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.

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.

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.

Investigating a novel population health management system to increase access to healthcare for children: a nested cross-sectional study within a cluster randomised controlled trial.

BACKGROUND: Early intervention for unmet needs is essential to improve health. Clear inequalities in healthcare use and outcomes exist. The Children and Young People's Health Partnership (CYPHP) model of care uses population health management methods to (1) identify and proactively reach children with asthma, eczema and constipation (tracer conditions); (2) engage these families, with CYPHP, by sending invitations to complete an online biopsychosocial Healthcheck Questionnaire; and (3) offer early intervention care to those children found to have unmet health needs. We aimed to understand this model's effectiveness to improve equitable access to care. METHODS: We used primary care and CYPHP service-linked records and applied the same methods as the CYPHP's population health management process to identify children aged <16 years with a tracer condition between 1 April 2018 and 30 August 2020, those who engaged by completing a Healthcheck and those who received early intervention care. We applied multiple imputation with multilevel logistic regression, clustered by general practitioner (GP) practice, to investigate the association of deprivation and ethnicity, with children's engagement and receiving care. RESULTS: Among 129 412 children, registered with 70 GP practices, 15% (19 773) had a tracer condition and 24% (4719) engaged with CYPHP's population health management system. Children in the most deprived, compared with least deprived communities, had 26% lower odds of engagement (OR 0.74; 95% CI 0.62 to 0.87). Children of Asian or black ethnicity had 31% lower odds of engaging, compared with white children (0.69 (0.59 to 0.81) and 0.69 (0.62 to 0.76), respectively). However, once engaged with the population health management system, black children had 43% higher odds of receiving care, compared with white children (1.43 (1.15 to 1.78)), and children from the most compared with least deprived communities had 50% higher odds of receiving care (1.50 (1.01 to 2.22)). CONCLUSION: Detection of unmet needs is possible using population health management methods and increases access to care for children from priority populations with the highest needs. Further health system strengthening is needed to improve engagement and enhance proportionate universalist access to healthcare. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT03461848).

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.

Co-design workshops with families experiencing multiple and interacting adversities including parental mental health, substance use, domestic violence, and poverty: intervention principles and insights from mothers, fathers, and young people.

BACKGROUND: Clustering and co-occurring of family adversities, including mental health problems, substance use, domestic violence and abuse, as well as poverty can increase health and behavioural risks for children, which persist throughout the life course. Yet, interventions that acknowledge and account for the complex interactive nature of such risks are limited. This study aimed to develop intervention principles based on reflections from mothers, fathers, and young people who experience multiple and interacting adversities. These principles will show how family members perceive an intervention may bring about positive change and highlight key insights into design and delivery. METHODS: A series of six co-design workshops with mothers, fathers, and young people who experienced multiple and interacting adversities (n = 41) were iteratively conducted across two regions in England (London and North-East) by four researchers. Workshop content and co-design activities were informed by advisory groups. Data from facilitator notes and activities were analysed thematically, resulting in a set of intervention principles. RESULTS: The intervention principles highlighted that: (1) to reduce isolation and loneliness parents and young people wanted to be connected to services, resources, and peer support networks within their local community, particularly by a knowledgeable and friendly community worker; (2) to address feelings of being misunderstood, parents and young people wanted the development of specialised trauma informed training for practitioners and to have the space to build trusting, gradual, and non-stigmatising relationships with practitioners; and (3) to address the needs and strengths of individual family members, mothers, fathers, and young people wanted separate, tailored, and confidential support. CONCLUSIONS: The current study has important implications for practice in supporting families that experience multiple and interacting adversities. The intervention principles from this study share common characteristics with other intervention models currently on offer in the United Kingdom, including social prescribing, but go beyond these to holistically consider the whole families' needs, environments, and circumstances. There should be particular focus on the child's as well as the mothers' and fathers' needs, independently of the family unit. Further refinement and piloting of the developing intervention are needed.

Families can experience multiple difficulties. These difficulties include parental mental health problems, alcohol and drug use, domestic violence, and poverty. These difficulties can impact the wellbeing of both parents and children. Currently, support that is provided to families rarely accounts for these complex and multiple difficulties. This study aimed to gather insights from mothers, fathers, and young people about how to best support families who experience multiple difficulties at the same time. We ran six workshops with community groups of mothers, fathers, and young people from London and North East England. We learned that: (1) Parents and young people wanted to be connected to services, resources and peer support networks within their local community. (2) Parents and young people wanted to build trusting, gradual, and non-stigmatising relationships with practitioners. (3) Parents and young people wanted support that was personalised to their own needs and that focused on their strengths. This research contributes key ideas for supporting families, which will be used alongside other studies to develop new ways of supporting families. The next steps will be to complete and test the developing support model, by delivering it to families and measuring how well it works.

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.

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.

"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.

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.

TSHR is the main causative locus in autosomal recessively inherited thyroid dysgenesis.

Congenital hypothyroidism (CH) is the most common neonatal endocrine disorder and results in mental retardation if untreated. Eighty-five percent of CH cases are due to disruptions in thyroid organogenesis and are mostly sporadic, but about 2% of thyroid dysgenesis is familial, indicating the involvement of genetic factors in the aetiology of the disease. In this study, we aimed to investigate the Mendelian (single-gene) causes of non-syndromic and non-goitrous congenital hypothyroidism (CHNG) in consanguineous or multi-case families. Here we report the results of the second part (n=105) of our large cohort (n=244), representing the largest such cohort in the literature, and interpret the overall results of the whole cohort. Additionally, 50 sporadic cases with thyroid dysgenesis and 400 unaffected control subjects were included in the study. In familial cases, first, we performed potential linkage analysis of four known genes causing CHNG (TSHR, PAX8, TSHB, and NKX2-5) using microsatellite markers and then examined the presence of mutations in these genes by direct sequencing. In addition, in silico analyses of the predicted structural effects of TSHR mutations were performed and related to the mutation specific disease phenotype. We detected eight new TSHR mutations and a PAX8 mutation but no mutations in TSHB and NKX2-5. None of the biallelic TSHR mutations detected in familial cases were present in the cohort of 50 sporadic cases. Genotype/phenotype relationships were established between TSHR mutations and resulting clinical presentations. Here we conclude that TSHR mutations are the main detectable cause of autosomal recessively inherited thyroid dysgenesis. We also outline a new genetic testing strategy for the investigation of suspected autosomal recessive non-goitrous CH.

Mutations in TTC37 cause trichohepatoenteric syndrome (phenotypic diarrhea of infancy).

BACKGROUND & AIMS: Trichohepatoenteric syndrome (THES) is an autosomal-recessive disorder characterized by life-threatening diarrhea in infancy, immunodeficiency, liver disease, trichorrhexis nodosa, facial dysmorphism, hypopigmentation, and cardiac defects. We attempted to characterize the phenotype and elucidate the molecular basis of THES. METHODS: Twelve patients with classic THES from 11 families had detailed phenotyping. Autozygosity mapping was undertaken in 8 patients from consanguineous families using 250,000 single nucleotide polymorphism arrays and linked regions evaluated using microsatellite markers. Linkage was confirmed to one region from which candidate genes were analyzed. The effect of mutations on protein production and/or localization in hepatocytes and intestinal epithelial cells from affected patients was characterized by immunohistochemistry. RESULTS: Previously unrecognized platelet abnormalities (reduced platelet alpha-granules, unusual stimulated alpha granule content release, abnormal lipid inclusions, abnormal platelet canalicular system, and reduced number of microtubules) were identified. The THES locus was mapped to 5q14.3-5q21.2. Sequencing of candidate genes showed mutations in TTC37, which encodes the uncharacterized tetratricopeptide repeat protein, thespin. Bioinformatic analysis suggested thespin to be involved in protein-protein interactions or chaperone. Preliminary studies of enterocyte brush-border ion transporter proteins (sodium hydrogen exchanger 2, sodium hydrogen exchanger 3, aquaporin 7, sodium iodide symporter, and hydrogen potassium adenosine triphosphatase [ATPase]) showed reduced expression or mislocalization in all THES patients with different profiles for each. In contrast the basolateral localization of Na/K ATPase was not altered. CONCLUSIONS: THES is caused by mutations in TTC37. TTC37 mutations have a multisystem effect, which may be owing to abnormal stability and/or intracellular localization of TTC37 target proteins.

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.

Tumor risks and genotype-phenotype-proteotype analysis in 358 patients with germline mutations in SDHB and SDHD.

Succinate dehydrogenase B (SDHB) and D (SDHD) subunit gene mutations predispose to adrenal and extraadrenal pheochromocytomas, head and neck paragangliomas (HNPGL), and other tumor types. We report tumor risks in 358 patients with SDHB (n=295) and SDHD (n=63) mutations. Risks of HNPGL and pheochromocytoma in SDHB mutation carriers were 29% and 52%, respectively, at age 60 years and 71% and 29%, respectively, in SDHD mutation carriers. Risks of malignant pheochromocytoma and renal tumors (14% at age 70 years) were higher in SDHB mutation carriers; 55 different mutations (including a novel recurrent exon 1 deletion) were identified. No clear genotype-phenotype correlations were detected for SDHB mutations. However, SDHD mutations predicted to result in loss of expression or a truncated or unstable protein were associated with a significantly increased risk of pheochromocytoma compared to missense mutations that were not predicted to impair protein stability (most such cases had the common p.Pro81Leu mutation). Analysis of the largest cohort of SDHB/D mutation carriers has enhanced estimates of penetrance and tumor risk and supports in silicon protein structure prediction analysis for functional assessment of mutations. The differing effect of the SDHD p.Pro81Leu on HNPGL and pheochromocytoma risks suggests differing mechanisms of tumorigenesis in SDH-associated HNPGL and pheochromocytoma.

Naturally occurring mutations alter the stability of polycystin-1 polycystic kidney disease (PKD) domains.

Mutations in polycystin-1 (PC1) can cause autosomal dominant polycystic kidney disease, which is a leading cause of renal failure. The available evidence suggests that PC1 acts as a mechanosensor, receiving signals from the primary cilia, neighboring cells, and extracellular matrix. PC1 is a large membrane protein that has a long N-terminal extracellular region (about 3000 amino acids) with a multimodular structure including 16 Ig-like polycystic kidney disease (PKD) domains, which are targeted by many naturally occurring missense mutations. Nothing is known about the effects of these mutations on the biophysical properties of PKD domains. Here we investigate the effects of several naturally occurring mutations on the mechanical stability of the first PKD domain of human PC1 (HuPKDd1). We found that several missense mutations alter the mechanical unfolding pathways of HuPKDd1, resulting in distinct mechanical phenotypes. Moreover, we found that these mutations also alter the thermodynamic stability of a structurally homologous archaeal PKD domain. Based on these findings, we hypothesize that missense mutations may cause autosomal dominant polycystic kidney disease by altering the stability of the PC1 ectodomain, thereby perturbing its ability to sense mechanical signals.

Novel TSHR mutations in consanguineous families with congenital nongoitrous hypothyroidism.

OBJECTIVE: Nonsyndromic autosomal recessively inherited nongoitrous congenital hypothyroidism (CHNG) can be caused by mutations in TSHR, PAX8, TSHB and NKX2-5. We aimed to investigate mutational frequencies of these genes and genotype/phenotype correlations in consanguineous families with CHNG. DESIGN: Because consanguinity in individuals with a presumptive genetic condition is often an indicator of an autosomal recessive inheritance and allows firmer correlations to be established between genotype and phenotype, we planned to execute our study in consanguineous families. PATIENTS: Hundred and thirty-nine children with CHNG phenotype born to consanguineous families. MEASUREMENTS: First, we investigated cases for evidence of linkage to the four known CHNG genes by microsatellite marker analysis. Mutation analysis by direct sequencing was then performed in those cases in whom linkage to the relevant candidate gene could not be excluded. In addition, in silico analysis of the predicted structural effects of TSHR mutations was performed and related to the mutation-specific disease phenotype. RESULTS: Homozygous germline TSHR mutations were detected in six families (5%), but no mutations were detected in PAX8, TSHB and NKX2-5. Four of TSHR mutations had not previously been described. Genotype-phenotype correlations were established and found to be related to the predicted structural effects of the mutations. CONCLUSIONS: Known causative genes account for the development of CHNG only in a minority of cases, and our cohort should provide a powerful resource to identify novel causative genes and to delineate the extent of locus heterogeneity in autosomal recessively inherited CHNG.

Mechanical unfolding of proteins: insights into biology, structure and folding.

Since user-friendly atomic force microscopes came onto the market a few years ago, scientists have explored the response of many proteins to applied force. This field has now matured beyond the phenomenological with exciting recent developments, particularly with regards to research into biological questions. For example, detailed mechanistic studies have suggested how mechanically active proteins perform their functions. Also, in vitro forced unfolding has been compared with in vivo protein import and degradation. Additionally, investigations have been carried out that probe the relationship between protein structure and response to applied force, an area that has benefited significantly from synergy between experiments and simulations. Finally, recent technological developments offer exciting new avenues for experimental studies.

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.