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Se propone un “modelo sinérgico” para avanzar en la integración de elementos clave de la salutogénesis y el modelo de activos para la salud, utilizando como marco para esta articulación la teoría bioecológica de Bronfenbrenner. El sentido de coherencia es clave para facilitar la transformación de recursos potenciales en activos disponibles, produciendo un desarrollo positivo de la salud. El modelo sinérgico puede aportar a la contextualización de las ideas en políticas y prácticas de salud pública, fortaleciendo la dimensión salud-bienestar y contribuyendo al desarrollo de modelos de salud más integrados y colectivos.

Las intervenciones centradas en cambios de conducta, sumadas a la escasa evidencia de mapeo y dinamización de activos en Universidades Promotoras de Salud (UPS), hacen necesario potenciar enfoques integrales y sistémicos que contribuyan al bienestar y empoderamiento de sus integrantes. El objetivo de este artículo es explorar propuestas de acción que contribuyan a fortalecer activos en una comunidad universitaria chilena. Se desarrolló un estudio cualitativo con 72 hombres/77 mujeres (estudiantes, trabajadores, jubilados y exestudiantes). Se realizaron 48 entrevistas individuales y 14 grupos focales. Se efectuó un análisis de contenido utilizando el software QRS NVivo 12. Las propuestas identificadas se agruparon en: desarrollo de la participación e inclusión, promoción de la salud mental, mantenimiento y mejora de áreas verdes e infraestructura, y fortalecimiento del acceso a actividades deportivas, culturales y de extensión universitaria. Las mujeres valoraron la difusión de activos comunitarios y el cuidado de las personas y el entorno. Y los hombres, el fortalecimiento del capital social, la docencia y la transferencia de conocimiento. Las propuestas de acción tienen una orientación colectiva que favorece el vínculo de las personas con su entorno y el desarrollo del sentido de comunidad. Desde una perspectiva de género, se observa reproducción de roles y estereotipos arraigados en el sistema patriarcal. Esto constituye un desafío para potenciar las UPS en tanto política pública, considerando los principios de participación, justicia social y equidad. Este estudio se enmarca dentro del proyecto VRID 217.089.007-1.0IN financiado por la Vicerrectorría de Investigación y Desarrollo de la Universidad de Concepción, Chile.

The ERK1/2 (also known as MAPK3 and MAPK1, respectively) signaling pathway is critical in organismal development and tissue morphogenesis. Deregulation of this pathway leads to congenital abnormalities with severe developmental dysmorphisms. The core ERK1/2 cascade relies on scaffold proteins, such as Shoc2 to guide and fine-tune its signals. Mutations in SHOC2 lead to the development of the pathology termed Noonan-like Syndrome with Loose Anagen Hair (NSLAH). However, the mechanisms underlying the functions of Shoc2 and its contributions to disease progression remain unclear. Here, we show that ERK1/2 pathway activation triggers the interaction of Shoc2 with the ubiquitin-specific protease USP7. We reveal that, in the Shoc2 module, USP7 functions as a molecular ‘switch’ that controls the E3 ligase HUWE1 and the HUWE1-induced regulatory feedback loop. We also demonstrate that disruption of Shoc2-USP7 binding leads to aberrant activation of the Shoc2-ERK1/2 axis. Importantly, our studies reveal a possible role for USP7 in the pathogenic mechanisms underlying NSLAH, thereby extending our understanding of how ubiquitin-specific proteases regulate intracellular signaling.

Aim: To explore the extent to which national policy in end-of-life care (EOLC) in England influences and guides local practice, helping to ensure that care for older people at the EOL is of a consistently good quality. Background: Whilst policy is recognised as an important component in determining the effectiveness of EOLC, there is scant literature which attempts to interrogate how this happens or to hypothesise the mechanisms linking policy to better outcomes. Method: This article reports on the second phase of a realist evaluation comprising three case studies of clinical commissioning groups, including 98 in-depth interviews with stakeholders, meeting observation and documentary analysis. Findings: This study reveals the key contextual factors which need to be in place at micro, meso and macro levels if good quality EOLC for older people is to be achieved. The findings provide insight into rising local inequalities and reveal areas of dissonance between stakeholder priorities. Whilst patients privilege the importance of receiving care and compassion in familiar surroundings at EOL, there remains a clear tension between this and the medical drive to cure disease and extend life. The apparent devaluing of social care and subsequent lack of resource has impacted significantly on the way in which dying is experienced. Patient experience at EOL, shaped by the care received both formally and informally, is driven by a fragmented health and social care system. Whilst the importance of system integration appears to have been recognised, significant challenges remain in terms of shaping policy to adequately reflect this. This study highlights the priority attached by patients and their families to the social and relational aspect of death and dying and shines a light on the stark disparities between the health and social care systems which became even more evident at the height of the Covid-19 pandemic.

Different models of care in context of chronicity and multimorbidity include community, health system, clinical practice, health policies, prevention, and health promotion. Among these, the role of the health team as a facilitator of self-management is pointed out, being people the protagonists of their process. Multimorbidity approach is mostly carried out from a risk and disease focused point of view, which limits the exploration of resources of people and their environment. Incorporating a positive health approach can contribute to a greater comprehensiveness. The purpose of this article is to propose an approach from the synergy model of health, integrating salutogenesis and health assets model, to help facilitate self-management promoting people's agency capacity. Potential areas of application of these models are presented to work in the context of multimorbidity, promoting health and well-being conditions in people and their families.

Background Referrals and waiting times for diagnostic assessment of possible autism in children have increased substantially within UK NHS recently, delaying opportunities for intervention and frustrating families. Research exploring which service models could improve quality and timeliness of autism assessment is a key NHSE priority. Objectives Explore evidence from research and grey literature about which autism assessment pathways work well, for whom and under what circumstances, to deliver high quality and timely diagnosis. Inform subsequent stages of our Realist Evaluation/study. Methods We performed a Rapid Realist Review (RRR), a well-established approach to synthesising evidence to identify service delivery models achieving desired outcomes. RRRs seek to develop programme theories (PTs), or explanations, of how, why and in what contexts an intervention works. The focus was a clearly defined intervention (diagnostic pathway), specific outcomes (high quality and timely) within particular parameters (Autism diagnostic services in UK). This was carried out in five iterative stages. We collected 129 grey literature and policy/guidelines from the background search, and 220 articles from primary search (Jan 2011-Dec 2019; seven databases, terms: autism, diagnostic pathway, model of service provision, assessment process). Following duplicate removal and screening of abstracts, two researchers carried out data extraction by hybrid approach: basic details from each included article (n=79) were recorded in an Excel data extraction form; highly relevant articles (n=45) were coded in NVivo. PTs were developed by cross comparison and synthesis of evidence from the articles and findings were discussed with expert stakeholders. Results 7 PTs were identified, the first 4 informing stages contributing to effective diagnostic pathways, the remaining 3, overarching principles. Potential facilitative service models were identified. If frontline health/education professionals are confident in recognizing symptoms of autism, understand referral pathways and take parents’ concerns seriously, then children and young people (CYP) will be referred appropriately, in a timely manner. If services provide clear guidelines for referrers on what information is needed, time will be saved and fewer CYP will be assessed unnecessarily. If a structured and consistent approach to service delivery is adopted, making best use of available staff and expertise then the number of assessments per individual may be reduced. If feedback takes an assets-based approach and management plans are individualized, then parental expectations will be moderated. If parents have a single point of contact, are provided explanations throughout and included in decision-making then diagnostic pathway may be less stressful. If ‘experts’ including CYP and parents work together and knowledge generated is embedded into local services, this will build capacity and support service planning. If professionals have access to tailored training appropriate to their role, and services engage in development and evaluation, then there will be a higher degree of consistency. Conclusions This first theory informed review of childhood autism diagnostic pathways has identified important aspects that may contribute to more efficient, high quality and family friendly service delivery. We will test whether the resulting PTs are met, and how service design could be further enhanced through a national survey of current practice and in depth case study of exemplar services.

Valosin-containing protein (VCP), also named p97, is an essential hexameric AAA+ ATPase with diverse functions in the ubiquitin system. Here we demonstrate that VCP is critical in controlling signals transmitted via the essential Shoc2-ERK1/2 signaling axis. The ATPase activity of VCP modulates the stoichiometry of HUWE1 in the Shoc2 complex as well as HUWE1-mediated allosteric ubiquitination of the Shoc2 scaffold and the RAF-1 kinase. Abrogated ATPase activity leads to augmented ubiquitination of Shoc2/RAF-1 and altered phosphorylation of RAF-1. We found that in fibroblasts from patients with inclusion body myopathy with Paget’s disease of bone and frontotemporal dementia (IBMPFD) that harbor germline mutations in VCP, the levels of Shoc2 ubiquitination and ERK1/2 phosphorylation are imbalanced. This study provides a mechanistic basis for the critical role of VCP in the regulation of the ERK1/2 pathway and reveals a previously unrecognized function of the ERK1/2 pathway in the pathogenesis of IBMPFD.

Autosomal Recessive Polycystic Kidney Disease (ARPKD) is a genetic disorder with an incidence of ~1:20,000 that manifests in a wide range of renal and liver disease severity in human patients and can lead to perinatal mortality. ARPKD is caused by mutations in PKHD1, which encodes the large membrane protein, Fibrocystin, required for normal branching morphogenesis of the ureteric bud during embryonic renal development. The variation in ARPKD phenotype suggests that in addition to PKHD1 mutations, other genes may play a role, acting as modifiers of disease severity. One such pathway involves non-canonical Wnt/Planar Cell Polarity (PCP) signalling that has been associated with other cystic kidney diseases, but has not been investigated in ARPKD. Analysis of the AtminGpg6 mouse showed kidney, liver and lung abnormalities, suggesting it as a novel mouse tool for the study of ARPKD. Further, modulation of Atmin affected Pkhd1 mRNA levels, altered non-canonical Wnt/PCP signalling and impacted cellular proliferation and adhesion, although Atmin does not bind directly to the C-terminus of Fibrocystin. Differences in ATMIN and VANGL2 expression were observed between normal human paediatric kidneys and age-matched ARPKD kidneys. Significant increases in ATMIN, WNT5A, VANGL2 and SCRIBBLE were seen in human ARPKD versus normal kidneys; no substantial differences were seen in DAAM2 or NPHP2. A striking increase in E-cadherin was also detected in ARPKD kidneys. This work indicates a novel role for non-canonical Wnt/PCP signalling in ARPKD and suggests ATMIN as a modulator of PKHD1., Graphical abstract Unlabelled Image, Highlights • The AtminGpg6 mouse displays kidney, liver and lung defects. • Atmin modulates Pkhd1 expression and affects cellular proliferation and adhesion in mIMCD3 cells. • Altered Wnt signalling is observed in Atmin/Pkhd1 knockdowns and in ARPKD kidneys.

ADPKD is the most common genetic disease of the kidney leading to end-stage renal disease necessitating renal replacement therapy at any time between the 1(st) and 8(th) decades of life due to widely variable rates of disease progression. This presents significant patient anxiety and a significant prognostic and therapeutic challenge. Tolvaptan is the only approved drug licensed to slow ADPKD progression by reducing renal cystic expansion but side-effects can limit its efficacy. To address the need to identify new biomarkers to monitor progression of ADPKD and to evaluate the therapeutic effects of Tolvaptan, proteomic analysis was conducted on defined (40-100nm) urinary exosomes isolated from ADPKD patients phenotyped and clinically monitored over a 10-year period. Comparative Gene Ontology analysis of Tandem Mass Tag labelled mass spectrometry-derived protein profiles from urinary exosomes from ADPKD patients with rapid (>10ml/min/5 years decline in estimated glomerular filtration rate) versus slow progression showed distinctive patterns of pathway up-regulation. Clear discrimination between rapid and slowly-progressive profiles were seen in all stages functional decline in ADPKD patients whether with mild (>70ml/min), moderate (50-69ml/min) or severe (

Health Promoting Universities (HPUs) are more likely to perform actions intended to change habits and increase personal empowerment, than they are to develop community actions. The objective of this research is to create an asset map to visualize collective actions in a Chilean HPU. A qualitative study, based on the ABCD model was conducted. There were 149 people, distributed into 48 semistructured interviews and 14 focus groups, who participated in this study (students, employees, ex-students and retirees). An asset map was elaborated, identifying the contributions of residents, associations and organizations, local institutions, physical resources, economic assets and local culture and with a new category, ‘connecting assets’. These categories show the range of resources in a university. According to the participants, the questions on asset identification were a tool for reflection, and by giving their opinions and discovering or drawing attention to new resources, they gained a better understanding of the assets in the university. Several participants stated that these talks could generate a positive emotional environment, which boosted their wellbeing. There were gender- and group-based differences in how the assets were valued. Students stressed assets related to services and benefits from the institution, green areas, and collective spaces. Employees, retirees and ex-students emphasized assets related to belonging, identity and traditions. Men appreciated openness and privacy in physical spaces. Women highlighted assets related to the institution. The resulting map, displays a range of resources that can help the university develop new possibilities for comprehensive and collective actions that would revitalize the HPU strategy. This study is part of the project VRID 217.089.007-1.0IN, funded by the Vice-rectorate for Research and Development of the University of Concepción, Chile.

Summary Physical activity (PA) contributes to health throughout life. In particular, young people can benefit from this. Schools can play a key role in providing learning conditions to experience meaningful PAs aimed at inspiring students to lifelong PA. In this article, we argue the need for a salutogenic approach in schools focussing on respecting and enhancing adolescents’ agency with regard to their PA. This approach entails listening to adolescents’ perspectives and inviting them to participate in actively designing and carrying out PA as a prerequisite for their inclusive engagement. We unpack the concept of agency by drawing on insights from the Capability Approach. This provides input for the integration of agency in health promoting schools and salutogenic approaches, to enhance PA-related agency. Finally, we outline a research agenda to, eventually, create opportunities for students in schools to expand their PA-related agency. Lay Summary Physical activity (PA) contributes to health throughout life. Schools can play a key role in fostering meaningful PA experiences to inspire students to lifelong PA. This requires schools to focus on students’ personal aspirations, providing them with the space to develop their autonomy and find opportunities to decide and act upon expanding their agency with respect to the physically active lifestyles they deem meaningful.

International audience; Retinoic acid (RA) activates RA receptors (RAR), resulting in RA response element (RARE)-dependent gene expression in renal collecting duct (CD). Emerging evidence supports a protective role for this activity in acute kidney injury (AKI) and chronic kidney disease (CKD). Herein, we examined this activity in RARE-LacZ transgenic mice and by RARE-Luciferase reporter assays in CD cells, and investigated how this activity responds to neurotransmitters and mediators of kidney injury. In RARE-LacZ mice, Adriamycin-induced heavy albuminuria was associated with reduced RA/RAR activity in CD cells. In cultured CD cells, RA/RAR activity was repressed by acetylcholine, albumin, aldosterone, angiotensin II, high glucose, cisplatin and lipopolysaccharide, but was induced by aristolochic acid I, calcitonin gene-related peptide, endothelin-1, gentamicin, norepinephrine and vasopressin. Compared with age-matched normal human CD cells, CD-derived renal cystic epithelial cells from patients with autosomal recessive polycystic kidney disease (ARPKD) had significantly lower RA/ RAR activity. Synthetic RAR agonist RA-568 was more potent than RA in rescuing RA/RAR activity repressed by albumin, high glucose, angiotensin II, aldosterone, cisplatin and lipopolysaccharide. Hence, RA/RAR in CD cells is a convergence point of regulation by neurotransmitters and mediators of kidney injury, and may be a novel therapeutic target. Acute kidney injury (AKI) is an abrupt renal insult followed by sudden decline of kidney functions 1,2 ; chronic kidney disease (CKD) is a long-term condition where the kidneys do not work effectively, resulting in chronic loss of renal functions 3,4. AKI occurs in 10-15% hospitalised patients and approximately 50% patients in intensive care, and is associated with high mortality 2 ; affecting 8-16% of the world's population 3,4 , CKD was the 12th most common cause of mortality and caused 4.6% of deaths globally in 2017 5. If this rising prevalence of CKD continues, it is predicted that CKD will become a top-5 cause of mortality worldwide by 2040 6. AKI and CKD are not distinct disease entities but rather are closely interconnected syndromes 7. Despite some shared aetiologies, risk factors and mechanisms, the pathophysiology of AKI and CKD can be quite different. Although AKI may be caused by systemic, vascular, glomerular and tubular diseases, the core pathophysiology of AKI is often predominated by tubulointerstitial injury 2. On the other hand, although a wide range of aetiologies may all cause CKD, the latter is most often a glomerular disease 4. However, regardless of the primary aetiologies of CKD, tubulointerstitial injury plays a crucial role in CKD progression to end-stage kidney disease 8. Thus, it is critical to investigate the mechanism of tubulointerstitial injury, which is as yet poorly understood. What we open

This article proposes to advance the connections between salutogenic theory and assets models for health improvement. There is a need to integrate their use in public health and health promotion so that their respective potentials can be fully developed. This requires their synergies to be made more explicit so that a more coherent approach can be taken to their utilization. A mechanism is therefore needed that helps to raise awareness of them and their value as a resource together. Bronfenbrenner’s bioecological theory provides one framework that can support better integration of salutogenesis with the applied nature of assets-based models. This paper proposes a new ‘synergy model for health’ that integrates key concepts associated with salutogenic theory—generalized and specific resistance resources (GRRs/SRRs) and generalized and specific resistance deficits and the sense of coherence (SOC). In doing so, it highlights those GRRs and SRRs which are assets that, either individually or collectively, help to develop a stronger SOC. Higher levels of SOC can then support the transformations of potential resources into available assets (that people can understand, manage and make sense of), capable of producing positive health development. The proposed ‘Synergy model of health’ aims to contribute to a deeper theoretical understanding of health and development through the integration of the key elements of both salutogenesis and assets models. This can facilitate a better contextualization of the ideas into public health policy and practice by making the salutogenic theory more action-oriented and the assets model more theoretical. This paper is supported by the Vice-Rectory for Research and Development, University of Concepción (VRID 217.089.007-1.0IN).

Aim: The review aimed to identify factors influencing opioid prescribing as regular pain-management medication for older people. Background: Chronic pain occurs in 45%–85% of older people, but appears to be under-recognised and under-treated. However, strong opiate prescribing is more prevalent in older people, increasing at the fastest rate in this age group. Methods: This review included all study types, published 1990–2017, which focused on opioid prescribing for pain management among older adults. Arksey and O’Malley’s framework was used to scope the literature. PubMed, EBSCO Host, the UK Drug Database, and Google Scholar were searched. Data extraction, carried out by two researchers, included factors explaining opioid prescribing patterns and prescribing trends. Findings: A total of 613 papers were identified and 53 were included in the final review consisting of 35 research papers, 10 opinion pieces and 8 grey literature sources. Factors associated with prescribing patterns were categorised according to whether they were patient-related, prescriber-driven, or system-driven. Patient factors included age, gender, race, and cognition; prescriber factors included attitudes towards opioids and judgements about ‘normal’ pain; and policy/system factors related to the changing policy landscape over the last three decades, particularly in the USA. Conclusions: A large number of context-dependent factors appeared to influence opioid prescribing for chronic pain management in older adults, but the findings were inconsistent. There is a gap in the literature relating to the UK healthcare system; the prescriber and the patient perspective; and within the context of multi-morbidity and treatment burden.

Background: Changes to the general practice (GP) contract in England (April 2019) introduced a new quality improvement (QI) domain. The clinical microsystems programme is an approach to QI with limited evidence in primary care. Aim: To explore experiences of GP staff participating in a clinical microsystems programme. Design and setting: GPs within one clinical commissioning group (CCG) in South East England. Normalisation process theory informed qualitative approach. Method: Review of all CCG clinical microsystems projects using pre-existing data. The Diffusion of Innovation Cycle was used to inform the sampling frame and GPs were invited to participate in interviews or focus groups. Ten practices participated; 11 coaches and 16 staff were interviewed. Results: The majority of projects were process-driven activities related to administrative systems. Projects directly related to health outputs were fewer and related to externally imposed targets. Four key elements facilitated practices to engage: feeling in control; receiving enhanced service payment; having a senior staff member championing the approach; and good practice–coach relationship. There appeared to be three key benefits in addition to project-specific ones: improved working relationships between CCG and practice; more cohesive practice team; and time to reflect. Conclusion: Small projects with clear parameters were more successful than larger ones or those spanning organisations. However, there was little evidence suggesting the key benefits were unique attributes of the microsystems approach and sustainability was problematic. Future research should focus on cross-organisational approaches to QI and identify what, if any, added value the approach provides.

Objectives To explore the extent to which national policy in end of life care in England influences and guides local practice, to ensure that care for patients over the age 75 years is of a consistently good quality. Method This paper reports on phase one of a larger study and focuses its discussion on the high-level (macro) determinants emerging from the analysis. Fifteen in-depth interviews were conducted with professionals involved in the development of English policy in end of life care. Results Factors influencing the quality of end of life care were stratified into three system levels: meso, macro and micro. English national policy was reported to be an important macro-level determinant of effective outcomes, and examples were provided to demonstrate how policy was influencing practice. Yet, the complexity of the area and the range of interacting contributory factors mean the value of policy alone is hard to assess. At the macro-level, concern was voiced around: whether policy was effective in tackling rising inequity; lack of mandatory leverage to exert change relating to end of life outcomes; the impact of ongoing infrastructural change on statutory services; workforce pressures; over-reliance on acute services and continued abdication of responsibility for end of life care to medical professionals supported by the continued dominance of the medical model of care. Conclusions The links between the existence of policy at the macro-level of the system and the effective enactment of good practice remain unclear, although strategies are suggested to help achieve greater national consistency in end of life care outcomes. Policymakers must pay attention to the following: controlling the rise in localism and its contribution to regional inequalities; the impact of continuous infrastructural change together with increasing workforce pressures; encouraging broader professional and public responsibility for recognition and care of those at the end of life.

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common genetic kidney disorder resulting in 10% of patients with renal failure. The molecular events responsible for the relentless growth of cysts are not defined. Thus, identification of novel drivers of ADPKD may lead to new therapies. Ankyrin Repeat and Single KH domain-1 (ANKHD1) controls cancer cell proliferation, yet its role in ADPKD is unexplored. Here, we present the first data that identify ANKHD1 as a driver of proliferative growth in cellular and mouse models of ADPKD. Using the first Ankhd1-deficient mice, we demonstrate that Ankhd1 heterozygosity potently reduces cystic growth and fibrosis, in a genetically orthologous mouse model of ADPKD. We performed transcriptome-wide profiling of patient-derived ADPKD cells with and without ANKHD1 siRNA silencing, revealing a major role for ANKHD1 in the control of cell proliferation and matrix remodelling. We validated the role of ANKHD1 in enhancing proliferation in patient-derived cells. Mechanistically ANKHD1 promotes STAT5 signalling in ADPKD mice. Hence, ANKHD1 is a novel driver of ADPKD, and its inhibition may be of therapeutic benefit.

Pulmonary rehabilitation (PR) for people with COPD leads to clinically significant improvements in quality of life and exercise capacity [1]. In England and Wales, UK, in 2013–2014, only 15% of eligible patients were referred (51% from primary care), of whom 31% did not attend assessment [2]. We aimed to generate a theory-informed understanding of enablers and barriers to PR referral and uptake from primary care., Healthcare service and patient barriers contribute to low referral to and uptake of pulmonary rehabilitation (PR). Solutions should support skilled clinician–patient conversations and span primary care–PR boundaries to prevent disjointed working. http://bit.ly/2PVKHZf

Background: We have undertaken a systematically searched literature review using a realist logic of analysis to help synthesise the diverse range of literature available on hospice at home services. Aim: To find out in the existing literature what features of hospice at home models work best, for whom and under what circumstances. Design: A realist logic of analysis was applied to synthesise the evidence focusing on mechanisms by which an intervention worked (or did not work). An initial programme theory was developed using the National Association for Hospice at Home standards, Normalisation Process Theory and through refinement using stakeholder engagement. Data sources: PubMed, Science Direct, AMED, BNI, CINAHL, EMBASE, Health Business Elite, HMIC, Medline, PsychINFO, SCOPUS, Web of Science, DARE, Google Scholar, NHS Evidence, NIHR CRN portfolio database, NIHR journal library of funded studies, including searches on websites of relevant professional bodies (August 2014, June 2017, June 2019). Results: Forty-nine papers were reviewed, of which 34 contributed evidence to at least one of the eight theory areas: marketing and referral, sustainable funding model, service responsiveness and availability, criteria for service admission, knowledge and skills of care providers, integration and coordination, anticipatory care, support directed at carers. Conclusions: Our literature review showed how it was possible to develop a coherent framework and test it against 34 published papers and abstracts. Central to this review was theory building, and as further evidence emerges, our programme theories can be refined and tested against any new empirical evidence.

Objective— SAA (serum amyloid A) is a family of acute-phase reactants that have proinflammatory and proatherogenic activities. SAA is more lipophilic than apoA-I (apolipoprotein A-I), and during an acute-phase response, Approach and Results— Delipidated human SAA was incubated with SAA-free human lipoproteins; then, samples were reisolated by fast protein liquid chromatography, and SAA analyzed by ELISA and immunoblot. Both in vitro and in vivo, we show that SAA associates with any lipoprotein and does not remain in a lipid-free form. Although SAA is preferentially found on high-density lipoprotein, it can exchange between lipoproteins. In the presence of CETP (cholesterol ester transfer protein), there is greater exchange of SAA between lipoproteins. Subjects with diabetes mellitus, but not those with metabolic syndrome, showed altered SAA lipoprotein distribution postprandially. Proteoglycan-mediated lipoprotein retention is thought to be an underlying mechanism for atherosclerosis development. SAA has a proteoglycan-binding domain. Lipoproteins containing SAA had increased proteoglycan binding compared with SAA-free lipoproteins. Conclusions— Thus, SAA is an exchangeable apolipoprotein and increases apoB-containing lipoproteins’ proteoglycan binding. We and others have previously reported the presence of SAA on low-density lipoprotein in individuals with obesity, diabetes mellitus, and metabolic syndrome. We propose that the presence of SAA on apoB-containing lipoproteins may contribute to cardiovascular disease development in these populations.

In a world increasingly characterised by uncertainty, social inequality, and ecological degradation, how can action researchers engage in ways that support regenerative systems change in the living systems of which they are part? How can the inhabitants of living systems co-create experiences and conditions of thrivability? These questions animated the reflective practice of the authors as they each engaged in collaborative action research projects in three different, socially complex and contested contexts. The article explores the dialogic methodologies the authors employed, the impacts and outcomes experienced by the participants, and the evolution of the authors’ own practices as action researchers and catalysts of change. Wilson draws on a three-year action research project in peri-urban Mexico on sustainable community development. Bush explores a year of engagement fostering resilient urban systems in Asheville, North Carolina. Walsh reflects on her ten-year praxis of fostering regenerative dialogue amid social conflict and vulnerability in a gentrifying neighbourhood of Austin, Texas. The comparative analysis of the three stories concludes with propositions for action research praxis in the context of social complexity. Keywords: action research, distributed leadership, generative dialogue, thrivability, regenerative design, complex social systems, situated spiritual practice. ----- Investigacion-accion en primera persona en sistemas sociales complejos: Tres historias de praxis Resumen En un mundo caracterizado cada vez mas por la incertidumbre, la inequidad social y la degradacion ecologica, ?como los investigadores de accion pueden involucrarse de forma que apoyen el cambio de los sistemas regenerativos en los sistemas vivos de los que forman parte? ?Como pueden los habitantes de los sistemas vivos co-crear experiencias y condiciones de thrivability? Estas preguntas animaron la practica reflexiva de los autores, ya que cada uno participo en proyectos de investigacionaccion colaborativa en tres contextos diferentes, socialmente complejos y disputados. El articulo explora las metodologias dialogicas que los autores emplearon, los impactos y resultados experimentados por los participantes, y la evolucion de las propias practicas de los autores como investigadores de accion y catalizadores del cambio. Wilson se basa en un proyecto de investigacion-accion de tres anos en la zona periurbana de Mexico sobre el desarrollo sostenible de la comunidad. Bush explora un ano de compromiso fomentando sistemas urbanos resilientes en Asheville, Carolina del Norte. Walsh reflexiona sobre su praxis de diez anos de fomento de dialogo regenerativo en medio de conflictos sociales y vulnerabilidad en un barrio gentrificado de Austin, Texas. El analisis comparativo de las tres historias concluye con propuestas para la praxis de la investigacion-accion en el contexto de la complejidad social. Palabras clave: investigacion-accion, liderazgo distribuido, dialogo generativo, thrivability, diseno regenerativo, sistemas sociales complejos, practica espiritual situada. ----- Bibliography: Wilson, Patricia A./Walsh, Elizabeth/Bush, Alan: First Person Action Research in Complex Social Systems: three stories of praxis, IJAR, 1-2018, pp. 5-29. https://doi.org/10.3224/ijar.v14i1.02

Objectives To explore how embedded patient and public involvement is within mainstream health research following two decades of policy-driven work to underpin health research with patient and public involvement in England. Methods Realist evaluation using Normalization Process Theory as a programme theory to understand what enabled patient and public involvement to be embedded as normal practice. Data were collected through a national scoping and survey, and qualitative methods to track patient and public involvement processes and impact over time within 22 nationally funded research projects. Results In research studies that were able to create reciprocal working relationships and to embed patient and public involvement this was contingent on: the purpose of patient and public involvement being clear; public contributors reflecting research end-beneficiaries; researchers understanding the value of patient and public involvement; patient and public involvement opportunities being provided throughout the research and ongoing evaluation of patient and public involvement. Key contested areas included: whether to measure patient and public involvement impact; seeking public contributors to maintain a balance between being research-aware and an outsider standpoint seen as ‘authentically’ lay; scaling-up patient and public involvement embedded within a research infrastructure rather than risk token presence and whether patient and public involvement can have a place within basic science. Conclusions While patient and public involvement can be well-integrated within all types of research, policy makers should take account of tensions that must be navigated in balancing moral and methodological imperatives.

Vascular biglycan contributes to atherosclerosis development and increased biglycan expression correlates with increased atherosclerosis. However, mice deficient in biglycan have either no reduction in atherosclerosis or an unexpected increase in atherosclerosis. Biglycan deficient mice have systemically elevated TGF-β, likely due to lack of sequestration of TGF-β in the extracellular matrix. The purpose of this study was to determine if prevention of TGF-β elevations in biglycan deficient mice affected atherosclerosis development.Biglycan deficient mice were crossed to Ldlr deficient mice. Diabetes was induced via streptozotocin and all mice were fed a high cholesterol diet. Diabetic biglycan wild type and biglycan deficient Ldlr deficient mice were injected with the TGF-β neutralizing antibody 1D11 or the irrelevant control antibody 13C4.Biglycan deficient mice had significantly elevated plasma TGF-β levels, which was further increased by diabetes, and significantly increased atherosclerosis. There was a significant correlation between TGF-β concentrations and atherosclerosis. However, despite nearly complete suppression of plasma TGF-β levels in mice treated with the TGF-β neutralizing antibody 1D11, there was no significant difference in atherosclerosis between mice with elevated TGF-β levels and mice with suppressed TGF-β levels.The increased atherosclerosis in biglycan deficient mice does not appear to be due to elevations in TGF-β.

Animal studies demonstrate that hyperlipidemia and renal lipid accumulation contribute to the pathogenesis of diabetic nephropathy (DN). We previously demonstrated that renal lipoproteins colocalize with biglycan, a renal proteoglycan. The purpose of this study was to determine whether prevention of renal lipid (apoB) accumulation attenuates DN. Biglycan-deficient and biglycan wild-type Ldlr−/− mice were made diabetic via streptozotocin and fed a high cholesterol diet. As biglycan deficiency is associated with elevated transforming growth factor-β (TGF-β), in some experiments mice were injected with either the TGF-β-neutralizing antibody, 1D11, or with 13C4, an irrelevant control antibody. Biglycan deficiency had no significant effect on renal apoB accumulation, but led to modest attenuation of DN with ∼30% reduction in albuminuria; however, biglycan deficiency caused a striking elevation in TGF-β. Use of 1D11 led to sustained suppression of TGF-β for approximately 8 weeks at a time. The 1D11 treatment caused decreased renal apoB accumulation, decreased albuminuria, decreased renal hypertrophy, and improved survival, compared with the 13C4 treatment. Thus, prevention of renal apoB accumulation is protective against development of DN. Furthermore, this study demonstrates that prevention of renal apoB accumulation is a mechanism by which TGF-β inhibition is nephroprotective.