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Background: Decision impact studies have become increasingly prevalent in genomic medicine, particularly in cancer research. Such studies are designed to provide evidence of clinical utility for genomic tests by evaluating their impact on clinical decision-making. This paper offers insights into understanding of the origins and intentions of these studies through an analysis of the actors and institutions responsible for the production of this new type of evidence. Methods: We conducted bibliometric and funding analyses of decision impact studies in genomic medicine research. We searched databases from inception to June 2022. The datasets used were primarily from Web of Science. Biblioshiny, additional R-based applications, and Microsoft Excel were used for publication, co-authorship and co-word analyses. Results: 163 publications were included for the bibliometric analysis; a subset of 125 studies were included for the funding analysis. Included publications started in 2010 and increased steadily over time. Decision impact studies were primarily produced for proprietary genomic assays for use in cancer care. The author and affiliate analyses reveal that these studies were produced by 'invisible colleges' of researchers and industry actors with collaborations focused on producing evidence for proprietary assays. Most authors had an industry affiliation, and the majority of studies were funded by industry. While studies were conducted in 22 countries, the majority had at least one author from the USA. Discussion: This study is a critical step in understanding the role of industry in the production of new types of research. Based on the data collected, we conclude that decision impact studies are industry-conceived and -produced evidence. The findings of this study demonstrate the depth of industry involvement and highlight a need for further research into the use of these studies in decision-making for coverage and reimbursement. [ABSTRACT FROM AUTHOR]

Background: Decision impact studies have become increasingly prevalent in cancer prognostic research in recent years. These studies aim to evaluate the impact of a genomic test on decision-making and appear to be a new form of evidence of clinical utility. The objectives of this review were to identify and characterize decision impact studies in genomic medicine in cancer care and categorize the types of clinical utility outcomes reported. Methods: We conducted a search of four databases, Medline, Embase, Scopus and Web of Science, from inception to June 2022. Empirical studies that reported a "decision impact" assessment of a genomic assay on treatment decisions or recommendations for cancer patients were included. We followed scoping review methodology and adapted the Fryback and Thornbury Model to collect and analyze data on clinical utility. The database searches identified 1803 unique articles for title/abstract screening; 269 articles moved to full-text review. Results: 87 studies met inclusion criteria. All studies were published in the last 12 years with the majority for breast cancer (72%); followed by other cancers (28%) (lung, prostate, colon). Studies reported on the impact of 19 different proprietary (18) and generic (1) assays. Across all four levels of clinical utility, outcomes were reported for 22 discrete measures, including the impact on provider/team decision-making (100%), provider confidence (31%); change in treatment received (46%); patient psychological impacts (17%); and costing or savings impacts (21%). Based on the data synthesis, we created a comprehensive table of outcomes reported for clinical utility. Conclusions: This scoping review is a first step in understanding the evolution and uses of decision impact studies and their influence on the integration of emerging genomic technologies in cancer care. The results imply that DIS are positioned to provide evidence of clinical utility and impact clinical practice and reimbursement decision-making in cancer care. Systematic review registration: Open Science Framework osf.io/hm3jr. [ABSTRACT FROM AUTHOR]

Background: While processes of adoption and the impacts of various health technologies have been extensively studied by health services and policy researchers, the influence of policy makers' governing styles on these processes have been largely neglected. Through a comparative analysis of non-invasive prenatal testing (NIPT) in the Canadian provinces of Ontario and Quebec, this article examines how decisions about this technology were shaped by contrasting political ideologies, resulting in vastly different innovation and adoption strategies and outcomes. Methods: A comparative qualitative investigation comprising of a document analysis followed by semi-structured interviews with key informants. Interview participants were researchers, clinicians, and private sector medical laboratory employees based in Ontario and Quebec, Canada. Interviews were conducted both in person and virtually– owing partly to the COVID-19 pandemic – to garner perspectives regarding the adoption and innovation processes surrounding non-invasive prenatal testing in both provinces. All interviews were recorded and transcribed verbatim and data were analyzed using thematic analysis. Results: Through an analysis of 21 in-depth interview transcripts and key documents, the research team identified three central themes: 1) health officials in each province demonstrated a unique approach to using the existing scholarly literature on NIPT; 2) each provincial government demonstrated its own preference for service delivery, with Ontario preferring private and Quebec preferring public; and finally, 3) both Ontario and Quebec's strategies to NIPT adoption and innovation was contextualized within each province's unique financial positioning and concerns. These findings illustrate how both Quebec's nationalist focus and use of industrial policy and Ontario's 'New Public Management' style had implications for how this emerging healthcare technology was made available within each province's publicly-financed health system. Conclusions: Our study reveals how these governments' differing approaches to using data and research, public versus private service delivery, and financial goals and concerns resulted in distinct testing technologies, access, and timelines for NIPT adoption. Our analysis demonstrates the need for health policy researchers, policy makers, and others to move beyond analyses solely considering clinical and health economic evidence to understand the impact of political ideologies and governing styles. [ABSTRACT FROM AUTHOR]

Carers of people with dementia can experience reduced health and well‐being, but little is known about how best to support them. There is some evidence to suggest that case management may improve outcomes for carers but less evidence about the features of case management services that can effectively support carers of people with dementia. Admiral Nursing operates a case management approach staffed by specialist nurses and is the only service of its kind in the United Kingdom dedicated to helping people with dementia and their carers. This paper reports qualitative findings from a mixed methods study of Admiral Nursing. For the qualitative strand of the project, data were collected in focus groups and in‐depth interviews with carers of people with dementia (n = 35) and analysed thematically using the framework approach. The aim of this analysis was to understand differences between the experiences of the carers in our sample with and without Admiral Nursing, applying Freeman's model of continuity of care (Freeman et al., Continuity of care, 2000). Participants who had received Admiral Nursing were recruited from two geographical locations and carers without experience of this service were recruited from two different areas. We found that carers in our sample felt 'supported' in circumstances where they received an ongoing service from an Admiral Nurse or other professional with expertise in dementia who was able to develop a meaningful relationship with them over time. We conclude that ongoing support, expertise in dementia and a meaningful relationship are key features of relationship continuity common in carers' reports of feeling supported. Specialist nurses are well placed to provide this continuity. [ABSTRACT FROM AUTHOR]

Background: There is recognition that the overuse of procedures, testing, and medications constitutes low-value care which strains the healthcare system and, in some circumstances, can cause unnecessary stress and harm for patients. Initiatives across dozens of countries have raised awareness about the harms of low-value care but have had mixed success and the levels of reductions realized have been modest. Similar to the complex drivers of implementation processes, there is a limited understanding of the individual and social behavioral aspects of de-implementation. While researchers have begun to use theory to elucidate the dynamics of de-implementation, the research remains largely atheoretical. The use of theory supports the understanding of how and why interventions succeed or fail and what key factors predict success. The purpose of this scoping review was to identify and characterize the use of theoretical approaches used to understand and/or explain what influences efforts to reduce low-value care.Methods: We conducted a review of MEDLINE, EMBASE, CINAHL, and Scopus databases from inception to June 2021. Building on previous research, 43 key terms were used to search the literature. The database searches identified 1998 unique articles for which titles and abstracts were screened for inclusion; 232 items were selected for full-text review.Results: Forty-eight studies met the inclusion criteria. Over half of the included articles were published in the last 2 years. The Theoretical Domains Framework (TDF) was the most commonly used determinant framework (n = 22). Of studies that used classic theories, the majority used the Theory of Planned Behavior (n = 6). For implementation theories, Normalization Process Theory and COM-B were used (n = 7). Theories or frameworks were used primarily to identify determinants (n = 37) and inform data analysis (n = 31). Eleven types of low-value care were examined in the included studies, with prescribing practices (e.g., overuse, polypharmacy, and appropriate prescribing) targeted most frequently.Conclusions: This scoping review provides a rigorous, comprehensive, and extensive synthesis of theoretical approaches used to understand and/or explain what factors influence efforts to reduce low-value care. The results of this review can provide direction and insight for future primary research to support de-implementation and the reduction of low-value care. [ABSTRACT FROM AUTHOR]

Objectives: Life story work involves gathering information about a person, their history and interests, and producing a tangible output, usually a book. It is used increasingly in dementia care. However, theory about if, how, and why it affects outcomes is poorly developed, making the choice of evaluation methods and appropriate outcomes difficult. This article uses a systematic review to uncover theories of change and outcomes for life story work in dementia care. We describe the methods and their use in identifying appropriate outcomes for evaluative research, and their potential for improving evaluation of 'theory poor' interventions. Methods: A systematic review, carried out using Centre for Reviews and Dissemination guidelines, searched for evidence on underlying theory, good practice, and effectiveness of life story work to inform a feasibility study for the formal evaluation of life story work in dementia care. For the theory element, a 'landscaping review' analysed the extracted text, using qualitative techniques and mind maps to uncover both explicit and implicit causal links between life story work and outcomes. We triangulated the review findings with qualitative research, which used focus groups with people with dementia, caregivers, and professionals that explored the outcomes that they would like to see from life story work. Results: Of the 56 publications reviewed, only 16 were useful for the theory analysis. Six overarching outcomes were identified: the self-worth and empowerment of people with dementia, individual psychological outcomes, improved relationships between care staff and the individual with dementia, better care, more effective engagement of family members/carers within the care setting, and helping carers to cope. Twelve final theories linking these outcomes to life story work via a causal pathway were elicited. There was substantial overlap in the outcomes identified by the review and by carers, people with dementia, and professionals. Together, the results informed our choice of outcome measures for the pilot evaluation. Conclusions: This approach may enable researchers to identify and develop the theory necessary before evaluation of a complex intervention in other under- or un-theorized areas. It has the potential both to shorten development stages (and thereby costs) in intervention research and improve the intervention itself. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus nuclear antigen 3C (EBNA3C) is a well-defined repressor of host gene expression in B cells transformed by Epstein-Barr virus (EBV) that cooperates with various cellular factors. It is established that EBNA3C interacts with the cellular factor RBPJ (RBP-Jκ or CBF1) through two distinct motifs: the TFGC motif, also called the homology domain (HD) motif, and the VWTP motif. In this study, we investigated the role of each motif in EBNA3C transcriptional repression activity by using two novel recombinant viruses with single RBPJ interaction motifs mutated (EBNA3C HDmut and EBNA3C W227S). Infection of primary B cells with either of these recombinant EBVs led to the successful establishment of lymphoblastoid cell lines (LCLs). Gene expression analysis showed that full repression of EBNA3C target genes is not achieved by EBNA3C HDmut compared to that with EBNA3C W227S or the EBNA3C wild type (WT). Focusing on the well-characterized EBNA3C-repressed genes COBLL1, ADAM28, and ADAMDEC1, we investigated the mechanism of EBNA3C-mediated transcriptional repression. Chromatin immunoprecipitation (ChIP) analysis indicated that EBNA3C HDmut is still able to recruit Polycomb proteins BMI1 and SUZ12 to COBLL1 as efficiently as EBNA3C WT does, leading to the full deposition of the repressive histone mark H3K27me3. However, we found that the activation-associated chromatin mark H3K4me3 is highly enriched at EBNA3C target genes in LCLs expressing EBNA3C HDmut. We show here that EBNA3C interacts with the histone lysine demethylase KDM2B and that this interaction is important for H3K4me3 removal and for the EBNA3C-mediated repression of COBLL1 and the ADAM28-ADAMDEC1 locus. IMPORTANCE EBV is a virus associated with human cancers and is well known for its ability to transform B lymphocytes into continuously proliferating lymphoblastoid cell lines. EBNA3C is considered an oncoprotein and has been shown to be essential for B cell transformation by EBV. EBNA3C is well characterized as a viral transcription factor, but very little is known about its mechanisms of action. In the present study, we demonstrate that removal of the activating histone mark H3K4me3 and deposition of the repressive mark H3K27me3 by EBNA3C on COBLL1 are achieved by at least two distinct mechanisms. Furthermore, we discovered that EBNA3C interacts with the lysine demethylase KDM2B and that this interaction is important for its transcriptional repressive function. The findings in this study provide new insights into the mechanism used by the oncoprotein EBNA3C to repress cellular target genes. [ABSTRACT FROM AUTHOR]

parker g., spiers g., cusworth l., birks y., gridley k. & mukherjee s. (2012) Care closer to home for children and young people who are ill: developing and testing a model of service delivery and organization. Journal of Advanced Nursing 68(9), 2034-2046. Abstract Aims. To report findings of a national survey of care closer to home services for children and young people and a typology based on these findings. Background. Providing care closer to home for children is a policy and practice aspiration internationally. While the main model of such services is children's community nursing, other models have also developed. Past research has proposed a relatively static typology of services, determined by where they are based, whether they are generic or specialist and whether they provide short- or longer-term input. As services develop, however, this typology needs further elaboration. Methods. A two-stage national survey of all primary care and hospital trusts in England, in mid-2008. Results. In all, 67% of trusts responded to the screening questionnaire and 75% of relevant services to the main stage questionnaire. Thirteen distinct types of services were identified initially. Cluster analysis of delivery and organization characteristics then identified a three-model typology: hospital-based, condition-specific services (36%); children's community nurses and other community services (45%) and other (mainly therapy-based) services (19%). The models differed in staffing, costs, functions, type of care provided and geographical coverage. Only a third of nurses in teams were paediatric-trained. Conclusion. Care closer to home services are an established part of care for children and young people who are ill. They deal with complex and technical care and can prevent or reduce the length of acute hospital admission. Lack of readily available information about caseloads, case mix and costs may hamper their further development. [ABSTRACT FROM AUTHOR]

Current health policy in England regarding the management of childhood illness advocates for care to be delivered as close to home as possible. The aim of this article is to report findings from a qualitative component of a larger study evaluating models of care closer to home (CCTH) for children and young people who are ill. The focus is on parents' psychosocial experience of receiving CCTH for their ill child. A qualitative case study design was used, with four Primary Care Trusts in England as the case study sites. In-depth, semi-structured interviews were conducted with 27 parents and one extended family caregiver of children using CCTH services within the case study sites. Interviews were conducted face-to-face and audio-recorded with permission. Data were collected in 2009. There was an overall preference for CCTH over hospital-based care where possible. The parents in this study experienced differing levels of responsibility as part of this care, and responded to this in different ways. Being supported emotionally and socially by practitioners was an important part of receiving CCTH for parents, especially when they had increased responsibility as part of this care. Developing relationships with practitioners appeared to be a medium through which parents received support. If the provision of CCTH continues to expand in line with current policy, provision of support for parents should be considered a fundamental aspect of service development. [ABSTRACT FROM AUTHOR]

Health and social care systems experience difficulty in delivering the continuity of care that service users want. Lack of clarity about what continuity means hinders service organisation and delivery. The NIHR Service Delivery and Organisation programme funded a series of research projects to tackle this conceptual confusion, and subsequently commissioned a review of the projects' outputs. The aim was to assess how the projects had progressed conceptualisation and measurement of continuity, and increased knowledge about what influenced it. This paper concentrates on two questions: what is continuity of care, and what influences it? We reviewed the projects' outputs and extracted data using techniques adapted from systematic reviewing methods. We treated the outputs as 'transcripts' and used the Framework approach to qualitative analysis to handle them. This maintained the coherence of individual projects while allowing cross-project themes to emerge. We then produced a narrative synthesis of findings. Service users and carers valued good relationships with professionals; this did not always mean seeing the same person and encompassed trust, the professional's style and communication skills, and the time made available. Service users and carers also valued understanding the patient's condition and treatment. This went beyond giving information, to include communication that recognised individuals' capacities and that was skilled, given sufficient time, and from a trusted source. Service users valued co-ordination between professionals and services; this covered communication, planning, and services' storage and use of information about them. Co-ordination with carers and others was also important. Experiences of continuity were influenced by service users' characteristics and circumstances, care trajectories, the structure and administration of services, professionals' characteristics, carer participation, the wider context of the 'whole person' and satisfaction. The review highlighted how service users, carers and professionals construct continuity dynamically between themselves. This has implications for both professional training and service users' expectations. [ABSTRACT FROM AUTHOR]

Several studies have used secondary data sources in order to learn about outcomes for adults who have been in contact with the care system in childhood. This article discusses two of the large-scale longitudinal datasets in the UK that are available to researchers and which include information on adults who were looked after in childhood: The National Child Developmental Study (NCDS) and The British Cohort Study (BCS70). These databases are considered to be among the best sources available to investigate long-term outcomes for looked-after children in the UK. This article describes these databases and the use made of them by researchers exploring the life chances of looked-after children. It also identifies the advantages as well as the limitations of these datasets and presents implications for this field of research. [ABSTRACT FROM AUTHOR]

Objective: To review systematically randomized trials (RCTs) on the effectiveness and costs of paediatric home care. Methods: National Health Service (NHS) Centre for Reviews and Dissemination guidelines were followed. In all, 20 electronic and other sources were searched, using specially designed strategies. Economic studies and other selected designs were included, but only RCT findings – on service use, clinical outcomes, costs, and impact on the family – are reported here. Analysis is descriptive, with pooled standard mean differences used where meta-analysis was possible. Results: About 1730 identified records up to August 2001 were potentially relevant. In all, 10 RCTs (24 papers) were finally included, covering five types of paediatric home care – for very low birth weight or medically 'fragile' infants, for asthma or diabetes, for technology-dependent children, for mental health, and generic home care. Paediatric home care may enhance physical and mental development for very low birth weight infants and may be cheaper but the evidence is not strong. Home care for diabetes or asthma may reduce parents' costs with some clinical but no social differences noticeable. No randomized trials for technologically dependent children were found. Home care for mental health may increase parental satisfaction with services and reduce some health service and residential care costs. Generic home care showed no clinical effects at early follow-up. Partial follow-up after five years suggested improved psychological adjustment. No cost data were available for this care model. Conclusions: Despite recent expansion, research evidence from randomized trials for paediatric home care is slight, and methods used are weak in places. Paediatric home care poses practical and ethical questions that cannot be addressed by RCTs. [ABSTRACT FROM AUTHOR]

Focuses on the policy changes in community health and social care funding in Great Britain. Transfer of resources from the security budget to local authorities; Objectives for the changes; Impact of the issue on hospital admissions.

Expression of EBNA3C is essential for the immortalization of B cells by EBV in vitro and, in co-operation with activated ras, EBNA3C has oncogenic activity in primary rodent fibroblasts. This suggested that this viral oncoprotein might disrupt the cyclin/CDK-pRb-E2F pathway, which regulates cell cycle progression at the restriction point (R-point) in G1 of the proliferation cycle. An assay was established in which transfected EBNA3C-positive cells could be sorted and simultaneously analysed for their distribution in the cell cycle. This revealed that in NIH3T3 fibroblasts compelled to arrest by serum-withdrawal, EBNA3C induces nuclear division that is often divorced from cytokinesis and so produces bi- and multinucleated cells. This was confirmed using the ecdysone-inducible system for expression of EBNA3C in human U2OS cells and by microinjection of expression vectors into NIH3T3 and U2OS. Further analysis revealed that in the inducible system, EBNA3C expression inhibits the accumulation of p27KIP1 but not the dephosphorylation of pRb. Experiments using the microtubule destabilizing drug nocodazole, showed that EBNA3C could abrogate the mitotic spindle checkpoint. Oncogene (2000) 19, 700–709. [ABSTRACT FROM AUTHOR]

Background: There is general scarcity of research on key elements of implementation processes and the factors which impact implementation success. Implementation of healthcare interventions is a complex process. Tools to support implementation can facilitate this process and improve effectiveness of the interventions and clinical outcomes. Understanding the impact of implementation support tools is a critical aspect of this process. The objective of this study was to solicit knowledge and agreement from relevant implementation science and knowledge translation healthcare experts in order to develop a process model of key elements in the implementation process.Methods: A two round, modified Delphi study involving international experts in knowledge translation and implementation (researchers, scientists, professors, decision-makers) was conducted. Participants rated and commented on all aspects of the process model, including the organization, content, scope, and structure. Delphi questions rated at 75% agreement or lower were reviewed and revised. Qualitative comments supported the restructuring and refinement. A second-round survey followed the same process as Round 1.Results: Fifty-four experts participated in Round 1, and 32 experts participated in Round 2. Twelve percent (n = 6) of the Round 1 questions did not reach agreement. Key themes for revision and refinement were: stakeholder engagement throughout the process, iterative nature of the implementation process; importance of context; and importance of using guiding theories or frameworks. The process model was revised and refined based on the quantitative and qualitative data and reassessed by the experts in Round 2. Agreement was achieved on all items in Round 2 and the Delphi concluded. Additional feedback was obtained regarding terminology, target users and definition of the implementation process.Conclusions: High levels of agreement were attained for all sub-domains, elements, and sub-elements of the Implementation Process Model. This model will be used to develop an Implementation Support Tool to be used by healthcare providers to facilitate effective implementation and improved clinical outcomes. [ABSTRACT FROM AUTHOR]

The relationship between research and policy making is complex and not always direct. This paper describes disability-related research for policy makers which is carried out at the Social Policy Research Unit (SPRU), University of York. A distinction between the ways in which research is formed and the ways in which it is informed is made. The informing of research influences how it is carried out; the research questions themselves, the choice of design and methods, the form of analysis, and the pattern of dissemination. The seminar series has helped SPRU reappraise its disability-related research. Disabled people must be able to influence the framing and elaboration of research questions more directly; there must be an increased commitment to employing and to training disabled researchers; dissemination must be wider; `crucial gateways' to policy makers and practitioners have to be identified, and the debate on informal care must be moved further on. [ABSTRACT FROM AUTHOR]

The DG75 Burkitt lymphoma-derived human B cell line is heterozygous for p53, carrying wild type (WT) and mutant (Arg283His) alleles. The cells constitutively express high levels of both p53 proteins and also Mdm2. Arg283His transactivates the p21Waf1, Mdm2, bax, cyclin G and IGF-BP3 promoters in transient transfection assays equally as well as, if not better than WT p53. It also suppresses the outgrowth of SAOS-2 cells and specifically binds DNA like wild type protein. However, in primary rodent fibroblasts Arg283His fails to suppress transformation by HPV16-E7 and (Ha-)ras and even has modest transforming activity when transfected alone with (Ha-)ras. When Arg283His is transiently transfected into SAOS-2 cells it efficiently induces apoptosis, so – unlike mutants such as Arg175Pro – its behaviour in transformation assays does not clearly correlate with loss of the apoptosis function. Immunofluorescence staining of both REF transformants and transiently transfected SAOS-2 revealed that this unusual mutant becomes excluded from the nucleus and produces striking cytoplasmic fluorescence. The best correlation with transformation, therefore, appears to be the lack of nuclear retention of Arg283His. Since this mutation does not map to any known nuclear localization signal and its presence seems to result in aberrant exclusion from the nucleus, then it may prove very useful in exploring mechanisms involved in the nuclear : cytoplasmic shuttling of p53. [ABSTRACT FROM AUTHOR]

The article highlights discrepancies in asthma care, discussing the unavailability of recommended treatments like epinephrine inhalers. Topics include disparities in affordability, the need for better inhaler options, and the role of environmental factors like air quality in asthma management, urging consideration for low-carbon healthcare practices.

Carers contribute essential support to enable people with dementia to continue living within the community. Admiral Nurses provide specialist dementia support for carers of people with dementia, including offering expert emotional support and guidance, and work to join up different parts of the health and social care system to address needs in a co‐ordinated way. The cost‐effectiveness of this service is not clear. We undertook a feasibility study to explore related outcomes and costs for these carers. A cross‐sectional, clustered survey was undertaken in England in 2017, in areas with and without Admiral Nursing (AN). The survey questionnaire included questions on the characteristics of the carers and the person with dementia, outcomes (care‐related quality of life [CRQoL], self‐efficacy and subjective well‐being), use of health and social care services, out‐of‐pocket costs and time spent on informal care. We used different econometric techniques to compare the outcomes and the costs of the carers with and without AN services: linear regression, propensity score matching and instrumental variables analysis. These techniques allowed us to control for differences in observed and unobserved characteristics between the two groups of carers which determined outcomes and costs. We concluded that AN services might have a positive effect on carers' CRQoL, self‐efficacy and subjective well‐being. Furthermore, we found little difference in costs between carers using AN and those using usual care, or in the costs of the people with dementia they care for. Our findings provided an initial indication as to whether AN services could be good value for money. The key limitation of the study was the difficulty in controlling for unobserved characteristics because of the cross‐sectional nature of our observational data. To diminish this limitation, our survey could be used in future studies following carers with and without AN services over time. [ABSTRACT FROM AUTHOR]

Hip arthroscopy has evolved into a well-established and rapidly growing field of orthopedic surgery for the management of labral tears. The purpose of this study was to review clinical outcomes of patients less than 25 years of age undergoing hip arthroscopy for treatment of a labral tear.~Background~Background~From 2005 to 2013, 82 hips in 76 patients with mean age of 20.4 (16-25 range) underwent hip arthroscopy for treatment of labral-chondral damage. The Western Ontario McMaster Universities Osteoarthritis Index (WOMAC) and hip disability and osteoarthritis outcome score (HOOS) were recorded at latest follow-up.~Methods~Methods~36 of 86 hips (42%) had isolated labral pathology with no associated bony pathology (normal alpha and centre-edge angle; no retroversion). Beck score (intraoperative cartilage damage) of 3 or more was significantly associated with an alpha angle of more than 55 degrees (odds ratio [OR], 3.6; confidence interval [CI], 1.2-11.0) and presence of femeroacetabular impingement (OR, 4.5; CI, 1.3-15.2). HOOS pain, sports/recreation, and quality of life significantly improved from preoperative to one year after surgery (p<0.05). 8 patients had re-operations for persistent pain; 5 underwent arthroscopic labral repair; 2 underwent arthroscopy with subsequent periacetabular osteotomy (PAO); 1 had only a periacetabular osteotomy (PAO). Complications included 2 lateral femoral cutaneous nerve deficits and 1 deep vein thrombosis.~Results~Results~Labral tears in patients less than 25 years of age occurs commonly without bony deformities, with those with normal head/neck contour demonstrating significantly less early cartilage damage than those with bony pathology. Hip arthroscopy in young patients can improve function and quality of life with minimal morbidity.~Conclusions~Conclusions [ABSTRACT FROM AUTHOR]

Mature human B cells infected by Epstein-Barr virus (EBV) become activated, grow, and proliferate. If the cells are infected ex vivo, they are transformed into continuously proliferating lymphoblastoid cell lines (LCLs) that carry EBV DNA as extra-chromosomal episomes, express 9 latency-associated EBV proteins, and phenotypically resemble antigen-activated B-blasts. In vivo similar B-blasts can differentiate to become memory B cells (MBC), in which EBV persistence is established. Three related latency-associated viral proteins EBNA3A, EBNA3B, and EBNA3C are transcription factors that regulate a multitude of cellular genes. EBNA3B is not necessary to establish LCLs, but EBNA3A and EBNA3C are required to sustain proliferation, in part, by repressing the expression of tumour suppressor genes. Here we show, using EBV-recombinants in which both EBNA3A and EBNA3C can be conditionally inactivated or using virus completely lacking the EBNA3 gene locus, that—after a phase of rapid proliferation—infected primary B cells express elevated levels of factors associated with plasma cell (PC) differentiation. These include the cyclin-dependent kinase inhibitor (CDKI) p18INK4c, the master transcriptional regulator of PC differentiation B lymphocyte-induced maturation protein-1 (BLIMP-1), and the cell surface antigens CD38 and CD138/Syndecan-1. Chromatin immunoprecipitation sequencing (ChIP-seq) and chromatin immunoprecipitation quantitative PCR (ChIP-qPCR) indicate that in LCLs inhibition of CDKN2C (p18INK4c) and PRDM1 (BLIMP-1) transcription results from direct binding of EBNA3A and EBNA3C to regulatory elements at these loci, producing stable reprogramming. Consistent with the binding of EBNA3A and/or EBNA3C leading to irreversible epigenetic changes, cells become committed to a B-blast fate <12 days post-infection and are unable to de-repress p18INK4c or BLIMP-1—in either newly infected cells or conditional LCLs—by inactivating EBNA3A and EBNA3C. In vitro, about 20 days after infection with EBV lacking functional EBNA3A and EBNA3C, cells develop a PC-like phenotype. Together, these data suggest that EBNA3A and EBNA3C have evolved to prevent differentiation to PCs after infection by EBV, thus favouring long-term latency in MBC and asymptomatic persistence. [ABSTRACT FROM AUTHOR]

Background: Reablement is a time-limited intervention that aims to support people to regain independence and enable them to resume their daily activities after they return home from an in-patient care setting, or to maintain independence to enable them to remain at home. There is some evidence that reablement can enhance independence and has the potential to contain costs. However, reablement services are funded and provided in different ways and by different organisations, and there is limited research evidence about the effectiveness of different reablement service models. This study will evaluate the effectiveness and cost-effectiveness of different reablement service models and service users' and carers' experiences of reablement in England, UK.Methods/design: The study will use a quasi-experimental mixed methods design that comprises three work packages (WP) extending over a period of 34 months. WP1 will conduct cluster analysis on survey data to develop a typology of current models of reablement services in order to describe the current reablement service landscape. WP2 will comprise a quantitative outcomes evaluation of the effectiveness of the different service models; a process evaluation and an economic evaluation. WP2 will be set within generic reablement services, where providers are using the most commonly employed generic reablement service types identified in WP1; the primary outcome measure is health-related quality of life measured by the EQ-5D-5L. WP3 will provide evidence about specialist reablement services and how specialist approaches and practices are organised and delivered.Discussion: Managing demands on care services is, and will remain, a crucial factor for the UK National Health Service as the number of people with long-term conditions rise. There has been, and will continue to be, significant investment in reablement services. The proposed study will address several key areas where there is limited evidence regarding the organisation and delivery of reablement services in England, UK. Specifically, it will provide new evidence on different models of reablement services that will be of direct benefit to health and social care managers, commissioners and their partner organisations. [ABSTRACT FROM AUTHOR]

Background: The Bernese periacetabular osteotomy (PAO) has entered its fourth decade and is frequently used for corrective osteotomy in patients with acetabular dysplasia. Although our capacity to preserve the joint after corrective osteotomy is excellent, gaining a better understanding on how well patients function after this surgery is important as well. Questions/purposes: (1) What changes in patient-reported outcomes scores occur in patients treated with PAO for hip dysplasia in the setting of a single-surgeon practice? (2) What are the predictors of clinical function and survivorship? Methods: All 67 patients presenting to a single surgeon's clinic with hip dysplasia treated with PAO between October 2005 and January 2013 were prospectively followed. Baseline demographic data as well as pre- and postoperative radiographic and functional measurements were obtained with a minimum of 1-year followup. Radiographic criteria included Tönnis grade, Tönnis angle, minimum joint space width, center-edge angle, presence of crossover sign, medial translation of the hip center, and alpha angle. We also used validated outcome measures including the WOMAC, the UCLA Activity Scale, and the SF-12. Multiple regression analysis was used to determine predictors of functional outcome scores. Results: There were increases in WOMAC, UCLA, and SF-12 Physical scores. Higher preoperative alpha angle was associated with a lower postoperative WOMAC score (β = −0.47; 95% confidence interval [CI], −0.92 to −0.02; R = 0.08; p = 0.04). The 5-year Kaplan-Meier survivorship was 94.1% (95% CI, 90.7-97.5) with reoperation (ie, hip arthroscopy and/or total hip arthroplasty) used as the endpoint for failure. With the limited numbers available, we could not identify any demographic or radiographic factors associated with reoperation. Conclusions: Overall survivorship for the PAO at our center at 5 years is comparable to other clinical series with overall functional scores improving. A greater alpha angle preoperatively was associated with poorer patient-reported outcome scores. Further research is needed to determine how and when intraarticular cartilage damage associated with dysplasia needs to be addressed. Level of Evidence: Level IV, therapeutic study. [ABSTRACT FROM AUTHOR]

Background: Choosing Wisely (CW) is an international movement comprised of campaigns in more than 20 countries to reduce low-value care (LVC). De-implementation, the reduction or removal of a healthcare practice that offers little to no benefit or causes harm, is an emerging field of research. Little is known about the factors which (i) sustain LVC; and (ii) the magnitude of the problem of LVC. In addition, little is known about the processes of de-implementation, and if and how these processes differ from implementation endeavours. The objective of this study was to explicate the myriad factors which impact the processes and outcomes of de-implementation initiatives that are designed to address national Choosing Wisely campaign recommendations.Methods: Semi-structured interviews were conducted with individuals implementing Choosing Wisely Canada recommendations in healthcare settings in four provinces. The interview guide was developed using concepts from the literature and the Implementation Process Model (IPM) as a framework. All interviews were conducted virtually, recorded, and transcribed verbatim. Data were analysed using thematic analysis.Findings: Seventeen Choosing Wisely team members were interviewed. Participants identified numerous provider factors, most notably habit, which sustain LVC. Contrary to reporting in recent studies, the majority of LVC in the sample was not 'patient facing'; therefore, patients were not a significant driver for the LVC, nor a barrier to reducing it. Participants detailed aspects of the magnitude of the problems of LVC, providing insight into the complexities and nuances of harm, resources and prevalence. Harm from potential or common infections, reactions, or overtreatment was viewed as the most significant types of harm. Unique factors influencing the processes of de-implementation reported were: influence of Choosing Wisely campaigns, availability of data, lack of targets and hard-coded interventions.Conclusions: This study explicates factors ranging from those which impact the maintenance of LVC to factors that impact the success of de-implementation interventions intended to reduce them. The findings draw attention to the significance of unintentional factors, highlight the importance of understanding the impact of harm and resources to reduce LVC and illuminate the overstated impact of patients in de-implementation literature. These findings illustrate the complexities of de-implementation. [ABSTRACT FROM AUTHOR]

To explore the role of p16INK4a as an intrinsic barrier to B cell transformation by EBV, we transformed primary B cells from an individual homozygous for a deletion in the CDKN2A locus encoding p16 INK4a and p14ARF. Using recombinant EBV-BAC viruses expressing conditional EBNA3C (3CHT), we developed a system that allows inactivation of EBNA3C in lymphoblastoid cell lines (LCLs) lacking active p16INK4a protein but expressing a functional 14ARF-fusion protein (p14/p16). The INK4a locus is epigenetically repressed by EBNA3C -- in cooperation with EBNA3A -- despite the absence of functional p16INK4a. Although inactivation of EBNA3C in LCLs from normal B cells leads to an increase in p16INK4a and growth arrest, EBNA3C inactivation in the p16INK4a-null LCLs has no impact on the rate of proliferation, establishing that the repression of INK4a is a major function of EBNA3C in EBV-driven LCL proliferation. This conditional LCL system allowed us to use microarray analysis to identify and confirm genes regulated specifically by EBNA3C, independently of proliferation changes modulated by the p16INK4a-Rb-E2F axis. Infections of normal primary B cells with recombinant EBV-BAC virus from which EBNA3C is deleted or with 3CHT EBV in the absence of activating ligand 4-hydroxytamoxifen, revealed that EBNA3C is necessary to overcome an EBV-driven increase in p16INK4a expression and concomitant block to proliferation 2-4 weeks post-infection. If cells are p16INK4a-null, functional EBNA3C is dispensable for the outgrowth of LCLs. [ABSTRACT FROM AUTHOR]

Background: Substantial acetabular cartilage damage is commonly present in patients suffering from femoral acetabular impingement (FAI). A better understanding of which patient is at risk of developing substantial cartilage damage is critical for establishing appropriate treatment guidelines. Questions/Purposes: We asked: (1) Does the cam deformity severity in FAI as assessed by alpha angle predict acetabular cartilage delamination? And (2) what are the clinical and radiographic findings in patients with acetabular cartilage delamination? Methods: One hundred sixty-seven patients (129 males, 38 females) with a mean age of 38 years (range, 17-59 years) underwent joint preservation surgery for cam-type FAI. All data were collected prospectively. We assessed center-edge angle and Tönnis grade on AP radiographs and alpha angle on specialized lateral radiographs. Acetabular cartilage damage was assessed intraoperatively using the classification of Beck et al., with Type 3 and greater qualifying as delamination. Results: For all hips, mean alpha angle was 65.5° (range, 41°-90°), and mean center-edge angle was 33.3° (range, 21°-52.5°). Patients with an alpha angle of 65° or greater had an odds ratio (OR) of 4.00 (95% CI, 1.26-12.71) of having Type 3 or greater damage. Increased age (OR, 1.04; 95% CI, 1.01-1.07) and male sex (OR, 2.24; 95% CI, 1.09-4.62) were associated with Type 3 or greater damage, while this was the opposite for acetabular coverage as assessed by center-edge angle (OR, 0.94; 95% CI, 0.89-0.99). Conclusions: Patients with cam-type FAI and an alpha angle of 65° or more are at increased risk of substantial cartilage damage while increasing acetabular coverage appears to have a protective effect. Level of Evidence: Level III, prognostic study. See the Instructions for Authors for a complete description of levels of evidence. [ABSTRACT FROM AUTHOR]

Introduction: A Continuity of Care Research Programme was undertaken in England in 2000-9. The Programme was informed by a conceptual framework proposed by Freeman and colleagues in an earlier scoping study. At the end of the Programme, a conceptual synthesis was carried out in order to confirm or refine the 'Freeman model' of continuity of care. Methods: A conceptual synthesis of the outputs of the Programme, using Critical Interpretive Synthesis. Results: The conceptual framework underpinning the Freeman model of continuity of care, which prioritises the perspectives of service users and carers, was variously utilised in the Programme. Analysis revealed indications of an emerging shift from the patient and carer 'perspectivist' paradigm of the Freeman model towards a new 'partnership' paradigm where continuity is recognised to be co-constructed by patients, families and professionals, all of whom have an active part to play in its accomplishment. Conclusions: The projects in the Programme have advanced understanding of patients' perspectives on continuity of care and on the complex nature of this concept. At the same time, they have raised issues and reported findings which may be indicative of an emergent paradigm shift in this area of research, towards a more dynamic partnership model. [ABSTRACT FROM AUTHOR]

Inheritance of germ-line mutant alleles of BRCA1 and BRCA2 confers a markedly increased risk of breast cancer and we have previously reported a higher incidence of p53 mutations in these tumours than in grade matched sporadic tumours. We have now characterized these p53 mutants. The results of these studies identify a novel class of p53 mutants previously undescribed in human cancer yet with multiple occurrences in BRCA-associated tumours which retain a profile of p53-dependent activities in terms of transactivation, growth suppression and apoptosis induction which is close or equal to wild-type. However, these mutants fail to suppress transformation and exhibit gain of function transforming activity in rat embryo fibroblasts. These mutants therefore fall into a novel category of p53 mutants which dissociate transformation suppression from other wild-type functions. The rarity of these mutants in human cancer and their multiple occurrence in BRCA-associated breast tumours suggests that these novel p53 mutants are selected during malignant progression in the unique genetic background of BRCA1- and BRCA2-associated tumours. [ABSTRACT FROM AUTHOR]

Much literature assesses the impact of various factors on response rates to postal questionnaires. Little work, however, evaluates the effect of 'controversial' questions on rates of return. Recent debates suggest that one such question concerns ethnic origin and some writers argue that asking this question could affect response rates. This research note explores this issue in more detail, first by examining the effect of an ethnicity question on the response rate of a postal questionnaire to practice nurses in England and Wales and, secondly, considering the arguments for and against including the question. [ABSTRACT FROM AUTHOR]

During anagen, cell proliferation in the germinative matrix of the hair follicle gives rise to the fiber and inner root sheath. The hair fiber is constructed from structural proteins belonging to four multigene families: keratin intermediate filaments, high‐sulfur matrix proteins, ultra high‐sulfur matrix proteins, and high glycine‐tyrosine proteins. Several hair‐specific keratin intermediate filament proteins have been characterized, and all have relatively cysteine‐rich N‐ and C‐terminal domains, a specialization that allows extensive disulfide cross‐linking to matrix proteins. We have cloned two complete type II hair‐specific keratin genes (ghHb1 and ghHb6). Both genes have nine exons and eight introns spanning about 7 kb and lying about 10 kb apart. The structure of both genes is highly conserved in the regions that encode the central rod domain but differs considerably in the C‐terminal coding and noncoding sequences, although some conservation of introns does exist. These genes have been localized to the type II keratin cluster on chromosome 12q13 by fluorescence in situ hybridization. They, and their type I partner ghHa1, are expressed in differentiating hair cortical cells during anagen. In cultured follicles, ghHa1 expression declined in cortical cells and was no longer visible after 6 d, whereas the basal epidermal keratin hK14 appeared in the regressing matrix. The transition from anagen to telogen is marked by downregulation of hair cortical specific keratins and the appearance of hK14 in the epithelial sac to which the telogen hair fiber is anchored. Further studies of the regulation of these genes will improve our understanding of the cyclical molecular changes that occur as the hair follicle grows, regresses, and rests. [ABSTRACT FROM AUTHOR]

Reablement – or restorative care – is a central feature of many western governments' approaches to supporting and enabling older people to stay in their own homes and minimise demand for social care. Existing evidence supports this approach although further research is required to strengthen the certainty of conclusions being drawn. In countries where reablement has been rolled out nationally, an additional research priority – to develop an evidence base on models of delivery – is emerging. This paper reports a prospective cohort study of individuals referred to three English social care reablement services, each representing a different model of service delivery. Outcomes included healthcare‐ and social care–related quality of life, functioning, mental health and resource use (service costs, informal carer time, out‐of‐pocket costs). In contrast with the majority of other studies, self‐report measures were the predominant source of outcomes and resource use data. Furthermore, no previous evaluation has used a global measure of mental health. Outcomes data were collected on entry to the service, discharge and 6 months post discharge. A number of challenges were encountered during the study and insufficient individuals were recruited in two research sites to allow a comparison of service models. Findings from descriptive analyses of outcomes align with previous studies and positive changes were observed across all outcome domains. Improvements observed at discharge were, for most, retained at 6 months follow‐up. Patterns of change in functional ability point to the importance of assessing functioning in terms of basic and extended activities of daily living. Findings from the economic evaluation highlight the importance of collecting data on informal carer time and also demonstrate the viability of collecting resource use data direct from service users. The study demonstrates challenges, and value, of including self‐report outcome and resource use measures in evaluations of reablement. [ABSTRACT FROM AUTHOR]

Introduction and hypothesis: To identify the association between the symptom severity and outcome of conservative management for OAB, SUI and MUI. Conservative treatments are recommended for overactive bladder (OAB), stress urinary incontinence (SUI) and mixed incontinence (MUI). It is unclear whether disease severity affects treatment outcome. Methods: Patients receiving conservative management were reviewed. Disease-specific questionnaires (OAB-q SF, ICIQ-UI SF) and bladder diaries recorded baseline symptoms. Success was defined by Patient Global Impression of Improvement questionnaire (PGI-I) response of "very much better" or "much better". Non-parametric statistical tests and logistic regression were used. Results: In 50 OAB patients success was associated with lower symptom severity [30 (0–80) vs. 80 (23–100), p = 0.0001], fewer urgency episodes [4 (0–12) vs. 6 (0–11), p = 0.032] and lower ICIQ-UI SF [5.5 (0–20) vs. 15 (0–21), p = 0.002], but higher QoL [67 (20–101) vs. 24 (6–58), p = 0.0001]. In 50 MUI patients, variables were fewer urgency episodes [3 (0–10) vs. 6 (0–16), p = 0.004] and lower ICIQ-UI [11 (1–18) vs. 15 (5–21), p = 0.03]. In 40 SUI patients, variables were fewer incontinence episodes [1 (0–4) vs. 2 (0–5), p = 0.05] and lower ICIQ-UI [11 (6–16) vs. 13.5 (11–19), p = 0.003]. Multiple regression confirmed OAB-q QoL [odds ratio (OR) 1.10 (95% confidence intervals 1.04, 1.1)] for OAB, urgency episodes [OR 0.74 (0.56, 0.98)] and ICIQ-UI [OR 0.83 (0.71, 0.98] for MUI and ICIQ-UI [OR 0.57 (0.40, 0.83)] for SUI. Conclusions: Milder baseline disease severity was associated with successful outcome. There is potential for triage at initial assessment to second-line interventions for women unlikely to achieve success. [ABSTRACT FROM AUTHOR]

Objective: To update a 2010 meta-review of systematic reviews of effective interventions to support carers of ill, disabled, or older adults. In this article, we report the most promising interventions based on the best available evidence. Methods: Rapid meta-review of systematic reviews published from January 2009 to 2016. Results: Sixty-one systematic reviews were included (27 high quality, 25 medium quality, and nine low quality). The quality of reviews has improved since the original review, but primary studies remain limited in quality and quantity. Fourteen high quality reviews focused on carers of people with dementia, four on carers of those with cancer, four on carers of people with stroke, three on carers of those at the end of life with various conditions, and two on carers of people with mental health problems. Multicomponent interventions featured prominently, emphasizing psychosocial or psychoeducational content, education and training. Improved outcomes for carers were reported for mental health, burden and stress, and wellbeing or quality of life. Negative effects were reported in reviews of respite care. As with earlier work, we found little robust evidence on the cost-effectiveness of reviewed interventions. Conclusions: There is no 'one size fits all' intervention to support carers. There is potential for effective support in specific groups of carers, such as shared learning, cognitive reframing, meditation, and computer-delivered psychosocial support for carers of people with dementia. For carers of people with cancer, effective support may include psychosocial interventions, art therapy, and counselling. Carers of people with stroke may also benefit from counselling. More good quality, theory-based, primary research is needed. [ABSTRACT FROM AUTHOR]

People with mental health conditions have a lower life expectancy and poorer physical health outcomes than the general population. Evidence suggests this is due to a combination of clinical risk factors, socioeconomic factors, and health system factors, notably a lack of integration when care is required across service settings. Several recent reports have looked at ways to better integrate physical and mental health care for people with severe mental illness (SMI). We built on these by conducting a mapping review that looked for the most recent evidence and service models in this area. This involved searching the published literature and speaking to people involved in providing or using current services. Few of the identified service models were described adequately and fewer still were evaluated, raising questions about the replicability and generalisability of much of the existing evidence. However, some common themes did emerge. Efforts to improve the physical health care of people with SMI should empower staff and service users and help remove everyday barriers to delivering and accessing integrated care. In particular, there is a need for improved communication among professionals and better information technology to support them, greater clarity about who is responsible and accountable for physical health care, and greater awareness of the effects of stigmatisation on the wider culture and environment in which services are delivered. [ABSTRACT FROM AUTHOR]

Aims Recent years have seen an increasing shift towards providing care in the community, epitomised by the role of Children's Community Nursing (CCN) teams. However, there have been few attempts to use robust evaluative methods to interrogate the impact of such services. This study sought to evaluate whether reduction in secondary care costs, resulting from the introduction of 2 CCN teams, was sufficient to offset the additional cost of commissioning. Methods Among the potential benefits of the CCN teams is a reduction in the burden placed on secondary care through the delivery of care at home; it is this potential reduction which is evaluated in this study via a 2-part analytical method. Firstly, an interrupted time series analysis used Hospital Episode Statistics data to interrogate any change in total paediatric bed days as a result of the introduction of 2 teams. Secondly, a costing analysis compared the cost savings from any reduction in total bed days with the cost of commissioning the teams. This study used a retrospective longitudinal study design as part of the transforming children's community services trial, which was conducted between June 2012 and June 2015. Results A reduction in hospital activity after introduction of the 2 nursing teams was found, (9634 and 8969 fewer bed days), but this did not reach statistical significance. The resultant cost saving to the National Health Service was less than the cost of employing the teams. Conclusion The study represents an important first step in understanding the role of such teams as a means of providing a high quality of paediatric care in an era of limited resource. While the cost saving from released paediatric bed days was not sufficient to demonstrate cost-effectiveness, the analysis does not incorporate wider measures of health care utilisation and nonmonetary benefits resulting from the CCN teams. [ABSTRACT FROM AUTHOR]

Objective To assess what is known about effective patient and public engagement in health service reconfiguration processes and identify implications for further research and health care practice. Methods Rapid systematic review of published and grey literature to identify methods or approaches to engagement in decisions about health service reconfiguration; and to examine how engagement has worked or not worked in specific examples of system change. Following a search for literature published in English from 2000 to March 2014, eight systematic reviews, seven primary studies and 24 case studies (of which 6 were exemplars) were included. We undertook a narrative synthesis to consider five aspects of engagement with health service reconfiguration. Results Engagement varied in nature and intensity, and efforts generally involved multiple methods. There was no evidence on the isolated impact of any particular engagement method or collection of methods. In general, engagement was most likely to be successful when started early, when led and supported by clinicians, and when it offered opportunities for genuine interaction. The impact of engagement was variably measured and demonstrated, and frequently defined as process measures rather than the outcomes of proposals for service reconfiguration. Little was reported on the potential negative impact of service user engagement. Conclusions Patients and the public can be engaged through various methods. Problems often arise because decision-makers paid insufficient attention to issues considered important by patients and the public. Guidance setting out the stages of reconfiguration and opportunities for service user input could be a helpful practical framework for future engagement activity. Future evaluation and explicit reporting of engagement and impact is needed. [ABSTRACT FROM AUTHOR]