, but they didn't have me": The contribution of parental mental health problems, substance use, and domestic violence and abuse on young people and parents.

BACKGROUND: The parental risk factors of mental health problems, substance use, and domestic violence and abuse each individually negatively impacts children's health and developmental outcomes. Few studies have considered the lived experience and support needs of parents and children in the real-world situation where these common risks cluster. OBJECTIVE: This study explores parents' and young people's lived experiences of the clustering of parental mental health problems, parental substance use, and domestic violence and abuse. METHODS: Semi-structured interviews were conducted with 18 mothers, 6 fathers, and 7 young people with experiences of these parental risk factors. Transcribed interviews were analysed using reflexive thematic analysis. RESULTS: Four themes were developed, 1) cumulative adversity, 2) the impact of syndemic risk, 3) families navigating risk, and 4) family support. Parents and young people described family situations of stress wherein they experienced cumulative impact of multiple parental risk factors. Parents sought to navigate stressors and parent in positive ways under challenging conditions, often impeded by their own childhood trauma and diminished confidence. Parents and young people spoke of the need for, and benefits of having, support; both as a family and as individuals, to successfully address this trio of parental risks and the related impact. CONCLUSIONS: This study highlights the high level of stress families experience and the efforts they go to mitigate risk. Services and interventions need to reflect the complexity of multiple needs and consider both the whole family and individuals when providing support.

Interventions to Reduce Parental Substance Use, Domestic Violence and Mental Health Problems, and Their Impacts Upon Children's Well-Being: A Systematic Review of Reviews and Evidence Mapping.

INTRODUCTION: Children exposed to parental intimate partner violence and abuse, mental illness, and substance use experience a range of problems which may persist into adulthood. These risks often co-occur and interact with structural factors such as poverty. Despite increasing evidence, it remains unclear how best to improve outcomes for children and families experiencing these adversities and address the complex issues they face. AIMS AND METHODS: Systematic review of systematic reviews. We searched international literature databases for systematic reviews, from inception to 2021, to provide an evidence overview of the range and effectiveness of interventions to support children and families where these parental risk factors had been identified. RESULTS: Sixty-two systematic reviews were included. The majority (n = 59) focused on interventions designed to address single risk factors. Reviews mostly focused on parental mental health (n = 38) and included psychological interventions or parenting-training for mothers. Only two reviews assessed interventions to address all three risk factors in combination and assessed structural interventions. Evidence indicates that families affected by parental mental health problems may be best served by integrated interventions combining therapeutic interventions for parents with parent skills training. Upstream interventions such as income supplementation and welfare reform were demonstrated to reduce the impacts of family adversity. CONCLUSION: Most intervention approaches focus on mitigating individual psychological harms and seek to address risk factors in isolation, which presents potentially significant gaps in intervention evidence. These interventions may not address the cumulative impacts of co-occurring risks, or social factors that may compound adversities.

Effect of the Children and Young People's Health Partnership model of paediatric integrated care on health service use and child health outcomes: a pragmatic two-arm cluster randomised controlled trial.

BACKGROUND: Paediatric health systems across high-income countries are facing avoidable adverse outcomes and increasing demands and costs. The aim of this study was to compare the effect of an enhanced usual care model with that of an integrated health-care model that offers local health clinics for general paediatric problems and early intervention and care for children and young people with tracer conditions. METHODS: In this pragmatic two-arm cluster randomised controlled trial, we compared the Children and Young People's Health Partnership (CYPHP) model of care versus enhanced usual care (EUC) among children registered at general practices in south London, UK. The CYPHP trial intervention was delivered between April 1, 2018, and June 30, 2021, and children younger than 16 years during the intervention period and registered at study practices on June 30, 2021, were included in the analysis. A restricted randomisation (1:1) following a computer-generated sequence was done by a masked independent statistician at the level of general practice cluster, stratified by borough (Lambeth or Southwark). Cluster allocation and data collection were masked, with unmasking of trial statisticians before analysis. The CYPHP model comprised all elements of EUC (electronic decision support, a primary care hotline, health checks, self-management support and health promotion, and resilience building and mental health first aid) plus local child health clinics delivered by paediatricians and general practitioners, and a nurse-led early intervention service for children with tracer conditions (asthma, eczema, and constipation). Primary outcomes were non-elective admissions (NELA; admissions coded as an emergency) among the whole trial population up to June 30, 2021, and paediatric quality of life (Pediatric Quality of Life Inventory [PedsQL]) among participants with tracer conditions at 6 months after recruitment. Secondary outcomes were primary and secondary care use, child mental health, parental wellbeing, standardised symptom scores for asthma, eczema, and constipation, health-care quality, and child absences from school and parent absences from work. The trial was registered on ClinicalTrials.gov, NCT03461848, and is complete. FINDINGS: The trial was conducted between April 1, 2018, and Dec 31, 2021. In total, 23 general practice clusters, consisting of 70 practices with 97 970 registered children, were randomised to CYPHP (n=11) or EUC (n=12). We found no effect, at the population level, of CYPHP versus EUC on non-elective admissions during the intervention period (adjusted mean incidence rate ratio [IRR] 1·00 [95% CI 0·91 to 1·10], p=0·99). Among children with tracer conditions, we found no difference in paediatric quality of life (PedsQL score) at 6 months (adjusted mean difference -0·033 [95% CI -0·122 to 0·055], p=0·46). As a secondary outcome, among children with tracer conditions and requiring care, NELA rates at 12 months did not differ between the CYPHP and EUC groups (66·1 per 1000 person-years vs 75·3 per 1000 person-years; adjusted mean IRR 0·87 [0·61-1·22], p=0·42). In children requiring care, a statistically significant improvement was observed in eczema symptoms at 6 months from baseline in the CYPHP group versus the EUC group (adjusted mean difference -1·370 [-2·630 to -0·122], p=0·032). Quality of asthma care significantly improved among children in the CYPHP group compared with children in the EUC group. No significant improvement was seen for all other secondary outcomes. INTERPRETATION: Although the CYPHP trial found a null effect for the primary outcomes, we found clinically important improvements in some secondary outcomes including care quality. Previous research has shown that large-scale system change requires time to observe a potential positive effect. FUNDING: Guy's and St Thomas Charity, the Lambeth and Southwark Clinical Commissioning Groups, and Evelina London Children's Hospital.

Mapping PedsQL™ scores to CHU9D utility weights for children with chronic conditions in a multi-ethnic and deprived metropolitan population.

PURPOSE: The Child Health Utility-9 Dimensions (CHU9D) is a patient-reported outcome measure to generate Quality-Adjusted Life Years (QALYs), recommended for economic evaluations of interventions to inform funding decisions. When the CHU9D is not available, mapping algorithms offer an opportunity to convert other paediatric instruments, such as the Paediatric Quality of Life Inventory™ (PedsQL), onto the CHU9D scores. This study aims to validate current PedsQL to CHU9D mappings in a sample of children and young people of a wide age range (0 to 16 years of age) and with chronic conditions. New algorithms with improved predictive accuracy are also developed. METHODS: Data from the Children and Young People's Health Partnership (CYPHP) were used (N = 1735). Four regression models were estimated: ordinal least squared, generalized linear model, beta-binomial and censored least absolute deviations. Standard goodness of fit measures were used for validation and to assess new algorithms. RESULTS: While previous algorithms perform well, performance can be enhanced. OLS was the best estimation method for the final equations at the total, dimension and item PedsQL scores levels. The CYPHP mapping algorithms include age as an important predictor and more non-linear terms compared with previous work. CONCLUSION: The new CYPHP mappings are particularly relevant for samples with children and young people with chronic conditions living in deprived and urban settings. Further validation in an external sample is required. Trial registration number NCT03461848; pre-results.

Children and Young People's Health Partnership Evelina London Model of Care: economic evaluation protocol of a complex system change.

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.

Quantitative 18F-fluorodeoxyglucose positron emission tomography/computed tomography to assess pulmonary inflammation in COPD.

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<0.05 for all). Similar results were observed in upper and middle lung regions. In COPD participants, plasma fibrinogen was associated with whole lung nKi (ß=0.30, p=0.02) in multivariate analysis adjusted for current smoking, forced expiratory volume in 1 s % predicted, systemic neutrophils and C-reactive protein levels. Mean percentage difference in nKi between the baseline and follow-up was 3.2%, and the within subject coefficient of variability was 7.7%. CONCLUSIONS: FDG PET/CT has potential as a noninvasive tool to enable whole lung and regional quantification of FDG uptake to assess smoking- and COPD-related pulmonary inflammation.

Post-COVID-19 paediatric inflammatory multisystem syndrome: association of ethnicity, key worker and socioeconomic status with risk and severity.

OBJECTIVES: Patients from ethnic minority groups and key workers are over-represented among adults hospitalised or dying from COVID-19. In this population-based retrospective cohort, we describe the association of ethnicity, socioeconomic and family key worker status with incidence and severity of Paediatric Inflammatory Multisystem Syndrome Temporally associated with SARS-CoV-2 (PIMS-TS). SETTING: Evelina London Children's Hospital (ELCH), the tertiary paediatric hospital for the South Thames Retrieval Service (STRS) region. PARTICIPANTS: 70 children with PIMS-TS admitted 14 February 2020-2 June 2020. OUTCOME MEASURES: Incidence and crude ORs are presented, comparing ethnicity and socioeconomic status of our cohort and the catchment population, using census data and Index of Multiple Deprivation (IMD). Regression is used to estimate the association of ethnicity and IMD with admission duration and requirement for intensive care, inotropes and ventilation. RESULTS: Incidence was significantly higher in children from black (25.0 cases per 100 000 population), Asian (6.4/100 000) and other (17.8/100 000) ethnic groups, compared with 1.6/100 000 in white ethnic groups (ORs 15.7, 4.0 and 11.2, respectively). Incidence was higher in the three most deprived quintiles compared with the least deprived quintile (eg, 8.1/100 000 in quintile 1 vs 1.6/100 000 in quintile 5, OR 5.2). Proportions of families with key workers (50%) exceeded catchment proportions. Admission length of stay was 38% longer in children from black ethnic groups than white (95% CI 4% to 82%; median 8 days vs 6 days). 9/10 children requiring ventilation were from black ethnic groups. CONCLUSIONS: Children in ethnic minority groups, living in more deprived areas and in key worker families are over-represented. Children in black ethnic groups had longer admissions; ethnicity may be associated with ventilation requirement.This project was registered with the ELCH audit and service evaluation team, ref. no 11186.

Discussion and documentation of future care: a before-and-after study examining the impact of an alternative approach to recording treatment decisions on advance care planning in an acute hospital.

OBJECTIVE: To determine whether discussion and documentation of decisions about future care was improved following the introduction of a new approach to recording treatment decisions: the Universal Form of Treatment Options (UFTO). METHODS: Retrospective review of the medical records of patients who died within 90 days of admission to oncology or respiratory medicine wards over two 3-month periods, preimplementation and postimplementation of the UFTO. A sample size of 70 per group was required to provide 80% power to observe a change from 15% to 35% in discussion or documentation of advance care planning (ACP), using a two-sided test at the 5% significance level. RESULTS: On the oncology ward, introduction of the UFTO was associated with a statistically significant increase in cardiopulmonary resuscitation decisions documented for patients (pre-UFTO 52% to post-UFTO 77%, p=0.01) and an increase in discussions regarding ACP (pre-UFTO 27%, post-UFTO 49%, p=0.03). There were no demonstrable changes in practice on the respiratory ward. Only one patient came into hospital with a formal ACP document. CONCLUSIONS: Despite patients' proximity to the end-of-life, there was limited documentation of ACP and almost no evidence of formalised ACP. The introduction of the UFTO was associated with a change in practice on the oncology ward but this was not observed for respiratory patients. A new approach to recording treatment decisions may contribute to improving discussion and documentation about future care but further work is needed to ensure that all patients' preferences for treatment and care at the end-of-life are known.

Children and Young People's Health Partnership (CYPHP) Evelina London model of care: protocol for an opportunistic cluster randomised controlled trial (cRCT) to assess child health outcomes, healthcare quality and health service use.

INTRODUCTION: Children and young people (CYP) in many high-income settings have poor healthcare outcomes, especially those with long-term conditions (LTCs). Emergency and outpatient hospital service use is increasing unsustainably. To address these problems, the Children and Young People's Health Partnership (CYPHP) has developed and is evaluating an integrated model of care as part of a health systems strengthening programme across two boroughs of London, UK that are characterised by mixed ethnic populations and varying levels of deprivation. The CYPHP Evelina London model of care comprises proactive case-finding and triage, specialist clinics and transformative education and training for professionals working with CYP. Services are delivered by multidisciplinary health teams with an emphasis on increased coordination across primary, community and hospital settings and integration of physical and mental healthcare that accounts for the CYP's social context. METHODS AND ANALYSIS: The phased roll out of the CYPHP Evelina London model allows an opportunistic population-based evaluation using a cluster randomised controlled trial design. Seventy general practices across two London boroughs, grouped into 23 clusters, were randomised to provide either the CYPHP model of care (n=11) or enhanced usual care (n=12).The evaluation will measure the impact of the CYPHP Evelina London model of care on child and parent health and well-being, healthcare quality and health service use up to 2 years postimplementation. A population-level evaluation will use routinely collected pseudonymised healthcare data to conduct a service-use analysis for all CYP registered with a participating general practice (n=~90 000) with the rate of non-elective admissions as the primary outcome. We will seek consent from a subset of this population, with specific conditions (target n=2138) to assess the impact on patient-reported outcomes using the Paediatric Quality of Life Inventory (PedsQL) and Warwick-Edinburgh Mental Well-Being Scale (WEBWMS) as, respectively, the child- and parent-related primary outcomes. ETHICS AND DISSEMINATION: Ethics approval obtained from South West-Cornwall & Plymouth Research Ethics Committee. Results will be submitted for publication in peer-reviewed journals. Findings will be generalisable to community-based models of care, especially in urban settings. Our process evaluation will identify barriers and enablers of implementation and delivery of care salient to the context and condition. TRIAL REGISTRATION NUMBER: NCT03461848; Pre-results.

The Children and Young People's Health Partnership Evelina London Model of Care: process evaluation protocol.

INTRODUCTION: Children and young people (CYP) in the UK have poor health outcomes, and there is increasing emergency department and hospital outpatient use. To address these problems in Lambeth and Southwark (two boroughs of London, UK), the local Clinical Commissioning Groups, Local Authorities and Healthcare Providers formed The Children and Young People's Health Partnership (CYPHP), a clinical-academic programme for improving child health. The Partnership has developed the CYPHP Evelina London model, an integrated healthcare model that aims to deliver effective, coordinated care in primary and community settings and promote better self-management to over approximately 90 000 CYP in Lambeth and Southwark. This protocol is for the process evaluation of this model of care. METHODS AND ANALYSIS: Alongside an impact evaluation, an in-depth, mixed-methods process evaluation will be used to understand the barriers and facilitators to implementing the model of care. The data collected mapped onto a logic model of how CYPHP is expected to improve child health outcomes. Data collection and analysis include qualitative interviews and focus groups with stakeholders, a policy review and a quantitative analysis of routine clinical and administrative data and questionnaire data. Information relating to the context of the trial that may affect implementation and/or outcomes of the CYPHP model of care will be documented. ETHICS AND DISSEMINATION: The study has been reviewed by NHS REC Cornwall & Plymouth (17/SW/0275). The findings of this process evaluation will guide the scaling up and implementation of the CYPHP Evelina London Model of Care across the UK. Findings will be disseminated through publications and conferences, and implementation manuals and guidance for others working to improve child health through strengthening health systems. TRIAL REGISTRATION NUMBER: NCT03461848.

Vascular inflammation and aortic stiffness: potential mechanisms of increased vascular risk in chronic obstructive pulmonary disease.

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 < 0.001 for both). By design, spirometry measures were lower in COPD and α1ATD-COPD patients compared to smokers and never-smokers. Aortic inflammation and stiffness were increased in COPD (TBR: 1.90 ± 0.38, aPWV: 9.9 ± 2.6 m/s) and α1ATD patients (TBR: 1.94 ± 0.43, aPWV: 9.5 ± 1.8 m/s) compared with smokers (TBR: 1.74 ± 0.30, aPWV: 7.8 ± 1.8 m/s, p < 0.05 all) and never-smokers (TBR: 1.71 ± 0.34, aPWV: 7.9 ± 1.7 m/s, p ≤ 0.05 all). CONCLUSIONS: In this cross-sectional prospective study, novel findings were that both usual COPD and α1ATD-COPD patients have increased aortic inflammation and stiffness compared to smoking and never-smoking controls, regardless of smoking history. These findings suggest that the presence of COPD lung disease per se may be associated with adverse aortic wall changes, and aortic inflammation and stiffening are potential mechanisms mediating increased vascular risk observed in COPD patients.

Identifying risk factors for L'Hermitte's sign after IMRT for head and neck cancer.

BACKGROUND: L'Hermitte's sign (LS) after chemoradiotherapy for head and neck cancer appears related to higher spinal cord doses. IMRT plans limit spinal cord dose, but the incidence of LS remains high. METHODS: One hundred seventeen patients treated with TomoTherapy™ between 2008 and 2015 prospectively completed a side-effect questionnaire (VoxTox Trial Registration: UK CRN ID 13716). Baseline patient and treatment data were collected. Radiotherapy plans were analysed; mean and maximum spinal cord dose and volumes receiving 10, 20, 30 and 40 Gy were recorded. Dose variation across the cord was examined. These data were included in a logistic regression model. RESULTS: Forty two patients (35.9%) reported LS symptoms. Concurrent weekly cisplatin did not increase LS risk (p = 0.70, OR = 1.23 {95% CI 0.51-2.34}). Of 13 diabetic participants (9 taking metformin), only 1 developed LS (p = 0.025, OR = 0.13 {95% CI 0.051-3.27}). A refined binary logistic regression model showed that patients receiving unilateral radiation (p = 0.019, OR = 2.06 {95% CI 0.15-0.84}) were more likely to develop LS. Higher V40Gy (p = 0.047, OR = 1.06 {95% CI 1.00-1.12}), and younger age (mean age 56.6 vs 59.7, p = 0.060, OR = 0.96 {95% CI 0.92-1.00}) were associated with elevated risk of LS, with borderline significance. CONCLUSIONS: In this cohort, concomitant cisplatin did not increase risk, and LS incidence was lower in diabetic patients. Patient age and dose gradients across the spinal cord may be important factors.

Fibrinogen does not relate to cardiovascular or muscle manifestations in COPD: cross-sectional data from the ERICA study.

Cardiovascular and skeletal muscle manifestations constitute important comorbidities in COPD, with systemic inflammation proposed as a common mechanistic link. Fibrinogen has prognostic role in COPD. We aimed to determine whether aortic stiffness and quadriceps weakness are linked in COPD, and whether they are associated with the systemic inflammatory mediator-fibrinogen. Aortic pulse wave velocity (aPWV), quadriceps maximal volitional contraction (QMVC) force and fibrinogen were measured in 729 patients with stable, Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages II-IV COPD. The cardiovascular and muscular manifestations exist independently (P=0.22, χ2). Fibrinogen was not associated with aPWV or QMVC (P=0.628 and P=0.621, respectively), making inflammation, as measured by plasma fibrinogen, an unlikely common aetiological factor.

The p38 mitogen activated protein kinase inhibitor losmapimod in chronic obstructive pulmonary disease patients with systemic inflammation, stratified by fibrinogen: A randomised double-blind placebo-controlled trial.

BACKGROUND: Cardiovascular 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. OBJECTIVES: This 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). METHODS: This 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). RESULTS: We 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. CONCLUSIONS: In 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.

Surrogate Markers of Cardiovascular Risk and Chronic Obstructive Pulmonary Disease: A Large Case-Controlled Study.

Cardiovascular disease is a common comorbidity and cause of mortality in chronic obstructive pulmonary disease. A better understanding of mechanisms of cardiovascular risk in chronic obstructive pulmonary disease patients is needed to improve clinical outcomes. We hypothesized that such patients have increased arterial stiffness, wave reflections, and subclinical atherosclerosis compared with controls and that these findings would be independent of smoking status and other confounding factors. A total of 458 patients with a diagnosis of chronic obstructive pulmonary disease and 1657 controls (43% were current or ex-smokers) with no airflow limitation were matched for age, sex, and body mass index. All individuals underwent assessments of carotid-femoral (aortic) pulse wave velocity, augmentation index, and carotid intima-media thickness. The mean age of the cohort was 67±8 years and 58% were men. Patients with chronic obstructive pulmonary disease had increased aortic pulse wave velocity (9.95±2.54 versus 9.27±2.41 m/s; P<0.001), augmentation index (28±10% versus 25±10%; P<0.001), and carotid intima-media thickness (0.83±0.19 versus 0.74±0.14 mm; P<0.001) compared with controls. Chronic obstructive pulmonary disease was associated with increased levels of each vascular biomarker independently of physiological confounders, smoking, and other cardiovascular risk factors. In this large case-controlled study, chronic obstructive pulmonary disease was associated with increased arterial stiffness, wave reflections, and subclinical atherosclerosis, independently of traditional cardiovascular risk factors. These findings suggest that the cardiovascular burden observed in this condition may be mediated through these mechanisms and supports the concept that chronic obstructive pulmonary disease is an independent risk factor for cardiovascular disease.

Applying physical science techniques and CERN technology to an unsolved problem in radiation treatment for cancer: the multidisciplinary 'VoxTox' research programme.

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.

The INVEST project: investigating the use of evidence synthesis in the design and analysis of clinical trials.

BACKGROUND: When designing and analysing clinical trials, using previous relevant information, perhaps in the form of evidence syntheses, can reduce research waste. We conducted the INVEST (INVestigating the use of Evidence Synthesis in the design and analysis of clinical Trials) survey to summarise the current use of evidence synthesis in trial design and analysis, to capture opinions of trialists and methodologists on such use, and to understand any barriers. METHODS: Our sampling frame was all delegates attending the International Clinical Trials Methodology Conference in November 2015. Respondents were asked to indicate (1) their views on the use of evidence synthesis in trial design and analysis, (2) their own use during the past 10 years and (3) the three greatest barriers to use in practice. RESULTS: Of approximately 638 attendees of the conference, 106 (17%) completed the survey, half of whom were statisticians. Support was generally high for using a description of previous evidence, a systematic review or a meta-analysis in trial design. Generally, respondents did not seem to be using evidence syntheses as often as they felt they should. For example, only 50% (42/84 relevant respondents) had used a meta-analysis to inform whether a trial is needed compared with 74% (62/84) indicating that this is desirable. Only 6% (5/81 relevant respondents) had used a value of information analysis to inform sample size calculations versus 22% (18/81) indicating support for this. Surprisingly large numbers of participants indicated support for, and previous use of, evidence syntheses in trial analysis. For example, 79% (79/100) of respondents indicated that external information about the treatment effect should be used to inform aspects of the analysis. The greatest perceived barrier to using evidence synthesis methods in trial design or analysis was time constraints, followed by a belief that the new trial was the first in the area. CONCLUSIONS: Evidence syntheses can be resource-intensive, but their use in informing the design, conduct and analysis of clinical trials is widely considered desirable. We advocate additional research, training and investment in resources dedicated to ways in which evidence syntheses can be undertaken more efficiently, offering the potential for cost savings in the long term.

Accumulated dose to the rectum, measured using dose-volume histograms and dose-surface maps, is different from planned dose in all patients treated with radiotherapy for prostate cancer.

OBJECTIVE: We sought to calculate accumulated dose (DA) to the rectum in patients treated with radiotherapy for prostate cancer. We were particularly interested in whether dose-surface maps (DSMs) provide additional information to dose-volume histograms (DVHs). METHODS: Manual rectal contours were obtained for kilovoltage and daily megavoltage CT scans for 10 participants from the VoxTox study (380 scans). Daily delivered dose recalculation was performed using a ray-tracing algorithm. Delivered DVHs were summated to create accumulated DVHs. The rectum was considered as a cylinder, cut and unfolded to produce daily delivered DSMs; these were summated to produce accumulated DSMs. RESULTS: Accumulated dose-volumes were different from planned in all participants. For one participant, all DA levels were higher and all volumes were larger than planned. For four participants, all DA levels were lower and all volumes were smaller than planned. For each of these four participants, ≥1% of pixels on the accumulated DSM received ≥5 Gy more than had been planned. CONCLUSION: Differences between accumulated and planned dose-volumes were seen in all participants. DSMs were able to identify differences between DA and planned dose that could not be appreciated from the DVHs. Further work is needed to extract the dose data embedded in the DSMs. These will be correlated with toxicity as part of the VoxTox Programme. ADVANCES IN KNOWLEDGE: DSMs are able to identify differences between DA and planned dose that cannot be appreciated from DVHs alone and should be incorporated into future studies investigating links between DA and toxicity.