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Lindy L Turnbull,1 Susan M Carr2 1Faculty of Health Sciences and Wellbeing, University of Sunderland, Sunderland, UK; 2Faculty of Health & Life Sciences, Northumbria University, Newcastle upon Tyne, UKCorrespondence: Lindy L TurnbullFaculty of Health Sciences and Wellbeing, University of Sunderland, Helen McArdle House, Chester Road, Sunderland SR1 3SD, UKEmail lindy.turnbull@sunderland.ac.ukPurpose: To investigate the meaning and manifestation of collaboration in practice including the experience and outcomes for patients and professionals.Methods: Grounded theory was used to investigate collaboration in an integrated outpatient parenteral antimicrobial therapy (OPAT) service. The sample consisted of staff and patients with experience of OPAT. Interviews and focus groups were used to generate data, and grounded theory methods were used to progress the study through constant comparative analysis and theoretical sampling to data saturation. Coding, categorizing, and techniques of situational analysis were used to analyze data and develop theory.Results: The relationship between the influences in the situation and the interaction which takes place between individuals was found to produce four different types of collaboration: developing, maintaining, limiting, and disrupting collaboration. The collaboration compass model was developed to illustrate and aid interactive navigation of collaborative situations.Discussion: The findings present the complexity of practice, and a model to explain the multiple influences and interaction which shape collaboration. In this model, patients are part of collaboration, and this ensures that patients’ views and experiences, as well as those of professionals, are included and represented in knowledge about collaboration. This adds a new dimension to existing interprofessional presentations of collaborative practice and examines collaboration as it is operationalized in practice and co-constructed between patients and professionals during day to day practice.Keywords: collaboration, integrated services, service development, patient participation, co-produced care, grounded theory

Susan M Carr,1–3 Monique Lhussier,1,3 Natalie Forster1,3 1Public Health Research, Department of Social Work, Education, and Community Wellbeing, Northumbria University, Newcastle upon Tyne, UK; 2Department of Education and Training, Federation University Australia, Ballarat, VIC, Australia; 3Fuse, Centre for Translational Research in Public Health, Newcastle upon Tyne, UK Abstract: The use of lay health advisers has become an established approach within public health, in particular for impact on health inequalities and engaging socially excluded groups. Evidence on how differences in terms of the multiple role dimensions impact the outcomes of programs is limited. This creates ambiguity for decision makers on which roles should be implemented in different contexts for different needs. This paper applies realist logic to an inquiry to explore the mechanisms that may operate in lay-led intervention models and understand how, why, and in what respect these lead to particular outcomes. It draws on a project focusing on health-related lifestyle advisers and further insights gained from a subsequent related project about outreach with traveler communities. Analysis highlights multiple and potentially interacting aspects of lay health-adviser roles that may influence their success, including characteristics of lay health advisers, characteristics of target populations, purpose or intent of interventions, and how advice is given. A model is proposed from which to examine the contexts and mechanisms of lay health advisers that may impact outcomes, and is subsequently applied to two examples of reported lay health-adviser interventions. The combination of skills and characteristics of lay health advisers must be considered when planning which interventions might be appropriate when targeting specific needs or target populations. Focus only on the peer/layperson distinction may overlook other potentially important skills and mechanisms of action integral to lay health-adviser roles. Keywords: realist logic, lay health advisers, inequalities, hard-to-reach populations, service design

Susan M Carr1,2, Pauline Pearson1, Lesley Young-Murphy3, Barbara Cleghorn41Centre for Community Health & Education Studies Research & Enterprise, Northumbria University, Newcastle upon Tyne, UK; 2School of Health, University of New England, Armidale, New South Wales, Australia; 3NHS North of Tyne, Newcastle upon Tyne, UK, 4Newcastle PCT, Newcastle upon Tyne, UKAbstract: This paper presents an overview of the challenges and potential of lean implementation for the health visiting service in England and examines the rhetoric and the reality of the situation. It is coauthored by academic researchers and senior service providers so as to embrace the multidimensional issues impacting on this subject. If lean thinking is to be implemented in relation to health visiting, it is important to understand how it is likely to be viewed by practitioners and line managers in settings where it is used. In order to contextualize the discussion, an introduction to the roles, systems, and structures of health visiting are provided. The literature on what lean implementation is, what it means, and in particular the application and potential of the approach to primary care and public health services is reviewed. The process and findings from a focus group convened within a large primary care organization in the National Health Service during their lean implementation is reported. The paper concludes that it is important for staff at all levels to see a clear link between strategic aims and objectives and the planning processes operated by providers and commissioners. It appears that the successful introduction of lean thinking should focus more on productive working and thereby reducing waste. This has the potential to refresh workforce models to ensure that health visiting and other practitioners liberate the use of their specialist knowledge and skills. In a context of enhanced partnership working, the stage is then set for providers to add value to the whole system and together improve service user outcomes.Keywords: strategic aims, planning processes, productive working, reducing waste, primary care, service user outcomes.

Much practice innovation knowledge is vulnerable owing to a lack of processes to share the learning experiences at individual and organizational levels. This article describes how members of a collaborative learning group within a public health intervention evaluation attempted to tackle the perennial challenges of sharing innovation learning. The outcome was the development of a user-friendly 10-point guide, which systematically describes key steps to be considered for the replication and sustainability of any multi-intervention approach to tackle a health improvement issue in a determined geographical area. Copyright © 2008 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

This paper aims to inform the development and evaluation of small-scale community-based initiatives by describing an evaluation of one such health promotion programme.Realistic evaluation is an under-explored resource for practice development, particularly within the context of informing evidence-based practice. A combination of the context-mechanism-outcome framework and principles of health impact assessment were used in the evaluation of the programme. Telephone interviews and half-day sessions were utilised in order to conduct reviews of the programme's work with both providers and users.This approach engaged the practitioners in the process of evaluation in a way that was novel to them, and introduced the possibility of a stepped approach to outcomes achievement and measurement. The evaluation gave the practitioners the means to understand and effectively formulate which outcomes were most appropriate to their particular intervention, and to design the means to assess these in future. [ABSTRACT FROM AUTHOR]

AIM: The purpose of this study was to explore the development of public health nursing in a primary care trust that focused around the evaluation of a newly introduced public health nursing role. The intention was to inform role development during the three year evaluation period. BACKGROUND: Despite health visitors having been identified in the recent past as being in prime position to assume the public health role envisioned by the British Government in the New NHS, the vision for the 'new look' health visitor has been rather blurred. METHODS: An action research approach utilised 22 individual and four group (number of participants 33) interviews with a range of stakeholders. Thematic analysis was used on all transcripts. FINDINGS: Four main headings were identified to organise and present the findings -- definitions of public health; continuum of practice; contextual factors in public health development; and inhibitors to public health practice development. The findings suggest that there are a number of factors challenging the health visiting response to the public health agenda. Facilitating clarity of role and purpose must be a management priority. A tool, developed from this study, offers a means to explore practice within a primary care -- public health continuum and provides a schema against which to set and action practice development. [ABSTRACT FROM AUTHOR]

BACKGROUND: Clinical reasoning is employed to develop solutions to health needs. The impact of the clinical environment on the organization of knowledge-guiding practice has received limited attention. This gap in the clinical landscape restricts the sharing of decision-making processes. AIMS: Focusing on the community, and specifically the patient's home as a context for nursing, this paper describes the creation of a collective conceptual map for a group of community nurses. There is a twofold aim of exploring the process of exposing and articulating the clinical framework and enhancing and sharing understanding of the clinical paradigm in this context. DESIGN: An interpretive research approach was utilized. Hermeneutic phenomenology guided the level of meaning accessed and constructivism was used to build an educational picture. METHODS: Multiple methods including focus groups, observation and narrative recordings were utilized to collect and analyse research data. RESULTS: All nurses may engage with the same concepts--health, need, care and partnerships--but organized into particular frames by the guiding practice philosophy and service organization. A four-stage framework for understanding clinical reasoning in the community setting is presented. This acknowledges the multi-faceted nature of health, the lived experience of health deficits, and is located in a participation and negotiated model of care. Practice examples are presented to expose the construction of need and response which often occurs in a triadic decision-making process. CONCLUSIONS: Environment of care has significant implications on need identification and response. RELEVANCE TO CLINICAL PRACTICE: Mechanisms to enhance the sharing of clinical reasoning and decision-making transparency are essential to aid inter- and intra-professional communication. Presentation of a clinical reasoning framework exposes the breath of 'signals' encountered in practice and the range of knowledge employed in understanding and responding to patient need. Copyright 2004 Blackwell Publishing Ltd [ABSTRACT FROM AUTHOR]

* The agenda for health care detailed in recent policy statements has a strong community and primary health care focus.* The impact of the community, and specifically the patient's home, as a location for practising and learning to practise nursing, is an issue which has received limited exploration. Recent research suggests that the context influences the practice agenda in a number of ways.* Highlighting the impact of working in the community context is timely in order that education providers, policy makers and managers are fully aware of the impact of moving care 'closer to home'. [ABSTRACT FROM AUTHOR]

Introduction: British Muslim School Children (BMSC) are required to follow special halal dietary requirements in accordance with their religion, which is often not accounted for in British schools. This often leaves BMSC limited to a vegetarian diet while at school, despite this not being their chosen diet or preference. This study explores the perceptions of key stakeholders regarding fairness and accessibility of school meals for BMSC, as well as discussing school food provision for those maintaining a religious diet in light of social justice. This is in the context of limited knowledge previously being explored in the North East of England regarding procurement and decision-making at a systems level to cater for BMSC., Methods: A qualitative research design was conducted. A total of 62 participants (39 BMSC, 15 parents, and 8 school and catering staff) took part in a semi-structured interview or focus group. Participants were recruited from six schools, with these schools selected based on their differing levels of BMSC in attendance. This project took place between March 2022 and October 2023., Results/discussion: Results suggested that where schools already catered for diverse food requirements, inclusive of BMSC dietary needs, food choices were still limited in the options and amount available. School and catering staff stated that cost implications contributed to their menu development process. Despite this, there was an evident willingness to learn about the cultural food options and how these can be implemented in future school menus. Suggestions discussed included an increase in the use of halal meat in order to provide a more inclusive school food experience for BMSC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Sattar, Carr, Lochhead and Defeyter.)

Protein arginine methyltransferase 5 (PRMT5) is over-expressed in a wide variety of cancers and is implicated as having a key oncogenic role, achieved in part through its control of the master transcription regulator E2F1. We investigated the relevance of PRMT5 and E2F1 in neuroblastoma (NB) and found that elevated expression of PRMT5 and E2F1 occurs in poor prognosis high-risk disease and correlates with an amplified Myelocytomatosis viral-related oncogene, neuroblastoma-derived (MYCN) gene. Our results show that MYCN drives the expression of splicing factor genes that, together with PRMT5 and E2F1, lead to a deregulated alternative RNA splicing programme that impedes apoptosis. Pharmacological inhibition of PRMT5 or inactivation of E2F1 restores normal splicing and renders NB cells sensitive to apoptosis. Our findings suggest that a sustained cancer-relevant alternative RNA splicing programme desensitises NB cells to apoptosis, and identify PRMT5 as a potential therapeutic target for high-risk disease., (© 2024 The Author(s). Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Legionella pneumophila is the waterborne pathogen primarily responsible for causing both Pontiac Fever and Legionnaire's Disease in humans. L. pneumophila is transmitted via aerosolized water droplets. The purpose of this study was to design and test primers to allow for rapid polymerase chain reaction (PCR) melt detection and identification of this infectious agent in cases of clinical or emergency response detection. New PCR primers were designed for this species of bacteria; the primer set was purchased from IDT and the target bacterial DNA was purchased from ATCC. The L. pneumophila primers targeted the macrophage infectivity potentiator gene ( mip ), which inhibits macrophage phagocytosis. The primers were tested for specificity, repeatability, and sensitivity using PCR-high-resolution melt (HRM) assays. The primer set was found to be specific to the designated bacteria and did not amplify the other twenty-one species from the panel. The L. pneumophila assay was able to be multiplexed. The duplex assay consists of primers for L. pneumophila and Vibrio parahaemolyticus , which are both waterborne pathogens. The triplex assay consists of primers for L. pneumophila , V. parahaemolyticus , and Campylobacter jejuni . The unique melting temperature for the L. pneumophila primer assay is 82.84 ± 0.19 °C, the C. jejuni assay is 78.10 ± 0.58 °C, and the V. parahaemolyticus assay is 86.74 ± 0.65 °C.

Objectives: To describe a population health-based program to support employee and dependent mental health and learn from engagement trends., Methods: Retrospective analysis of a program utilizing an assessment of mental health risk. For scoring "at risk," a Care Concierge is offered to connect users with resources., Results: Participation was offered to 56,442 employees and dependents. Eight thousand seven hundred thirty-one completed the assessment (15%). Of those, 4,644 (53%) scored moderate or higher. A total of 418 (9%) engaged the Care Concierge. Factors that negatively influenced the decision to engage care included bodily pain, financial concerns. Positive influences were younger age, high stress, anxiety, PTSD and low social support., Conclusion: Proactive assessment plus access to a Care Concierge facilitates mental healthcare utilization. Several factors influence likelihood to engage in care. A better understanding of these factors may allow for more targeted outreach and improved engagement., Competing Interests: MF was employed by Quest Diagnostics. JoH was employed by BHS. JeH was employed by emVitals. SC was employed by Johns Hopkins Healthcare. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Woodard, Bailey, Esagoff, Fragala, Hayward, Hunter, Hsu, Kim, Peters and Carr.)

Background: Induced pluripotent stem cells (iPSCs) directed to endothelial identity (iPSC-ECs) are emerging as a potent tool for regenerative medicine in vascular disease. However, iPSC-ECs lose expression of key identity markers under standard in vitro conditions, limiting their clinical applications., Methods: To model physiological in vivo conditions, we examined the bioenergetics, presence of key cell markers, and proliferative and angiogenic capacity in iPSC-ECs at late and early passage under hyperoxic (21%) and physiological (4%) oxygen concentrations., Results: Physoxia resulted in relative preservation of mitochondrial bioenergetic activity, as well as CD144 expression in late passage iPSC-ECs, but not proliferative capacity or tube formation. Single cell RNA sequencing (scRNA-seq) revealed that late passage hyperoxic iPSC-ECs develop an endothelial-to-mesenchymal phenotype. Comparing scRNA-seq data from iPSC-ECs and from atherosclerotic ECs revealed overlap of their transcriptional phenotypes., Conclusions: Taken together, our studies demonstrate that physiological 4% oxygen culture conditions were sufficient to improve mitochondrial function in high passage cells, but alone was insufficient to preserve angiogenic capacity. Furthermore, late passage cells under typical conditions take on an endothelial-to-mesenchymal phenotype with similarities to ECs found in atherosclerosis., Competing Interests: None.

Post-translational modifications (PTMs) of proteins are central to epigenetic regulation and cellular signalling, playing an important role in the pathogenesis and progression of numerous diseases. Growing evidence indicates that protein arginine citrullination, catalysed by peptidylarginine deiminases (PADs), is involved in many aspects of molecular and cell biology and is emerging as a potential druggable target in multiple diseases including cancer. However, we are only just beginning to understand the molecular activities of PADs, and their underlying mechanistic details in vivo under both physiological and pathological conditions. Many questions still remain regarding the dynamic cellular functions of citrullination and its interplay with other types of PTMs. This review, therefore, discusses the known functions of PADs with a focus on cancer biology, highlighting the cross-talk between citrullination and other types of PTMs, and how this interplay regulates downstream biological events. This article is part of the Theo Murphy meeting issue 'The virtues and vices of protein citrullination'.

Previous morpho-molecular studies of evolutionary relationships within the economically important genus of honey bees (Apis), including the Western Honey Bee (A. mellifera L.), have suggested Out of Africa or Asia origins and subsequent spread to Europe. I test these hypotheses by a meta-analysis of complete mitochondrial DNA coding regions (11.0 kbp) from 22 nominal subspecies represented by 78 individual sequences in A. mellifera. Parsimony, distance, and likelihood analyses identify six nested clades: Things Fall Apart with Out of Africa or Asia hypotheses. Molecular clock-calibrated phylogeographic analysis shows instead a basal origin of A. m. mellifera in Europe ~ 780 Kya, and expansion to Southeast Europe and Asia Minor ~ 720 Kya. Eurasian bees spread southward via a Levantine/Nilotic/Arabian corridor into Africa ~ 540 Kya. An African clade re-established in Iberia ~ 100 Kya spread thereafter to westerly Mediterranean islands and back into North Africa. Nominal subspecies within the Asia Minor and Mediterranean clades are less differentiated than are individuals within other subspecies. Names matter: paraphyletic anomalies are artefacts of mis-referral in GenBank of sequences to the wrong subspecies, or use of faulty sequences, which are clarified by inclusion of multiple sequences from available subspecies., (© 2023. The Author(s).)

Rationale: Nicotine has been reported to be a strong risk factor for atherosclerosis. However, the underlying mechanism by which nicotine controls atherosclerotic plaque stability remain largely unknown. Objective: The aim of this study was to evaluate the impact of lysosomal dysfunction mediated NLRP3 inflammasome activation in vascular smooth muscle cell (VSMC) on atherosclerotic plaque formation and stability in advanced atherosclerosis at the brachiocephalic arteries (BA). Methods and Results: Features of atherosclerotic plaque stability and the markers for NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome were monitored in the BA from nicotine or vehicle-treated apolipoprotein E deficient ( Apoe -/- ) mice fed with Western-type diet (WD). Nicotine treatment for 6 weeks accelerated atherosclerotic plaque formation and enhanced the hallmarks of plaque instability in BA of Apoe -/- mice. Moreover, nicotine elevated interleukin 1 beta (IL-1β) in serum and aorta and was preferred to activate NLRP3 inflammasome in aortic vascular smooth muscle cells (VSMC). Importantly, pharmacological inhibition of Caspase1, a key downstream target of NLRP3 inflammasome complex, and genetic inactivation of NLRP3 significantly restrained nicotine-elevated IL-1β in serum and aorta, as well as nicotine-stimulated atherosclerotic plaque formation and plaque destabilization in BA. We further confirmed the role of VSMC-derived NLRP3 inflammasome in nicotine-induced plaque instability by using VSMC specific TXNIP (upstream regulator of NLRP3 inflammasome) deletion mice. Mechanistic study further showed that nicotine induced lysosomal dysfunction resulted in cathepsin B cytoplasmic release. Inhibition or knockdown of cathepsin B blocked nicotine-dependent inflammasome activation. Conclusions: Nicotine promotes atherosclerotic plaque instability by lysosomal dysfunction-mediated NLRP3 inflammasome activation in vascular smooth muscle cells., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Protein arginine methyltransferase (PRMT) 5 is over-expressed in a variety of cancers and the master transcription regulator E2F1 is an important methylation target. We have explored the role of PRMT5 and E2F1 in regulating the non-coding genome and report here a striking effect on long non-coding (lnc) RNA gene expression. Moreover, many MHC class I protein-associated peptides were derived from small open reading frames in the lncRNA genes. Pharmacological inhibition of PRMT5 or adjusting E2F1 levels qualitatively altered the repertoire of lncRNA-derived peptide antigens displayed by tumour cells. When presented to the immune system as either ex vivo-loaded dendritic cells or expressed from a viral vector, lncRNA-derived peptides drove a potent antigen-specific CD8 T lymphocyte response, which translated into a significant delay in tumour growth. Thus, lncRNA genes encode immunogenic peptides that can be deployed as a cancer vaccine., (© 2023. The Author(s).)

(1) Background: Apolipoprotein E (ApoE) is a critical plasma apolipoprotein for lipid transport and nonlipid-related functions. Humans possess three isoforms of ApoE (2, 3, and 4). ApoE2, which exhibits beneficial effects on cardiac health, has not been adequately studied. (2) Methods: We investigated the cardiac phenotypes of the humanized ApoE knock-in (hApoE KI) rats and compared to wild-type (WT) and ApoE knock-out (ApoE KO) rats using echocardiography, ultrasound, blood pressure measurements, histology strategies, cell culture, Seahorse XF, cardiomyocyte contractility and intracellular Ca 2+ tests, and Western blotting; (3) Results: hApoE2 rats exhibited enhanced heart contractile function without signs of detrimental remodeling. Isolated adult hApoE2 cardiomyocytes had faster and stronger sarcomere contractility because of more mitochondrial energy generation and stimulation-induced fast and elevated intracellular Ca 2+ transient. The abundant energy is a result of elevated mitochondrial function via fatty acid β-oxidation. The fast and elevated Ca 2+ transient is associated with decreased sarcoplasmic reticulum (SR) Ca 2+ ATPase (SERCA2) and increased expression of cardiac ryanodine receptor 2 (RyR2) conducting a potent Ca 2+ release from SR.; (4) Conclusions: Our studies validated the association of polymorphic ApoEs with cardiac health in the rat model, and revealed the possible mechanisms of the protective effect of ApoE2 against heart diseases.

The aim of this study was to identify how the family care of people living with dementia could be supported to make reliance on family care sustainable in the long term despite the impact of stress. A Realist Evaluation (Pawson & Tilley, 1997) was conducted to investigate this aim. An initial review established 'coping' as a primary means of mediating stressors associated with caregiving. However, there was a need to specify which coping approaches/strategies are most effective. In-depth interviews were conducted with a purposive sample of family carers (n = 18) in a suburb in North East England from 2016 to 2017. Analysis of the data revealed 'social coping' (SC) that included an emotional support component as a critical mediator of family carer stress. Several key hindrances to the utilisation of SC, including underpinning causal factors, are explicated. Ways in which these hindrances might be overcome are discussed and guidelines introduced for how family carers, formal providers and practitioners can facilitate SC as a critical coping strategy in sustaining the family care of people with dementia over the long term., (© 2020 The Authors. Health and Social Care in the Community published by John Wiley & Sons Ltd.)

The pRb-E2F pathway is a critical point of regulation in the cell cycle and loss of control of the pathway is a hallmark of cancer. E2F1 is the major target through which pRb exerts its effects and arginine methylation by PRMT5 plays a key role in dictating E2F1 activity. Here we have explored the functional role of the PRMT5-E2F1 axis and highlight its influence on different aspects of cancer cell biology including viability, migration, invasion and adherence. Through a genome-wide expression analysis, we identified a distinct set of genes under the control of PRMT5 and E2F1, including some highly regulated genes, which influence cell migration, invasio and adherence through a PRMT5-dependent mechanism. Most significantly, a coincidence was apparent between the expression of PRMT5 and E2F1 in human tumours, and elevated levels of PRMT5 and E2F1 correlated with poor prognosis disease. Our results suggest a causal relationship between PRMT5 and E2F1 in driving the malignant phenotype and thereby highlight an important pathway for therapeutic intervention.

The Beothuk were a Native American people who formerly occupied the island of Newfoundland, and who are generally accepted to have become culturally extinct in 1829. The Beothuk succeeded the Maritime Archaic people on the island after a hiatus of ca. 1.4 ka, and were themselves succeeded by the extant Mi'kmaq within historic times. Genetic continuity between ancient and modern Native Americans remains of interest. Complete aDNA mitogenomes from ancient Beothuk and Maritime Archaic were compared with the most closely related modern mitogenomes as obtained by BLAST search of GenBank. Beothuk mitogenomes in five clades are in one case identical to and otherwise differ by minima of three to eight SNPs from the most closely related modern mitogenomes. Maritime Archaic mitogenomes in 12 clades are in one case identical to and otherwise differ by minima of one to nine SNPs from the most similar modern mitogenomes. The single available modern Mi'kmaq mitogenome differs from the most similar Beothuk and Maritime Archaic mitogenomes by 12 and 22 SNPs, respectively. Phylogenetic analysis and sequence similarities imply lineage extinction of most ancient clades, as well as continuity of two Beothuk and at least one Maritime Archaic lineages in modern Native Americans and their descendants.

Shrinking state spending in the UK has been accompanied by a profound restructuring of the welfare system, leading to financial insecurity for many people, culminating in extreme stress and serious deterioration of physical and mental health. Theory surrounding the impact of welfare advice on stress is lacking; this paper undertakes an in depth exploration of the experiences of stress among welfare advice seekers, considering these in light of existing substantive theories of stress and coping to generate new insight. A thematic analysis explored the experiences of stress in welfare advice seekers. Four overarching themes and twelve subthemes emerged. They are further understood utilising traditional theories of stress (Transactional Model of Stress and Coping and the Conservation of Resources theory), which then underpin the development of a 'Stress Support Matrix' and a holistic theory related specifically to welfare, stress and coping., Competing Interests: The authors have declared that no competing interests exist.

High-fidelity single-shot readout of spin qubits requires distinguishing states much faster than the T 1 time of the spin state. One approach to improving readout fidelity and bandwidth (BW) is cryogenic amplification, where the signal from the qubit is amplified before noise sources are introduced and room-temperature amplifiers can operate at lower gain and higher BW. We compare the performance of two cryogenic amplification circuits: a current-biased heterojunction bipolar transistor circuit (CB-HBT), and an AC-coupled HBT circuit (AC-HBT). Both circuits are mounted on the mixing-chamber stage of a dilution refrigerator and are connected to silicon metal oxide semiconductor (Si-MOS) quantum dot devices on a printed circuit board (PCB). The power dissipated by the CB-HBT ranges from 0.1 to 1 μW whereas the power of the AC-HBT ranges from 1 to 20 μW. Referred to the input, the noise spectral density is low for both circuits, in the 15 to 30 fA/[Formula: see text] range. The charge sensitivity for the CB-HBT and AC-HBT is 330 μe/[Formula: see text] and 400 μe/[Formula: see text], respectively. For the single-shot readout performed, less than 10 μs is required for both circuits to achieve bit error rates below 10 -3 , which is a putative threshold for quantum error correction.

E2F is a family of master transcription regulators involved in mediating diverse cell fates. Here, we show that residue-specific arginine methylation (meR) by PRMT5 enables E2F1 to regulate many genes at the level of alternative RNA splicing, rather than through its classical transcription-based mechanism. The p100/TSN tudor domain protein reads the meR mark on chromatin-bound E2F1, allowing snRNA components of the splicing machinery to assemble with E2F1. A large set of RNAs including spliced variants associate with E2F1 by virtue of the methyl mark. By focusing on the deSUMOylase SENP7 gene, which we identified as an E2F target gene, we establish that alternative splicing is functionally important for E2F1 activity. Our results reveal an unexpected consequence of arginine methylation, where reader-writer interplay widens the mechanism of control by E2F1, from transcription factor to regulator of alternative RNA splicing, thereby extending the genomic landscape under E2F1 control.

Attention has turned to welfare advice as a potential health and social care intervention. However, establishing direct evidence of health impact has proven difficult. This is compounded by the need to understand both the facilitative contexts and mechanisms through which this impact occurs. This study investigated if, how and in which circumstances an intensive advice service had an impact on stress and well-being (as precursors to health impacts), for clients attending a branch of Citizens Advice, located in the North East of England. A mixed methods realist evaluation of three intensive advice services offered by Citizens Advice (CA) was operationalised in five phases: (a) Building programme theories, (b) refining programme theories, (c) Development of a data recording tool, (d) Testing programme theories with empirical data, (e) Impact interviews. This paper focuses on phase 4. The Warwick Edinburgh Mental Wellbeing Scale (WEMWBS) and Perceived Stress Scale (PSS) were completed by 191 clients, with a 91% follow-up rate (data collected: February 2016 to March 2017). Twenty-two CA clients participated in interviews (data collected: October 2015 to November 2016). The PSS indicated a significant decrease in stress from initial consultation to approximately 4-6 weeks post advice from 31.4 to 10.3 (p < 0.001) and the WEMWBS indicated a significant increase in client well-being from a mean of 26.9 to 46.5 (p < 0.001). Nine refined programme theories are presented which combine the qualitative and quantitative analysis; they are underpinned by three abstract theories: Capabilities model, The Decision to Trust Model, and Third Space. An explanatory framework is presented covering the micro, meso, and macro levels of CA. Use of a stress and well-being lens has allowed insight into the precursors of health in those receiving intensive advice. Using these measures whilst explaining contextual and mechanistic properties, begins to build a complex and real picture of how advice services impact on health., (© 2018 John Wiley & Sons Ltd.)

Claims have long been made as to the survival to the present day of descendants of the Newfoundland Beothuk, a group generally accepted to have become extinct with the death of the last known member, Shanawdithit, in 1829. Interest has recently been revived by the availability of commercial genetic testing, which some claim can assign living individuals to specific Native American groups. We compare complete mitogenome sequences (16569 bp) from aDNA of eight distinct Beothuk lineages, including Shanawdithit's uncle Nonosabasut and his wife Demasduit, with three Newfoundland Mi'kmaq lineages and 21 other living Native Americans drawn from GenBank. A Newfoundland Mi'kmaq lineage in Haplogroup A is more similar to three Native Americans (1-3 SNPs) than to the most closely related Beothuk (24 SNPs). Nonosabasut in Haplogroup X is identical to a non-Beothuk Native American. Demasduit in Haplogroup C differs from three other Native Americans by 1-4 substitutions. Within a 2168 bp region of the HVS sequences available from living Mi'kmaq of the Miawpukek First Nation in Newfoundland, lineages in Haplogroups C, X, and A differ by 1, 4, and 8 substitutions, from the most similar Beothuk, and are more similar to other Native Americans. MtDNA genome sequences in living persons identical or similar to those of Beothuk do not necessarily indicate Beothuk ancestry. Mi'kmaq lineages cannot at this time be associated with any Beothuk lineages more closely than those of other Native Americans.

Loneliness and adapting to an unfamiliar environment can increase emotional vulnerability in culturally and linguistically diverse (CALD) university students. According to Blaszczynski and Nower's pathways model of problem and pathological gambling, this emotional vulnerability could increase the risk of problem gambling. The current study examined whether loneliness was associated with problem gambling risk in CALD students relative to their Australian peers. Additionally, differences in coping strategies were examined to determine their buffering effect on the relationship. A total of 463 female and 165 male university students (aged 18-38) from Australian (38%), mixed Australian and CALD (23%) and CALD (28%) backgrounds responded to an online survey of problem gambling behaviour, loneliness, and coping strategies. The results supported the hypothesis that loneliness would be related to problem gambling in CALD students. There was no evidence of a moderating effect of coping strategies. Future research could test whether the introduction of programs designed to alleviate loneliness in culturally diverse university students reduces their risk of developing problem gambling.

High-resolution mitogenomics of within-species relationships can answer such phylogeographic questions as how species survived the most recent glaciation, as well as identify contemporary factors such as physical barriers, isolation, and gene flow. We examined the mitogenomic population structure of three at-risk species of wolffish: Atlantic (Anarhichas lupus), spotted (A. minor), and northern (A. denticulatus). These species are extensively sympatric across the North Atlantic but exhibit very different life history strategies, a combination that results in concordant and discordant patterns of genetic variation and structure. Wolffish haplogroups were not structured geographically: Atlantic and spotted wolffish each comprised three shallow clades, whereas northern wolffish comprised two deeper but unstructured lineages. We suggest that wolffish species survived in isolation in multiple glacial refugia, either refugia within refugia (Atlantic and spotted wolffish) or more distant refugia (northern wolffish), followed by secondary admixture upon post-glacial recolonisation of the North Atlantic.

Post-glacial origins of woodland caribou (Rangifer tarandus subsp.) on the island of Newfoundland and their relationship to mainland populations have been uncertain. Sequence analysis of 2223 bp of the mitochondrial DNA control region and cytochrome b gene from 233 Newfoundland caribou identified 32 haplotypes in four major clades. Comparison with other Nearctic caribou confirms a closer affinity of the basal Clade A with animals from the mainland, and as an outgroup to Clades B, C, and D that are endemic to the island. This indicates re-entry of caribou to post-glacial Newfoundland across the Strait of Belle Isle from Labrador, rather than from southern coastal refugia. Newfoundland caribou are a distinct subspecies, Rangifer tarandus terranovae (Bangs, 1896). Hierarchical AMOVA shows significant clinal differentiation of the major clades from northwest to southeast across the island. The isolated Avalon Peninsula population in the extreme southeast is genetically depauperate. Founder effects are evident in herds introduced to previously unoccupied areas by wildlife managers over the past 40-50 years. Reindeer introduced in the early 20th century have not contributed to mtDNA diversity in Newfoundland caribou.

Objectives: Pancreatic duct disruption (PDD) after acute pancreatitis can cause pancreatic collections in the early phase and biliary stenosis (BS) or gastric outlet obstruction (GOO) in the late phase. We aimed to document those late complications after moderate or severe acute pancreatitis., Methods: Between September 2010 and August 2014, 141 patients showed pancreatic collections on computed tomography. Percutaneous drainage was primarily performed for patients with signs or symptoms of uncontrolled pancreatic juice leakage. Pancreatic duct disruption was defined as persistent amylase-rich drain fluid or a pancreatic duct cut-off on imaging. Clinical course of the patients who developed BS or GOO was investigated., Results: Among the 141 patients with collections, 33 patients showed PDD in the pancreatic head/neck area. Among them, 9 patients (27%) developed BS 65 days after onset and required stenting for 150 days, and 5 patients (15%) developed GOO 92 days after onset and required gastric decompression and jejunal tube feeding for 147 days (days shown in median). All 33 patients recovered successfully without requiring surgical intervention., Conclusions: Anatomic proximity of the bile duct or duodenum to the site of PDD and severe inflammation seemed to contribute to the late onset of BS or GOO. Conservative management successfully reversed these complications.

The historical phylogeography, biogeography, and ecology of Atlantic cod ( Gadus morhua ) have been impacted by cyclic Pleistocene glaciations, where drops in sea temperatures led to sequestering of water in ice sheets, emergence of continental shelves, and changes to ocean currents. High-resolution, whole-genome mitogenomic phylogeography can help to elucidate this history. We identified eight major haplogroups among 153 fish from 14 populations by Bayesian, parsimony, and distance methods, including one that extends the species coalescent back to ca. 330 kya. Fish from the Barents and Baltic Seas tend to occur in basal haplogroups versus more recent distribution of fish in the Northwest Atlantic. There was significant differentiation in the majority of trans-Atlantic comparisons (Φ ST  = .029-.180), but little or none in pairwise comparisons within the Northwest Atlantic of individual populations (Φ ST  = .000-.060) or defined management stocks (Φ ST  = .000-.023). Monte Carlo randomization tests of population phylogeography showed significantly nonrandom trans-Atlantic phylogeography versus absence of such structure within various partitions of trans-Laurentian, Northern cod (NAFO 2J3KL) and other management stocks, and Flemish Cap populations. A landlocked meromictic fjord on Baffin Island comprised multiple identical or near-identical mitogenomes in two major polyphyletic clades, and was significantly differentiated from all other populations (Φ ST  = .153-.340). The phylogeography supports a hypothesis of an eastern origin of genetic diversity ca. 200-250 kya, rapid expansion of a western superhaplogroup comprising four haplogroups ca. 150 kya, and recent postglacial founder populations.

Introduction: Advances in longevity and medicine mean that many more people in the UK survive life-threatening diseases but are instead susceptible to life-limiting diseases such as dementia. Within the next 10 years those affected by dementia in the UK is set to rise to over 1 million, making reliance on family care of people with dementia (PWD) essential. A central challenge is how to improve family carer support to offset the demands made by dementia care which can jeopardise carers' own health. This review investigates 'what works to support family carers of PWD'., Methods: Rapid realist review of a comprehensive range of databases., Results: Five key themes emerged: (1) extending social assets, (2) strengthening key psychological resources, (3) maintaining physical health status, (4) safeguarding quality of life and (5) ensuring timely availability of key external resources. It is hypothesized that these five factors combine and interact to provide critical biopsychosocial and service support that bolsters carer 'resilience' and supports the maintenance and sustenance of family care of PWD., Conclusions: 'Resilience-building' is central to 'what works to support family carers of PWD'. The resulting model and Programme Theories respond to the burgeoning need for a coherent approach to carer support., (© The Author 2016. Published by Oxford University Press on behalf of Faculty of Public Health.)

The retinoblastoma tumour suppressor protein (pRb) classically functions to regulate early cell cycle progression where it acts to enforce a number of checkpoints in response to cellular stress and DNA damage. Methylation at lysine (K) 810, which occurs within a critical CDK phosphorylation site and antagonises a CDK-dependent phosphorylation event at the neighbouring S807 residue, acts to hold pRb in the hypo-phosphorylated growth-suppressing state. This is mediated in part by the recruitment of the reader protein 53BP1 to di-methylated K810, which allows pRb activity to be effectively integrated with the DNA damage response. Here, we report the surprising observation that an additional methylation-dependent interaction occurs at K810, but rather than the di-methyl mark, it is selective for the mono-methyl K810 mark. Binding of the mono-methyl PHF20L1 reader to methylated pRb occurs on E2F target genes, where it acts to mediate an additional level of control by recruiting the MOF acetyltransferase complex to E2F target genes. Significantly, we find that the interplay between PHF20L1 and mono-methyl pRb is important for maintaining the integrity of a pRb-dependent G1-S-phase checkpoint. Our results highlight the distinct roles that methyl-lysine readers have in regulating the biological activity of pRb.

Objectives: Adolescent risk behaviours are a key health concern. The purpose of this research is to gaina deeper understanding of how, why, for whom, and inwhat circumstances complex adolescent risk behaviourprevention programmes are most successful., Methods and Analysis: To understand how adolescent risk behaviour prevention programmes work in a reallife context, a realist synthesis will be undertaken, operationalised in four phases. Phase one Developing a framework to map the theoretical and conceptual landscape of adolescent risk behaviour prevention. Guided by stakeholder consultation. Phase two Formulating initial programme theories through exploration of the literature, along with primary data from professional stakeholder interviews. Phase three Refining programme theories through more purposeful, in depth screening of the literature, along with primary qualitative data, from young people and professionals. Data will be collected through semi structured focus groups, to explore specific elements of the emerging programme theories. Phase four Testing programme theories through interviews with youth workers, following consultation with young people, using vignettes to explore the relationship between specific programme theories. This relatively novel method of primary and secondary data integration within a realist synthesis will provide deeper insight in to young peoples lived experience of risk behaviour prevention programmes, while maintaining transparency in the process of programme theory development., Data Analysis: A realist logic of analysis will be used to align data from each phase with context mechanism outcome configurations or specific elements thereof. Substantive theory will then be sought to understand and explain the findings., Ethics and Dissemination: This study has been approved by the Ethics committee at Northumbria University, UK. Findings will be disseminated through knowledge exchange with stakeholders, publications in peer-reviewed journals, conference presentations, and formal and informal reports., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

The retinoblastoma tumor suppressor protein pRb is a master regulator of cellular proliferation, principally through interaction with E2F and regulation of E2F target genes. Here, we describe the H1.2 linker histone as a major pRb interaction partner. We establish that H1.2 and pRb are found in a chromatin-bound complex on diverse E2F target genes. Interrogating the global influence of H1.2 on the genome-wide distribution of pRb indicated that the E2F target genes affected by H1.2 are functionally linked to cell-cycle control, consistent with the ability of H1.2 to hinder cell proliferation and the elevated levels of chromatin-bound H1-pRb complex, which occur in growth-arrested cells. Our results define a network of E2F target genes as susceptible to the regulatory influence of H1.2, where H1.2 augments global association of pRb with chromatin, enhances transcriptional repression by pRb, and facilitates pRb-dependent cell-cycle arrest., (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)

Aim: To establish whether respite care addresses the needs of palliative care service users and carers., Background: Respite care is often described in UK policy and guidance as a key need to providing support for this group and yet little is known about it and there is a lack of research to support its efficacy., Design: The approach was qualitative and the methodology was interpretive. The method used was constructivist grounded theory., Methods: Data collection was carried out by unstructured informal interview with three couples and two bereaved carers who had experienced hospice respite care., Results: Findings showed that respite care is valued by palliative care service users and carers although there are some fundamental tensions in service models which limit its potential., Conclusion: A reframing of respite care as an empathic response within a new palliative care approach is proposed. Within this, the centrality of the relationship is reinforced.

Ross's Gull (Rhodostethia rosea) is the rarest of Canadian high-arctic gulls, and is listed as Threatened under Canada's Species-At-Risk Act. The large majority of birds breed in Siberia: the origins and affinities of four extremely small breeding colonies observed since 1978 in the Canadian high arctic are unknown. We compared a 515-bp region of the mtDNA Control Region amplified from material in museum collections taken from non-breeding birds in Canada (n = 8) and Alaska (n = 6), the latter passage migrants from the Siberian populations. The Alaskan birds all have distinct haplotypes that differ by as many as six SNPs: Canadian birds taken in the vicinity of the breeding colonies show only two of these. We hypothesize the origins of the Canadian breeding colonies as recent founder events by small numbers of passage migrants from Siberia via Alaska. Ross's Gull maintains a very tenuous breeding presence in the Canadian high Arctic.

The high-arctic Ivory Gull (Pagophila eburnea) has recently undergone a sharp decline in numbers, and in Canada it is listed as "Endangered" under the Species-At-Risk Act. To test for circumpolar genetic distinctiveness, we examined 264 bp of the mtDNA Control Region Domain I from 127 museum specimens collected during the breeding season from northern Canada, Greenland, and Norway, and during the non-breeding season from adjacent overwintering grounds in Canada, Greenland, and a disjunct area in Alaska adjacent to the Bering Sea. Partition of genetic variance according to various phylogeographic and breeding ground models indicates no strong population structure, except that Alaska birds are consistently differentiated from other locations, and there are significant temporal shifts in haplotype frequencies. The evidence suggests that Ivory Gulls in Canada, Greenland, and Norway are a single genetic entity, in contrast to Alaska birds, which may represent a distinctive Siberian population.

Background: Improving the health of Traveller Communities is an international public health concern but there is little evidence on effective interventions. This study aimed to explain how, for whom and in what circumstances outreach works in Traveller Communities., Methods: A realist synthesis was undertaken. Systematic literature searches were conducted between August and November 2011. Grey literature was sought and key stakeholders were involved throughout the review process. Iterative steps of data extraction, analysis and synthesis, followed by additional searches were undertaken., Results: An explanatory framework details how, why and in what circumstances participation, behaviour change or social capital development happened. The trust status of outreach workers is an important context of outreach interventions, in conjunction with their ability to negotiate the intervention focus. The higher the outreach worker's trust status, the lower the imperative that they negotiate the intervention focus. A 'menu' of reasoning mechanisms is presented, leading to key engagement outcomes., Conclusions: Adopting a realist analysis, this study offers a framework with explanatory purchase as to the potential of outreach to improve health in marginalized groups., (© The Author 2015. Published by Oxford University Press on behalf of Faculty of Public Health.)

Purpose: To compare outcomes after percutaneous catheter drainage (PCD) for acute necrotizing pancreatitis versus those in a randomized controlled trial as a reference standard., Materials and Methods: Between September 2010 and August 2014, CT-guided PCD was the primary treatment for 39 consecutive patients with pancreatic necrosis. The indication for PCD was the clinical finding of uncontrolled pancreatic juice leakage rather than infected necrosis. Subsequent to PCD, the drains were proactively studied with fluoroscopic contrast medium every 3 days to ensure patency and position. Drains were ultimately maneuvered to the site of leakage. These 39 patients were compared with 43 patients from the Pancreatitis, Necrosectomy versus Step-up Approach (PANTER) trial., Results: The CT severity index was similar between studies (median of 8 in each). Time from onset of acute pancreatitis to PCD was shorter in the present series (median, 23 d vs 30 d). The total number of procedures (PCD and subsequent fluoroscopic drain studies) per patient was greater in the present series (mean, 14 vs 2). More patients in the PANTER trial had organ failure (62% vs 84%), required open or endoscopic necrosectomy (0% vs 60%), and experienced in-hospital mortality (0% vs 19%; P < .05 for all)., Conclusions: Even though patients in the present series had a similar CT severity index as those in the PANTER trial, the former group showed lower incidences of organ failure, need for necrosectomy, and in-hospital mortality. The use of a proactive PCD protocol early, before the development of severe sepsis, appeared to be effective., (Copyright © 2016 SIR. Published by Elsevier Inc. All rights reserved.)

Introduction: Welfare advice services can be used to address health inequalities, for example, through Citizens Advice Bureau (CAB). Recent reviews highlight evidence for the impact of advice services in improving people's financial position and improving mental health and well-being, daily living and social relationships. There is also some evidence for the impact of advice services in increasing accessibility of health services, and reducing general practitioner appointments and prescriptions. However, direct evidence for the impact of advice services on lifestyle behaviour and physical health is currently much less well established. There is a need for greater empirical testing of theories around the specific mechanisms through which advice services and associated financial or non-financial benefits may generate health improvements., Methods and Analysis: A realist evaluation will be conducted, operationalised in 5 phases: building the explanatory framework; refining the explanatory framework; testing the explanatory framework through empirical data (mixed methods); development of a bespoke data recording template to capture longer term impact; and verification of findings with a range of CAB services. This research will therefore aim to build, refine and test an explanatory framework about how CAB services can be optimally implemented to achieve health improvement., Ethics and Dissemination: The study was approved by the ethics committee at Northumbria University, UK. Project-related ethical issues are described and quality control aspects of the study are considered. A stakeholder mapping exercise will inform the dissemination of results in order to ensure all relevant institutions and organisations are targeted., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Methylation of lysine and arginine residues on histones has long been known to determine both chromatin structure and gene expression. In recent years, the methylation of non-histone proteins has emerged as a prevalent modification which impacts on diverse processes such as cell cycle control, DNA repair, senescence, differentiation, apoptosis and tumourigenesis. Many of these non-histone targets represent transcription factors, cell signalling molecules and tumour suppressor proteins. Evidence now suggests that the dysregulation of methyltransferases, demethylases and reader proteins is involved in the development of many diseases, including cancer, and several of these proteins represent potential therapeutic targets for small molecule compounds, fuelling a recent surge in chemical inhibitor design. Such molecules will greatly help us to understand the role of methylation in both health and disease., (© 2015 FEBS.)