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Background: Poverty can have significant impacts on health and wellbeing. However, asking patients about their broader socio-economic circumstances is not routine within primary care consultations., Aim: To understand healthcare professionals' experiences of communicating with patients about their socio-economic circumstances and how a bespoke training programme supported these conversations in routine consultations., Design & Setting: Healthcare professionals from 30 GP practices across England received training to improve understanding and communication with patients about the ways that poverty impacted their mental health., Method: Semi-structured interviews were undertaken with 49 GPs and allied health professionals to understand barriers and enablers to communication around poverty and the impact of the training on their consultation practice., Results: Health professionals often lacked confidence in discussing socio-economic issues and welcomed information on how to do this sensitively. Asking questions relating to poverty-related stresses was felt to lead to better understanding around the causes of mental distress, avoidance of problematic assumptions and inappropriate antidepressant prescribing and to enable more coordinated and appropriate support from practice teams., Conclusion: Asking patients about their socio-economic circumstances can facilitate provision of appropriate support., (Copyright © 2024, The Authors.)

Background: Children and young people (CYP) in care experience poorer physical health and overall wellbeing in comparison to their peers. Despite this, relatively little is known about what their oral health needs and behaviours are. The aim of this scoping review was to provide a global perspective on the oral health status and behaviours of CYP in care and care leavers. It also aimed to synthesise interventions that have been trialled in this population to improve oral health., Methods: Five databases were searched, Ovid Embase, Ovid MEDLINE, CINAHL (EBSCOhost), SocINDEX (EBSCOhost) and Dentistry and Oral Sciences Source (EBSCOhost), alongside grey literature sources up to January 2023. Eligibility criteria were studies that (i) reported on children and adolescents aged 25 years or younger who are currently in formal/informal foster or residential care and care leavers, (ii) pertained to oral health profile, behaviours or oral health promotion interventions (iii) and were published in the English language. Thematic analysis was used to develop the domains for oral health behaviours and interventions., Results: Seventy-one papers were included. Most papers were published from very high or medium Human Development Index countries. CYP in care were found to experience high levels of decay, dental trauma, periodontal disease and poorer oral health-related quality of life. Oral health behaviours included limited oral health self-care behaviours and a lack of oral health-based knowledge. The trialled interventions involved oral health education, supervised brushing and treatment or preventative dental care., Conclusions: This scoping review reveals that CYP in care experience poorer oral health in comparison to their peers. They are also less likely to carry out oral health self-care behaviours. This review highlights a scarcity of interventions to improve the oral health of this population and a paucity of evidence surrounding the oral health needs of care leavers.

Aims: This scoping review aimed to explore three research questions: 1. What is the dental care access for children and young people (CYP) in care and care leavers? 2. What factors influence CYP in care and care leavers' access to dental care? 3. What pathways have been developed to improve access to oral health care for CYP in care and care leavers?, Methods: Five databases (Ovid MEDLINE, Ovid Embase, CINAHL, SocINDEX and Dentistry and Oral Sciences Source) and grey literature sources were systematically searched. Articles relating to CYP in care or care leavers aged 0-25 years old, published up to January 2023 were included. Abstracts, posters and publications not in the English language were excluded. The data relating to dental care access were analysed using thematic analysis., Results: The search identified 942 articles, of which 247 were excluded as duplicates. A review of the titles and abstracts yielded 149 studies. Thirty-eight were eligible for inclusion in the review: thirty-three peer-reviewed articles, one PhD thesis and four grey literature sources. All papers were published from very high or medium Human Development Index countries. The studies indicate that despite having higher treatment needs, CYP in care and care leavers experience greater difficulty in accessing dental services than those not care-experienced. Organisational, psycho-social and logistical factors influence their access to dental care. Their experience of dental care may be impacted by adverse childhood events. Pathways to dental care have been developed, but little is known of their impact on access. There are very few studies that include care leavers. The voices of care-experienced CYP are missing from dental access research., Conclusions: care-experienced CYP are disadvantaged in their access to dental care, and there are significant barriers to their treatment needs being met.

Cellular senescence is a well-established driver of aging and age-related diseases. There are many challenges to mapping senescent cells in tissues such as the absence of specific markers and their relatively low abundance and vast heterogeneity. Single-cell technologies have allowed unprecedented characterization of senescence; however, many methodologies fail to provide spatial insights. The spatial component is essential, as senescent cells communicate with neighboring cells, impacting their function and the composition of extracellular space. The Cellular Senescence Network (SenNet), a National Institutes of Health (NIH) Common Fund initiative, aims to map senescent cells across the lifespan of humans and mice. Here, we provide a comprehensive review of the existing and emerging methodologies for spatial imaging and their application toward mapping senescent cells. Moreover, we discuss the limitations and challenges inherent to each technology. We argue that the development of spatially resolved methods is essential toward the goal of attaining an atlas of senescent cells., (© 2023. Springer Nature America, Inc.)

Background: Physical activity can support smoking cessation for smokers wanting to quit, but there have been no studies on supporting smokers wanting only to reduce. More broadly, the effect of motivational support for such smokers is unclear., Objectives: The objectives were to determine if motivational support to increase physical activity and reduce smoking for smokers not wanting to immediately quit helps reduce smoking and increase abstinence and physical activity, and to determine if this intervention is cost-effective., Design: This was a multicentred, two-arm, parallel-group, randomised (1 : 1) controlled superiority trial with accompanying trial-based and model-based economic evaluations, and a process evaluation., Setting and Participants: Participants from health and other community settings in four English cities received either the intervention ( n  = 457) or usual support ( n  = 458)., Intervention: The intervention consisted of up to eight face-to-face or telephone behavioural support sessions to reduce smoking and increase physical activity., Main Outcome Measures: The main outcome measures were carbon monoxide-verified 6- and 12-month floating prolonged abstinence (primary outcome), self-reported number of cigarettes smoked per day, number of quit attempts and carbon monoxide-verified abstinence at 3 and 9 months. Furthermore, self-reported (3 and 9 months) and accelerometer-recorded (3 months) physical activity data were gathered. Process items, intervention costs and cost-effectiveness were also assessed., Results: The average age of the sample was 49.8 years, and participants were predominantly from areas with socioeconomic deprivation and were moderately heavy smokers. The intervention was delivered with good fidelity. Few participants achieved carbon monoxide-verified 6-month prolonged abstinence [nine (2.0%) in the intervention group and four (0.9%) in the control group; adjusted odds ratio 2.30 (95% confidence interval 0.70 to 7.56)] or 12-month prolonged abstinence [six (1.3%) in the intervention group and one (0.2%) in the control group; adjusted odds ratio 6.33 (95% confidence interval 0.76 to 53.10)]. At 3 months, the intervention participants smoked fewer cigarettes than the control participants (21.1 vs. 26.8 per day). Intervention participants were more likely to reduce cigarettes by ≥ 50% by 3 months [18.9% vs. 10.5%; adjusted odds ratio 1.98 (95% confidence interval 1.35 to 2.90] and 9 months [14.4% vs. 10.0%; adjusted odds ratio 1.52 (95% confidence interval 1.01 to 2.29)], and reported more moderate-to-vigorous physical activity at 3 months [adjusted weekly mean difference of 81.61 minutes (95% confidence interval 28.75 to 134.47 minutes)], but not at 9 months. Increased physical activity did not mediate intervention effects on smoking. The intervention positively influenced most smoking and physical activity beliefs, with some intervention effects mediating changes in smoking and physical activity outcomes. The average intervention cost was estimated to be £239.18 per person, with an overall additional cost of £173.50 (95% confidence interval -£353.82 to £513.77) when considering intervention and health-care costs. The 1.1% absolute between-group difference in carbon monoxide-verified 6-month prolonged abstinence provided a small gain in lifetime quality-adjusted life-years (0.006), and a minimal saving in lifetime health-care costs (net saving £236)., Conclusions: There was no evidence that behavioural support for smoking reduction and increased physical activity led to meaningful increases in prolonged abstinence among smokers with no immediate plans to quit smoking. The intervention is not cost-effective., Limitations: Prolonged abstinence rates were much lower than expected, meaning that the trial was underpowered to provide confidence that the intervention doubled prolonged abstinence., Future Work: Further research should explore the effects of the present intervention to support smokers who want to reduce prior to quitting, and/or extend the support available for prolonged reduction and abstinence., Trial Registration: This trial is registered as ISRCTN47776579., Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 27, No. 4. See the NIHR Journals Library website for further project information.

Background: Ongoing alcohol use is strongly associated with progressive liver damage and higher mortality in patients with alcohol-related liver disease (ArLD). Reduction in alcohol use is therefore the cornerstone of treatment to improve the long-term outcome of these patients. However, a large proportion of patients continue to use alcohol and do not access or engage with alcohol treatment services after a diagnosis of ArLD. We reviewed the literature on factors associated with ongoing alcohol consumption among patients with ArLD to identify barriers or facilitators to their accessing alcohol treatment., Methods: A search of MEDLINE and EMBASE was conducted using search strategies relating to ArLD and the psychosocial factors hypothesized to influence alcohol reduction and/or abstinence., Results: There were few relevant studies pertinent to this population group. Several studies reported a high prevalence of mental health diagnoses associated with the severity of alcohol dependence. Social and environmental factors were shown to be important determinants of alcohol use. Common themes perceived as barriers to treatment from qualitative interviews with ArLD patients across studies included poor communication between the clinical team and patient, lack of symptoms recognized by patients themselves, and perceived loss of control over their condition., Conclusions: We recommend that future clinical studies of patient cohorts with ArLD include detailed psychosocial assessments to capture information on mental health and social factors. Qualitative studies are required to explore the patient journey pre and post hospital admission, which should focus on identifying facilitators and barriers to accessing treatment. Well-designed, controlled studies are needed to identify patient, social, and environmental factors associated with relapse to alcohol use after a diagnosis of ArLD. These data will enable us to adapt our support for patients to enhance engagement with services and improve long-term outcomes., (© 2022 The Authors. Alcoholism: Clinical & Experimental Research published by Wiley Periodicals LLC on behalf of Research Society on Alcoholism.)

Introduction: Smoking reduction can lead to increased success in quitting. This study aims to determine if a client-focused motivational support package for smoking reduction (and quitting) and increasing (or otherwise using) physical activity (PA) can help smokers who do not wish to quit immediately to reduce the amount they smoke, and ultimately quit. This paper reports the study design and methods., Methods and Analysis: A pragmatic, multicentred, parallel, two group, randomised controlled superiority clinical trial, with embedded process evaluation and economics evaluation. Participants who wished to reduce smoking with no immediate plans to quit were randomised 1:1 to receive either (1) tailored individual health trainer face-to-face and/or telephone support to reduce smoking and increase PA as an aid to smoking reduction (intervention) or (2) brief written/electronic advice to reduce or quit smoking (control). Participants in both arms of the trial were also signposted to usual local support for smoking reduction and quitting. The primary outcome measure is 6-month carbon monoxide-confirmed floating prolonged abstinence following participant self-reported quitting on a mailed questionnaire at 3 and 9 months post-baseline. Participants confirmed as abstinent at 9 months will be followed up at 15 months., Ethics and Dissemination: Approved by SW Bristol National Health Service Research Committee (17/SW/0223). Dissemination will include publication of findings for the stated outcomes, parallel process evaluation and economic evaluation in peer-reviewed journals. Results will be disseminated to trial participants and healthcare providers., Trial Registration Number: ISRCTN47776579; Pre-results., Competing Interests: Competing interests: AG, AJS, AT, CJG, CG, CW, DP, HH, JC, JK, LC, LH, MG, MU, PA, RLM, SCr, SCa, TH, TS, TPT and WI report a grant from NIHR (NIHR HTA award ref 15/111/01) during the conduct of the study. PA is an NIHR Senior Investigator and is part funded by NIHR Oxford Biomedical Research Centre and Applied Research Centre. SCr reports grants from NIHR HTA during the conduct of the study, and various other grants from NIHR and UK charities outside the submitted work. She is also Interim Codirector (and previously Director) of the UKCRC-registered Peninsula Clinical Trials Unit, which is in receipt of NIHR Clinical Trials Unit Support Funding (current award ends 31 August 2021). LP reports consultancy fees from NIHR during the conduct of the study; grants from Living Streets Charity, personal fees from NIHR, personal fees from NIHR PHR, personal fees from NIHR PHR rapid response, grants from Wellcome Trust seed corn (internal funding) outside the submitted work; and discloses that the physical activity group in Sport and Health Sciences at the University of Exeter has a collaboration with Activinsights (the manufacturer of the physical activity monitor), to provide study design advice and data analysis, but that analysis of the physical activity data in the present study was not undertaken as part of that service., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

The aim of this review is to systematically describe and quantify the effects of PA interventions on alcohol and other drug use outcomes, and to identify any apparent effect of PA dose and type, possible mechanisms of effect, and any other aspect of intervention delivery (e.g. key behaviour change processes), within a framework to inform the design and evaluation of future interventions. Systematic searches were designed to identify published and grey literature on the role of PA for reducing the risk of progression to alcohol and other drug use (PREVENTION), supporting individuals to reduce alcohol and other drug use for harm reduction (REDUCTION), and promote abstinence and relapse prevention during and after treatment of alcohol and other drug use (TREATMENT). Searches identified 49,518 records, with 49,342 excluded on title and abstract. We screened 176 full text articles from which we included 32 studies in 32 papers with quantitative results of relevance to this review. Meta-analysis of two studies showed a significant effect of PA on prevention of alcohol initiation (risk ratio [RR]: 0.72, 95%CI: 0.61 to 0.85). Meta-analysis of four studies showed no clear evidence for an effect of PA on alcohol consumption (Standardised Mean Difference [SMD]: 0.19, 95%, Confidence Interval -0.57 to 0.18). We were unable to quantitatively examine the effects of PA interventions on other drug use alone, or in combination with alcohol use, for prevention, reduction or treatment. Among the 19 treatment studies with an alcohol and other drug use outcome, there was a trend for promising short-term effect but with limited information about intervention fidelity and exercise dose, there was a moderate to high risk of bias. We identified no studies reporting the cost-effectiveness of interventions. More rigorous and well-designed research is needed. Our novel approach to the review provides a clearer guide to achieve this in future research questions addressed to inform policy and practice for different populations and settings., Competing Interests: JN has received, through her University, research funding from Mundipharma Research Ltd and Camurus AB to study novel opioid pharmacotherapy delivery systems and nasal naloxone., (© 2020 The Authors.)

Chromatin modifiers play critical roles in epidermal development, but the functions of histone deacetylases in this context are poorly understood. The class I HDAC, HDAC3, is of particular interest because it plays divergent roles in different tissues by partnering with tissue-specific transcription factors. We found that HDAC3 is expressed broadly in embryonic epidermis and is required for its orderly stepwise stratification. HDAC3 protein stability in vivo relies on NCoR and SMRT, which function redundantly in epidermal development. However, point mutations in the NCoR and SMRT deacetylase-activating domains, which are required for HDAC3's enzymatic function, permit normal stratification, indicating that HDAC3's roles in this context are largely independent of its histone deacetylase activity. HDAC3-bound sites are significantly enriched for predicted binding motifs for critical epidermal transcription factors including AP1, GRHL, and KLF family members. Our results suggest that among these, HDAC3 operates in conjunction with KLF4 to repress inappropriate expression of Tgm1 , Krt16 , and Aqp3 In parallel, HDAC3 suppresses expression of inflammatory cytokines through a Rela -dependent mechanism. These data identify HDAC3 as a hub coordinating multiple aspects of epidermal barrier acquisition., (© 2020 Szigety et al.; Published by Cold Spring Harbor Laboratory Press.)

Objectives: To evaluate a county-wide deincentivisation of the Quality and Outcomes Framework (QOF) payment scheme for UK General Practice (GP)., Setting: In 2014, National Health Service England signalled a move towards devolution of QOF to Clinical Commissioning Groups. Fifty-five GPs in Somerset established the Somerset Practice Quality Scheme (SPQS)-a deincentivisation of QOF-with the goal of redirecting resources towards Person Centred Coordinated Care (P3C), especially for those with long-term conditions (LTCs). We evaluated the impact on processes and outcomes of care from April 2016 to March 2017., Participants and Design: The evaluation used data from 55 SPQS practices and 17 regional control practices for three survey instruments. We collected patient experiences ('P3C-EQ'; 2363 returns from patients with 1+LTC; 36% response rate), staff experiences ('P3C-practitioner'; 127 professionals) and organisational data ('P3C-OCT'; 36 of 55 practices at two time points, 65% response rate; 17 control practices). Hospital Episode Statistics emergency admission data were analysed for 2014-2017 for ambulatory-sensitive conditions across Somerset using interrupted time series., Results: Patient and practitioner experiences were similar in SPQS versus control practices. However, discretion from QOF incentives resulted in time savings in the majority of practices, and SPQS practice data showed a significant increase in P3C oriented organisational processes, with a moderate effect size (Wilcoxon signed rank test; p=0.01; r=0.42). Analysis of transformation plans and organisational data suggested stronger federation-level agreements and informal networks, increased multidisciplinary working, reallocation of resources for other healthcare professionals and changes to the structure and timings of GP appointments. No disbenefits were detected in admission data., Conclusion: The SPQS scheme leveraged time savings and reduced administrative burden via discretionary removal of QOF incentives, enabling practices to engage actively in a number of schemes aimed at improving care for people with LTCs. We found no differences in the experiences of patients or healthcare professionals between SPQS and control practices., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Recent advances in genomics and imaging technologies have increased our ability to interrogate the 3D conformation of chromosomes and to better understand principles of organization and dynamics, as well as how their alteration can lead to disease. In this review we describe how these technologies have shed new light into the role of the 3D organization of the genome in defining cellular states in aging and age-associated diseases. We compare the genomic organization in cellular senescence and cancer, discuss the role of the lamina in maintaining the structural and functional integrity of the genome, and we highlight the recent findings on how this organization breaks down in disease states., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: To ascertain whether person centred coordinated care (P3C) is being delivered in healthcare services, components relating to the construct need to be measured. Patient reported measures (PRMs) can be used to provide a measurement of patients' experiences of P3C. Traditionally, they have been used to assess whether interventions are delivering P3C. Recently there has been an increased interest in using them to directly enhance P3C in clinical practice by, for example, improving practitioner-patient communication. However, there is limited research available on how P3C can be implemented in practice. This study aimed to extend this literature base by exploring how professionals use PRMs to enhance P3C., Methods: Cross sectional thematic analysis of 26 semi-structured interviews with a variety of professionals who have experience of how PRMs can be used to make improvements to P3C. Inductive themes were mapped onto components of P3C care that fell under five established domains of P3C (Information and Communication; My Goals/Outcomes; Decision making; Care Planning and Transitions) to explore whether and how individual components of P3C were being improved through PRMs. Barriers and facilitators that affected the delivery and the results of the PRMs were also identified., Results: Three P3C domains (Information and Communication, My Goals/Outcomes and Care Planning) were mapped frequently onto themes generated by the participants' interviews about PRM use. However, the domain 'Decision Making' was only mapped onto one theme and 'Transitions' was not mapped at all. Participant reports suggested that PRM use by practitioners enhanced patients' ability to self-manage, communicate, engage and reflect during consultations. Barriers to PRM use were related to a lack of a whole service approach to implementation., Conclusions: Practitioners use both PROMs and PREMs in various ways to improve different aspects of patient care. By sharing experiences professionals can benefit from each other's learning and work together to extend the potential value that PRMs can offer to P3C delivery.

Background: Person-centred coordinated care (P3C) is a priority for stakeholders (ie, patients, carers, professionals, policy makers). As a part of the development of an evaluation framework for P3C, we set out to identify patient-reported experience measures (PREMs) suitable for routine measurement and feedback during the development of services., Methods: A rapid review of the literature was undertaken to identity existing PREMs suitable for the probing person-centred and/or coordinated care. Of 74 measures identified, 7 met our inclusion criteria. We critically examined these against core domains and subdomains of P3C. Measures were then presented to stakeholders in codesign workshops to explore acceptability, utility, and their strengths/weaknesses., Results: The Long-Term Condition 6 questionnaire was preferred for its short length, utility, and tone. However, it lacked key questions in each core domain, and in response to requests from our codesign group, new questions were added to cover consideration as a whole person, coordination, care plans, carer involvement, and a single coordinator. Cognitive interviews, on-going codesign, and mapping to core P3C domains resulted in the refinement of the questionnaire to 11 items with 1 trigger question. The 11-item modified version was renamed the P3C Experiences Questionnaire., Conclusions: Due to a dearth of brief measures available to capture people's experience of P3C for routine practice, an existing measure was modified using an iterative process of adaption and validation through codesign workshops. Next steps include psychometric validation and modification for people with dementia and learning difficulties., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Person Centred Coordinated Care (P3C) is a UK priority for patients, carers, professionals, commissioners and policy makers. Services are developing a range of approaches to deliver this care with a lack of tools to guide implementation., Methodology: A scoping review and critical examination of current policy, key literature and NHS guidelines, together with stakeholder involvement led to the identification of domains, subdomains and component activities (processes and behaviours) required to deliver P3C. These were validated through codesign with stakeholders via a series of workshops and cognitive interviews., Results: Six core domains of P3C were identified as follows: (i) my goals, (ii) care planning, (iii) transitions, (iv) decision making (v), information and communication and (vi) organizational support activities. These were populated by 29 core subdomains (question items). A number of response codes (components) to each question provide examples of the processes and activities that can be actioned to achieve each core subdomain of P3C., Conclusion: The P3C-OCT provides a coherent approach to monitoring progress and supporting practice development towards P3C. It can be used to generate a shared understanding of the core domains of P3C at a service delivery level, and support reorganization of care for those with complex needs. The tool can reliably detect change over time, as demonstrated in a sample of 40 UK general practices. It is currently being used in four UK evaluations of new models of care and being further developed as a training tool for the delivery of P3C., (© 2017 The Authors Health Expectations Published by John Wiley & Sons Ltd.)

Background: Patient-reported measure (PRM) questionnaires were originally used in research to measure outcomes of intervention studies. They have now evolved into a diverse family of tools measuring a range of constructs including quality of life and experiences of care. Current health and social care policy increasingly advocates their use for embedding the patient voice into service redesign through new models of care such as person-centered coordinated care (P3C). If chosen carefully and used efficiently, these tools can help improve care delivery through a variety of novel ways, including system-level feedback for health care management and commissioning. Support and guidance on how to use these tools would be critical to achieve these goals., Objective: The objective of this study was to develop evidence-based guidance and support for the use of P3C-PRMs in health and social care policy through identification of PRMs that can be used to enhance the development of P3C, mapping P3C-PRMs against an existing model of domains of P3C, and integration and organization of the information in a user-friendly Web-based database., Methods: A pragmatic approach was used for the systematic identification of candidate P3C-PRMs, which aimed at balancing comprehensiveness and feasibility. This utilized a number of resources, including existing compendiums, peer-reviewed and gray literature (using a flexible search strategy), and stakeholder engagement (which included guidance for relevant clinical areas). A subset of those candidate measures (meeting prespecified eligibility criteria) was then mapped against a theoretical model of P3C, facilitating classification of the construct being measured and the subsequent generation of shortlists for generic P3C measures, specific aspects of P3C (eg, communication or decision making), and condition-specific measures (eg, diabetes, cancer) in priority areas, as highlighted by stakeholders., Results: In total, 328 P3C-PRMs were identified, which were used to populate a freely available Web-based database. Of these, 63 P3C-PRMs met the eligibility criteria for shortlisting and were classified according to their measurement constructs and mapped against the theoretical P3C model. We identified tools with the best coverage of P3C, thereby providing evidence of their content validity as outcome measures for new models of care. Transitions and medications were 2 areas currently poorly covered by existing measures. All the information is currently available at a user-friendly web-based portal (p3c.org.uk), which includes all relevant information on each measure, such as the constructs targeted and links to relevant literature, in addition to shortlists according to relevant constructs., Conclusions: A detailed compendium of P3C-PRMs has been developed using a pragmatic systematic approach supported by stakeholder engagement. Our user-friendly suite of tools is designed to act as a portal to the world of PRMs for P3C, and have utility for a broad audience, including (but not limited to) health care commissioners, managers, and researchers., (©Helen Lloyd, Hannah Wheat, Jane Horrell, Thavapriya Sugavanam, Benjamin Fosh, Jose M Valderas, James Close. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 14.02.2018.)

Background: Fragmented care results in poor outcomes for individuals with complexity of need. Person-centred coordinated care (P3C) is perceived to be a potential solution, but an absence of accessible evidence and the lack of a scalable 'blue print' mean that services are 'experimenting' with new models of care with little guidance and support. This paper presents an approach to the implementation of P3C using collaborative action, providing examples of early developments across this programme of work, the core aim of which is to accelerate the spread and adoption of P3C in United Kingdom primary care settings., Methods: Two centrally funded United Kingdom organisations (South West Collaboration for Leadership in Applied Health Research and Care and South West Academic Health Science Network) are leading this initiative to narrow the gap between research and practice in this urgent area of improvement through a programme of service change, evaluation and research. Multi-stakeholder engagement and co-design are core to the approach. A whole system measurement framework combines outcomes of importance to patients, practitioners and health organisations. Iterative and multi-level feedback helps to shape service change while collecting practice-based data to generate implementation knowledge for the delivery of P3C. The role of the research team is proving vital to support informed change and challenge organisational practice. The bidirectional flow of knowledge and evidence relies on the transitional positioning of researchers and research organisations., Results: Extensive engagement and embedded researchers have led to strong collaborations across the region. Practice is beginning to show signs of change and data flow and exchange is taking place. However, working in this way is not without its challenges; progress has been slow in the development of a linked data set to allow us to assess impact innovations from a cost perspective. Trust is vital, takes time to establish and is dependent on the exchange of services and interactions. If collaborative action can foster P3C it will require sustained commitment from both research and practice. This approach is a radical departure from how policy, research and practice traditionally work, but one that we argue is now necessary to deal with the most complex health and social problems.

Human WNT10A mutations are associated with developmental tooth abnormalities and adolescent onset of a broad range of ectodermal defects. Here we show that β-catenin pathway activity and adult epithelial progenitor proliferation are reduced in the absence of WNT10A, and identify Wnt-active self-renewing stem cells in affected tissues including hair follicles, sebaceous glands, taste buds, nails and sweat ducts. Human and mouse WNT10A mutant palmoplantar and tongue epithelia also display specific differentiation defects that are mimicked by loss of the transcription factor KLF4. We find that β-catenin interacts directly with region-specific LEF/TCF factors, and with KLF4 in differentiating, but not proliferating, cells to promote expression of specialized keratins required for normal tissue structure and integrity. Our data identify WNT10A as a critical ligand controlling adult epithelial proliferation and region-specific differentiation, and suggest downstream β-catenin pathway activation as a potential approach to ameliorate regenerative defects in WNT10A patients.