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PDF file - 322K, Supplemental Figure 1. Disease free survival (DFS) and distant metastasis free survival (DMFS) in breast cancer whole cohort (A), Lymph node negative (B) and lymphnode positive (C). Supplemental Figure 2. Disease free survival (DFS) and distant metastasis free survival (DMFS) in breast cancerlow risk, no adjuvant therapy (A), high risk, received endocrine therapy (B) and high risk, received CMF chemotherapy (C). Supplemental Figure 3. Disease free survival (DFS) and distant metastasis free survival (DMFS) in breast cancerER negative tumours (A), Triple negative tumours (B). Supplemental Figure 4. Clonogenic survival assay (A), Annexin-V FITC assay (B).

PDF file - 104K, Supplemental Table S1: Clinicopathological characteristics of whole breast cancer cohort Supplemental Table S2: Clinicopathological characteristics of validation setSupplementary Table S3: Antigens, primary antibodies, clone, source, optimal dilution and scoring system used for each immunohistochemical marker Supplementary Table S4: siRNA constructs for XRCC1 knockdown

XRCC1 is a key component of DNA base excision repair, single strand break repair, and backup nonhomologous end-joining pathway. XRCC1 (X-ray repair cross-complementing gene 1) deficiency promotes genomic instability, increases cancer risk, and may have clinical application in breast cancer. We investigated XRCC1 expression in early breast cancers (n = 1,297) and validated in an independent cohort of estrogen receptor (ER)-α–negative breast cancers (n = 281). Preclinically, we evaluated XRCC1-deficient and -proficient Chinese hamster and human cancer cells for synthetic lethality application using double-strand break (DSB) repair inhibitors [KU55933 (ataxia telangectasia–mutated; ATM inhibitor) and NU7441 (DNA-PKcs inhibitor)]. In breast cancer, loss of XRCC1 (16%) was associated with high grade (P < 0.0001), loss of hormone receptors (P < 0.0001), triple-negative (P < 0.0001), and basal-like phenotypes (P = 0.001). Loss of XRCC1 was associated with a two-fold increase in risk of death (P < 0.0001) and independently with poor outcome (P < 0.0001). Preclinically, KU55933 [2-(4-Morpholinyl)-6-(1-thianthrenyl)-4H-pyran-4-one] and NU7441 [8-(4-Dibenzothienyl)-2-(4-morpholinyl)-4H-1-benzopyran-4-one] were synthetically lethal in XRCC1-deficient compared with proficient cells as evidenced by hypersensitivity to DSB repair inhibitors, accumulation of DNA DSBs, G2–M cell-cycle arrest, and induction of apoptosis. This is the first study to show that XRCC1 deficiency in breast cancer results in an aggressive phenotype and that XRCC1 deficiency could also be exploited for a novel synthetic lethality application using DSB repair inhibitors. Cancer Res; 73(5); 1621–34. ©2012 AACR.

BackgroundEmergency Care and Treatment Plans are recommended for all primary care patients in the United Kingdom who are expected to experience deterioration of their health. The Recommended Summary Plan for Emergency Care and Treatment (ReSPECT) was developed to integrate resuscitation decisions with discussions about wider goals of care. It summarises treatment recommendations discussed and agreed between patients and their clinicians for a future emergency situation and was designed to meet the needs of different care settings. Our aim is to explore GPs’ experiences of using ReSPECT and how it transfers across the primary care and secondary care interface.MethodsWe conducted five focus groups with GPs in areas being served by hospitals in England that have implemented ReSPECT. Participants were asked about their experience of ReSPECT, how they initiate ReSPECT-type conversations, and their experiences of ReSPECT-type recommendations being communicated across primary and secondary care. Focus groups were transcribed and analysed using Thematic Analysis.ResultsGPs conceptualise ReSPECT as an end of life planning document, which is best completed in primary care. As an end of life care document, completing ReSPECT is an emotional process and conversations are shaped by what a ‘good death’ is thought to be. ReSPECT recommendations are not always communicated or transferable across care settings. A focus on the patient’s preferences around death, and GPs’ lack of specialist knowledge, could be a barrier to completion of ReSPECT that is transferable to acute settings.ConclusionConceptualising ReSPECT as an end of life care document suggests a difference in how general practitioners understand ReSPECT from its designers. This impacts on the transferability of ReSPECT recommendations to the hospital setting.

Background: The Recommended Summary Plan for Emergency Care and Treatment (ReSPECT) is an emergency care and treatment planning (ECTP) process, developed to offer a patient-centred approach to deciding about and recording treatment recommendations. Conversations between clinicians and patients or their representatives are central to the ReSPECT process. This study aims to understand why, when, and how ReSPECT conversations unfold in practice.\ud \ud Methods: ReSPECT conversations were observed in hospitals within six acute National Health Service (NHS) trusts in England; the clinicians who conducted these conversations were interviewed. Following observation-based thematic analysis, five ReSPECT conversation types were identified: resuscitation and escalation; confirmation of decision; bad news; palliative care; and clinical decision. Interview-based thematic analysis examined the reasons and prompts for each conversation type, and the level of detail and patient engagement in these different conversations.\ud \ud Results: Whereas resuscitation and escalation conversations concerned possible futures, palliative care and bad news conversations responded to present-tense changes. Conversations were timed to respond to organisational, clinical, and patient/relative prompts. While bad news and palliative care conversations included detailed discussions of treatment options beyond CPR, this varied in other conversation types. ReSPECT conversations varied in doctors’ engagement with patient/relative preferences, with only palliative care conversations consistently including an open-ended approach.\ud \ud Conclusions: While ReSPECT supports holistic, person-centred, anticipatory decision-making in some situations, a gap remains between the ReSPECT’s aims and their implementation in practice. Promoting an understanding and valuing of the aims of ReSPECT among clinicians, supported by appropriate training and structural support will enhance ReSPECT conversations.

Aims The out-of-hospital cardiac arrest (OHCA) outcomes project is a national research registry. One of its aims is to explore sources of variation in OHCA survival outcomes. This study reports the development and validation of risk prediction models for return of spontaneous circulation (ROSC) at hospital handover and survival to hospital discharge. Methods and results The study included OHCA patients who were treated during 2014 and 2015 by emergency medical services (EMS) from seven English National Health Service ambulance services. The 2014 data were used to identify important variables and to develop the risk prediction models, which were validated using the 2015 data. Model prediction was measured by area under the curve (AUC), Hosmer–Lemeshow test, Cox calibration regression, and Brier score. All analyses were conducted using mixed-effects logistic regression models. Important factors included age, gender, witness/bystander cardiopulmonary resuscitation (CPR) combined, aetiology, and initial rhythm. Interaction effects between witness/bystander CPR with gender, aetiology and initial rhythm and between aetiology and initial rhythm were significant in both models. The survival model achieved better discrimination and overall accuracy compared with the ROSC model (AUC = 0.86 vs. 0.67, Brier score = 0.072 vs. 0.194, respectively). Calibration tests showed over- and under-estimation for the ROSC and survival models, respectively. A sensitivity analysis individually assessing Index of Multiple Deprivation scores and location in the final models substantially improved overall accuracy with inconsistent impact on discrimination. Conclusion Our risk prediction models identified and quantified important pre-EMS intervention factors determining survival outcomes in England. The survival model had excellent discrimination.

Introduction: Bystander cardiopulmonary resuscitation (BCPR) is strongly advocated by resuscitation councils for paediatric out-of-hospital cardiac arrests (OHCAs). However, there are limited reports on rates of BCPR in children and its relationship with return of spontaneous circulation (ROSC) or survival outcomes. Objective: We describe the rate of BCPR and its association with any ROSC and survival- to- hospital-discharge. Methods: We conducted retrospective analysis of prospectively collected paediatric (

Introduction: Restart a Heart (RSAH) is an annual CPR mass training initiative delivered predominantly by ambulance services in the UK. The aim of this study was to identify to what extent voluntary participation in the 2019 initiative delivered training to the population with the highest need.Methods: A cross-sectional observational study of location characteristics for RSAH training events conducted by UK ambulance services. Descriptive statistics were used to analyse event and area characteristics. National cardiac arrest registry data were used to establish proportions of training coverage in "hot spot" areas with above national median incidence of cardiac arrest and below median bystander CPR rates. The significance of observed differences were tested using chi-square for proportions and t-test for means.Results: Twelve of 14 UK ambulance services participated, training 236,318 people. Most of the events (82%) were held in schools, and schoolchildren comprised most participants (81%). RSAH events were held in areas that were less densely populated (p < 0.001), were more common in affluent areas (p < 0.001), and had a significantly lower proportion of black residents (p < 0.05) and higher proportion of white residents (p < 0.05). Events were held in 28% of known "hot spot" areas in England.Conclusion: With mandatory CPR training for school children in England, Scotland and Wales there is an opportunity to re-focus RSAH resources to deliver training for all age groups in OHCA "hot spots", communities with higher proportions of black residents, and areas of deprivation. In Northern Ireland, we recommend targeting schools in areas with similar characteristics.

Highlights • Bystander CPR rates for non-EMS witnessed out-of-hospital cardiac arrests have risen steadily in West Yorkshire. • There was a non-significant increase in bystander CPR rates in postcode districts with ‘Restart a Heart’ training. • Mass training initiatives have a positive impact on bystander CPR rates., Aim Bystander CPR rates have steadily increased in England between 2014 and 2018. In West Yorkshire, there have been two important developments during this time. We aimed to describe whether postcode districts (PCDs) with more cumulative annual ‘Restart a Heart’ (RSAH) and/or Community First Responder (CFR) scheme activity between 2014 and 2018 were associated with greater improvements in non-EMS bystander CPR rates for out-of-hospital cardiac arrest (OHCA) when compared with PCDs in the same region with lesser or no such historic activity during the same time period. Method We collated data from the OHCA Outcomes Registry for all non-EMS witnessed OHCA in West Yorkshire treated by Yorkshire Ambulance Service. We analysed clusters of PCDs with high and low levels of RSAH and CFR activity between 2014 and 2018 using descriptive statistics, and comparisons were made between groups using chi-square and t-test. Results The reported bystander CPR rate for non-EMS witnessed OHCA cases for West Yorkshire rose from 38.4% in 2014 to 69.7% in 2018. The largest increases were seen in PCDs with high RSAH activity (+34.3%) and in the combination of high RSAH and low CFR activity (+38.5%). There was no significant difference when considering the interaction between RSAH and CFR groups. Conclusion The data infers the possibility of a non-significant association between improved non-EMS bystander CPR rates and RSAH training and CFR scheme activity. We recommend coordinated mass training, in particular for children in regions where CPR is not a mandatory part of the school curriculum.

Introduction:\ud Do-not-attempt-cardiopulmonary-resuscitation (DNACPR) practice has been shown to be variable and sub-optimal. This paper describes the development of the Recommended Summary Plan for Emergency Care and Treatment (ReSPECT). ReSPECT is a process which encourages shared understanding of a patient’s condition and what outcomes they value and fear, before recording clinical recommendations about cardiopulmonary-resuscitation (CPR) within a broader plan for emergency care and treatment.\ud \ud Methods:\ud ReSPECT was developed iteratively, with integral stakeholder engagement, informed by the Knowledge-to-Action cycle. Mixed methods included: synthesis of existing literature; a national online consultation exercise; cognitive interviews with users; a patient-public involvement (PPI) workshop and a usability pilot, to ensure acceptability by both patients and professionals.\ud \ud Results:\ud The majority (89%) of consultation respondents supported the concept of emergency care and treatment plans. Key features identified in the evaluation and incorporated into ReSPECT were: The importance of discussions between patient and clinician to inform realistic treatment preferences and clarity in the resulting recommendations recorded by the clinician on the form. The process is compliant with UK mental capacity laws. Documentation should be recognised across all health and care settings. There should be opportunity for timely review based on individual need.\ud \ud Conclusion:\ud ReSPECT is designed to facilitate discussions about a person’s preferences to inform emergency care and treatment plans (including CPR) for use across all health and care settings. It has been developed iteratively with a range of stakeholders. Further research will be needed to assess the influence of ReSPECT on patient-centred decisions, experience and health outcomes.

Background The uptake of evidence-based knowledge in practice is influenced by context. Observations are suggested as a valuable but under-used approach in implementation research for gaining a holistic understanding of contexts. Aim The aim of this paper is to demonstrate how data from observations can provide insights about context and evidence use in implementation research. Methods Data were collected over 24 months in a randomised trial with an embedded realist evaluation in 24 nursing homes across four European countries; notes from 183 observations (representing 335 hours) were triangulated with interview transcripts and context survey data (from 357 staff interviews and 725 questionnaire responses, respectively). Results Although there were similarities in several elements of context within survey, interview and observation data, the observations provided additional features of the implementation context. In particular, observations demonstrated if and how the resources (staffing and supplies) and leadership (formal and informal, teamwork, and professional autonomy) affected knowledge use and implementation. Further, the observations illuminated the influence of standards and the physical nursing environment on evidence-based practice, and the dynamic interaction between different aspects of context. Linking Evidence to Action Although qualitative observations are resource-intensive, they add value when used with other data collection methods, further enlightening the understanding of the implementation context and how evidence use and sharing are influenced by context elements. Observations can enhance an understanding of the context, evidence use and knowledge-sharing triad in implementation research. Funding Agencies|European UnionEuropean Union (EU) [223646]

Background\ud The Recommended Summary Plan for Emergency Care and Treatment (ReSPECT) form, which supports the ReSPECT process, is designed to prompt clinicians to discuss wider emergency treatment options with patients and to structure the documentation of decision-making for greater transparency.\ud \ud Methods\ud Following an accountability for reasonableness framework (AFR), we analysed 141 completed ReSPECT forms (versions 1.0 and 2.0), collected from six National Health Service (NHS) hospitals in England during the early adoption of ReSPECT. Structured through an evaluation tool developed for this study, the analysis assessed the extent to which the records reflected consistency, transparency, and ethical justification of decision-making.\ud \ud Results\ud Recommendations relating to CPR were consistently recorded on all forms and were contextualised within other treatment recommendations in most forms. The level of detail provided about treatment recommendations varied widely and reasons for treatment recommendations were rarely documented. Patient capacity, patient priorities and preferences, and the involvement of patients/relatives in ReSPECT conversations were recorded in some, but not all, forms. Clinicians almost never documented their weighing of potential burdens and benefits of treatments on the ReSPECT forms.\ud \ud Conclusion\ud In most ReSPECT forms, CPR recommendations were captured alongside other treatment recommendations. However, ReSPECT form design and associated training should be modified to address inconsistencies in form completion. These modifications should emphasise the recording of patient values and preferences, assessment of patient capacity, and clinical reasoning processes, thereby putting patient/family involvement at the core of good clinical practice. Version 3.0 of ReSPECT responds to these issues.

Introduction\ud \ud This study reports the epidemiology and outcomes from out-of-hospital cardiac arrest (OHCA) in England during 2014.\ud \ud Methods\ud \ud Prospective observational study from the national OHCA registry. The incidence, demographic and outcomes of patients who were treated for an OHCA between 1st January 2014 and 31st December 2014 in 10 English ambulance service (EMS) regions, serving a population of almost 54 million, are reported in accordance with Utstein recommendations.\ud \ud Results\ud \ud 28,729 OHCA cases of EMS treated cardiac arrests were reported (53 per 100,000 of resident population). The mean age was 68.6 (SD = 19.6) years and 41.3% were female. Most (83%) occurred in a place of residence, 52.7% were witnessed by either the EMS or a bystander. In non-EMS witnessed cases, 55.2% received bystander CPR whilst public access defibrillation was used rarely (2.3%). Cardiac aetiology was the leading cause of cardiac arrest (60.9%). The initial rhythm was asystole in 42.4% of all cases and was shockable (VF or pVT) in 20.6%. Return of spontaneous circulation at hospital transfer was evident in 25.8% (n = 6302) and survival to hospital discharge was 7.9%.\ud \ud Conclusion\ud \ud Cardiac arrest is an important cause of death in England. With less than one in ten patients surviving, there is scope to improve outcomes. Survival rates were highest amongst those who received bystander CPR and public access defibrillation.

Aims\ud \ud The aim of the project was to identify the neighbourhood characteristics of areas in England where out-of-hospital cardiac arrest (OHCA) incidence was high and bystander cardiopulmonary resuscitation (BCPR) was low using registry data.\ud \ud Methods and results\ud \ud Analysis was based on 67 219 cardiac arrest events between 1 April 2013 and 31 December 2015. Arrest locations were geocoded to give latitude/longitude. Postcode district was chosen as the proxy for neighbourhood. High-risk neighbourhoods, where OHCA incidence based on residential population was >127.6/100 000, or based on workday population was >130/100 000, and BCPR in bystander witnessed arrest was

Background Bystander cardiopulmonary resuscitation ( CPR ) and public access defibrillator ( PAD ) use can save the lives of people who experience out‐of‐hospital cardiac arrest. Little is known about the proportions of UK adults trained, their characteristics and willingness to act if witnessing an out‐of‐hospital cardiac arrest, or the public's knowledge regarding where the nearest PAD is located. Methods and Results An online survey was administered by YouGov to a nonprobabilistic purposive sample of UK adults, achieving 2084 participants, from a panel that was matched to be representative of the population. We used descriptive statistics and multivariate logistic regression modeling for analysis. Almost 52% were women, 61% were aged CPR , and 19.4% in PAD use. Most with training in any resuscitation technique had trained at work (54.7%). Compared with people not trained, those trained in PAD use said they were more likely to use one (odds ratio: 2.61), and those trained in CPR or chest‐compression‐only CPR were more likely to perform it (odds ratio: 5.39). Characteristics associated with being trained in any resuscitation technique included youth, female sex, higher social grade, and full‐time employment. Conclusions In the United Kingdom, training makes a difference in people's willingness to act in the event of a cardiac arrest. Although there is considerable opportunity to increase the proportion of the general population trained in CPR , consideration should be also given to encouraging training in PAD use and targeting training for those who are older or from lower social grades.

OBJECTIVE To describe a dorsoproximal midline (DPM) standing technique for proximal interphalangeal joint (PIPJ) injection and to compare it to established dorsolateral flexed (DLF), palmaroproximal (PP), and dorsolateral standing (DLS) techniques. STUDY DESIGN Ex vivo study. SAMPLE POPULATION Sixty cadaver equine thoracic limbs. METHODS Limbs were divided into four groups (n = 15 each group), DLF, DPM, PP, and DLS. For each technique, three operators injected radiopaque contrast and methylene blue into the PIPJ in five limbs. The number of attempts required was recorded. Successful injection was confirmed by radiographic presence of contrast media within the PIPJ. Iatrogenic cartilage damage was assessed by gross examination. Statistical analysis was performed by Wilcoxon signed-rank test (P

Purpose of the study\ud \ud Variation in the recording of DNACPR decisions between healthcare organisations creates policy and communication challenges when patients are transferred between organisations. A recent UK stud y identified the need for a nationwide system to record resuscitation decisions alongside other treatment escalation decisions. The development of the UK - based Recommended Summary for Emergency care and Treatment Plan (ReSPECT) process was a response to this need. ReSPECT has been available to healthcare organisations to adoption since Spring 2017. The purpose of this study was to record current variation in the way in which DNACPR decisions are recorded in UK hospitals and identify the current uptake of the ReSPECT process. \ud \ud Materials and methods\ud \ud We conducted an online survey between October 2017 and March 2018 of all UK adult NHS hospitals participating in the National Cardiac Arrest Audit (NCAA). Descriptive statistics were used to report the results. \ud \ud Results \ud \ud Of the 187 hospitals surveyed, 114 (61%) responded. Most hospitals reported using a DNACPR form (n=57, 50%). Other hospitals used either a DNACPR form with separate treatment escalation plan (n=35, 31%), an ECTP or DNACPR form combined with a treatment escalation plan (n=20, 18%), or another system (n=2, 2%). In total, 8 hospitals (7%) were using the ReSPECT system. \ud \ud Conclusions\ud \ud There is variation in the way in which DNACPR decisions are recorded in UK hospitals. To date, only a small number of hospitals have implemented the ReSPECT process \ud

Background: Emerging evidence focuses on the importance of the role of leadership in successfully transferring research evidence into practice. However, little is known about the interaction betwee ...

Aim To examine the application of core concepts from Complexity Theory to explain the findings from a process evaluation undertaken in a trial evaluating implementation strategies for recommendations about reducing surgical fasting times. Background The proliferation of evidence-based guidance requires a greater focus on its implementation. Theory is required to explain the complex processes across the multiple healthcare organizational levels. This social healthcare context involves the interaction between professionals, patients and the organizational systems in care delivery. Complexity Theory may provide an explanatory framework to explain the complexities inherent in implementation in social healthcare contexts. Design A secondary thematic analysis of qualitative process evaluation data informed by Complexity Theory. Method Seminal texts applying Complexity Theory to the social context were annotated, key concepts extracted and core Complexity Theory concepts identified. These core concepts were applied as a theoretical lens to provide an explanation of themes from a process evaluation of a trial evaluating the implementation of strategies to reduce surgical fasting times. Sampled substantive texts provided a representative spread of theoretical development and application of Complexity Theory from late 1990's–2013 in social science, healthcare, management and philosophy. Findings Five Complexity Theory core concepts extracted were ‘self-organization’, ‘interaction’, ‘emergence’, ‘system history’ and ‘temporality’. Application of these concepts suggests routine surgical fasting practice is habituated in the social healthcare system and therefore it cannot easily be reversed. A reduction to fasting times requires an incentivised new approach to emerge in the surgical system's priority of completing the operating list. Conclusion The application of Complexity Theory provides a useful explanation for resistance to change fasting practice. Its utility in implementation research warrants further attention and evaluation.

Background: Facilitation is a promising implementation intervention, which requires theory-informed evaluation. This paper presents an exemplar of a multi-country realist process evaluation that was embedded in the first international randomised controlled trial evaluating two types of facilitation for implementing urinary continence care recommendations. We aimed to uncover what worked (and did not work), for whom, how, why and in what circumstances during the process of implementing the facilitation interventions in practice.Methods: This realist process evaluation included theory formulation, theory testing and refining. Data were collected in 24 care home sites across four European countries. Data were collected over four time points using multiple qualitative methods: observation (372 h), interviews with staff (n = 357), residents (n = 152), next of kin (n = 109) and other stakeholders (n = 128), supplemented by facilitator activity logs. A combined inductive and deductive data analysis process focused on realist theory refinement and testing.Results: The content and approach of the two facilitation programmes prompted variable opportunities to align and realign support with the needs and expectations of facilitators and homes. This influenced their level of confidence in fulfilling the facilitator role and ability to deliver the intervention as planned. The success of intervention implementation was largely dependent on whether sites prioritised their involvement in both the study and the facilitation programme. In contexts where the study was prioritised (including release of resources) and where managers and staff support was sustained, this prompted collective engagement (as an attitude and action). Internal facilitators' (IF) personal characteristics and abilities, including personal and formal authority, in combination with a supportive environment prompted by managers triggered the potential for learning over time. Learning over time resulted in a sense of confidence and personal growth, and enactment of the facilitation role, which resulted in practice changes.Conclusion: The scale and multi-country nature of this study provided a novel context to conduct one of the few trial embedded realist-informed process evaluations. In addition to providing an explanatory account of implementation processes, a conceptual platform for future facilitation research is presented. Finally, a realist-informed process evaluation framework is outlined, which could inform future research of this nature.Trial registration: Current controlled trials ISRCTN11598502.

Background: Health care practice needs to be underpinned by high quality research evidence, so that the best possible care can be delivered. However, evidence from research is not always utilised in practice. This study used the Promoting Action on Research Implementation in Health Services (PARIHS) framework as its theoretical underpinning to test whether two different approaches to facilitating implementation could affect the use of research evidence in practice.Methods: A pragmatic clustered randomised controlled trial with embedded process and economic evaluation was used. The study took place in four European countries across 24 long-term nursing care sites, for people aged 60 years or more with documented urinary incontinence. In each country, sites were randomly allocated to standard dissemination, or one of two different types of facilitation. The primary outcome was the documented percentage compliance with the continence recommendations, assessed at baseline, then at 6, 12, 18, and 24 months after the intervention.Data were analysed using STATA15, multi-level mixed-effects linear regression models were fitted to scores for compliance with the continence recommendations, adjusting for clustering.Results: Quantitative data were obtained from reviews of 2313 records. There were no significant differences in the primary outcome (documented compliance with continence recommendations) between study arms and all study arms improved over time.Conclusions: This was the first cross European randomised controlled trial with embedded process evaluation that sought to test different methods of facilitation. There were no statistically significant differences in compliance with continence recommendations between the groups. It was not possible to identify whether different types and "doses" of facilitation were influential within very diverse contextual conditions. The process evaluation (Rycroft-Malone et al., Implementation Science. doi: 10.1186/s13012-018-0811-0) revealed the models of facilitation used were limited in their ability to overcome the influence of contextual factors.Trial registration: Current Controlled Trials ISRCTN11598502. Date 4/2/10.The research leading to these results has received funding from the European Union's Seventh Framework Programme (FP7/2007–2013) under grant agreement no. 223646.

This study developed from observations that playworkers in after school clubs in a county in the south of England were struggling to respond to what they saw as challenging behaviour. The study used a hybrid of participatory action research and ethnography in order to extend playworkers’ understanding of Sturrock and Else’s (1998) model of therapeutic playwork and explore their perceptions of its usefulness in after school settings. Playworkers attended introductory training on Sturrock and Else’s (2005) model of therapeutic playwork and then reflected on their practice. They articulated a different understanding of challenging behaviour, seeing it as children playing out latent material or strong emotions, expressing transference, or manifesting a breakdown in the play process. Participants believed they became more reflective practitioners, more able to read the play process and more self-aware, and they advocated championing this perspective to other practitioners.

BackgroundProximal femoral fracture is a major health problem in old age, with annual UK health and social care costs of £2.3B. Rehabilitation has the potential to maximise functional recovery and maintain independent living, but evidence of clinical effectiveness and cost-effectiveness is lacking.ObjectivesTo develop an enhanced community-based rehabilitation package following surgical treatment for proximal femoral fracture and to assess acceptability and feasibility for a future definitive randomised controlled trial (RCT) and economic evaluation.DesignPhase I – realist review, survey and focus groups to develop the rehabilitation package. Phase II – parallel-group, randomised (using a dynamic adaptive algorithm) feasibility study with focus groups and an anonymised cohort study.SettingRecruitment was from orthopaedic wards of three acute hospitals in the Betsi Cadwaladr University Health Board, North Wales. The intervention was delivered in the community following hospital discharge.ParticipantsOlder adults (aged ≥ 65 years) who had received surgical treatment for hip fracture, lived independently prior to fracture, had mental capacity (assessed by the clinical team) and received rehabilitation in the North Wales area.InterventionsParticipants received usual care (control) or usual care plus an enhanced rehabilitation package (intervention). Usual care was variable and consisted of multidisciplinary rehabilitation delivered by the acute hospital, community hospital and community services depending on need and availability. The intervention was designed to enhance rehabilitation by improving patients’ self-efficacy and increasing the amount and quality of patients’ practice of physical exercise and activities of daily living. It consisted of a patient-held information workbook, a goal-setting diary and six additional therapy sessions.Main outcome measuresThe primary outcome measure was the Barthel Activities of Daily Living (BADL) index. The secondary outcome measures included the Nottingham Extended Activities of Daily Living (NEADL) scale, EuroQol-5 Dimensions, ICEpop CAPability measure for Older people, General Self-Efficacy Scale, Falls Efficacy Scale – International (FES-I), Self-Efficacy for Exercise scale, Hospital Anxiety and Depression Scale (HADS) and service use measures. Outcome measures were assessed at baseline and at 3-month follow-up by blinded researchers.ResultsSixty-two participants were recruited (23% of those who were eligible), 61 were randomised (control,n = 32; intervention,n = 29) and 49 (79%) were followed up at 3 months. Compared with the cohort study, a younger, healthier subpopulation was recruited. There were minimal differences in most outcomes between the two groups, including the BADL index, with an adjusted mean difference of 0.5 (Cohen’sd = 0.29). The intervention group showed a medium-sized improvement on the NEADL scale relative to the control group, with an adjusted mean difference between groups of 3.0 (Cohen’sd = 0.63). There was a trend for greater improvement in FES-I and HADS in the intervention group, but with small effect sizes, with an adjusted mean difference of 4.2 (Cohen’sd = 0.31) and 1.3 (Cohen’sd = 0.20), respectively. The cost of delivering the intervention was £231 per patient. There was a possible small relative increase in quality-adjusted life-years in the intervention group. No serious adverse events relating to the intervention were reported.ConclusionsTrial methods were feasible in terms of eligibility, recruitment and retention, although recruitment was challenging. The NEADL scale was more responsive than the BADL index, suggesting that the intervention could enable participants to regain better levels of independence compared with usual care. This should be tested in a definitive Phase III RCT. There were two main limitations of the study: the feasibility study lacked power to test for differences between the groups and a ceiling effect was observed in the primary measure.Trial registrationCurrent Controlled Trials ISRCTN22464643.FundingThis project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 21, No. 44. See the NIHR Journals Library for further project information.

Objectives To report a resection and anastomosis technique to treat trauma-induced tracheal stenosis. Study Design Case report. Animals A 9-year-old Warmblood gelding. Methods Endoscopy, radiography, and ultrasonography were used to diagnose a single ring tracheal stenosis; the stenotic region was resected and adjacent tracheal rings anastomosed with an end-to-end technique. Results The anastomosis healed completely despite formation of a unilateral partial mucosal stenosis “web,” which was subsequently removed by transendoscopic laser surgery. During tracheal anastomosis, the left recurrent laryngeal nerve was damaged, causing laryngeal hemiplegia, later treated successfully by laryngoplasty. The horse returned to its previous level of work. Conclusions This tracheal resection and anastomosis technique successfully provided the horse with a large tracheal lumen, and despite major complications, allowed a return to full athletic work.

Objective To describe a complication observed endoscopically in horses after prosthetic laryngoplasty (LP). Study Design Case series. Animals Horses (n = 5) that had previous LP. Methods Four horses had endoscopic examination as part of a larger prospective study and had saliva emanating from their upper esophageal opening. One other horse was referred with clinical signs of severe upper esophageal obstruction 2 months after LP. Results Four horses were observed to have saliva emanating from their upper esophageal opening during endoscopic examination 21–58 months after LP. Esophageal reflux was noted endoscopically at rest (n = 1) and during exercise (4). All 5 horses were reported to cough postoperatively, and 2 horses coughed severely when eating. On necropsy, the horse referred with signs of esophageal obstruction had dilation of the proximal esophagus associated with food impaction and had fibrosis and thickening of the left cricopharyngeus and thyropharyngeus muscles. Conclusions Iatrogenic damage to the caudal pharyngeal constrictor muscles, the intrinsic musculature of the upper esophagus, or their innervation, or damage to the peri-esophageal fascia or esophageal adventitia may cause upper esophageal incompetence in horses after LP.

XRCC1 is a key component of DNA base excision repair, single strand break repair, and backup nonhomologous end-joining pathway. XRCC1 (X-ray repair cross-complementing gene 1) deficiency promotes genomic instability, increases cancer risk, and may have clinical application in breast cancer. We investigated XRCC1 expression in early breast cancers (n = 1,297) and validated in an independent cohort of estrogen receptor (ER)-α–negative breast cancers (n = 281). Preclinically, we evaluated XRCC1-deficient and -proficient Chinese hamster and human cancer cells for synthetic lethality application using double-strand break (DSB) repair inhibitors [KU55933 (ataxia telangectasia–mutated; ATM inhibitor) and NU7441 (DNA-PKcs inhibitor)]. In breast cancer, loss of XRCC1 (16%) was associated with high grade (P < 0.0001), loss of hormone receptors (P < 0.0001), triple-negative (P < 0.0001), and basal-like phenotypes (P = 0.001). Loss of XRCC1 was associated with a two-fold increase in risk of death (P < 0.0001) and independently with poor outcome (P < 0.0001). Preclinically, KU55933 [2-(4-Morpholinyl)-6-(1-thianthrenyl)-4H-pyran-4-one] and NU7441 [8-(4-Dibenzothienyl)-2-(4-morpholinyl)-4H-1-benzopyran-4-one] were synthetically lethal in XRCC1-deficient compared with proficient cells as evidenced by hypersensitivity to DSB repair inhibitors, accumulation of DNA DSBs, G2–M cell-cycle arrest, and induction of apoptosis. This is the first study to show that XRCC1 deficiency in breast cancer results in an aggressive phenotype and that XRCC1 deficiency could also be exploited for a novel synthetic lethality application using DSB repair inhibitors. Cancer Res; 73(5); 1621–34. ©2012 AACR.

OBJECTIVE: To conduct a rigorous feasibility study for a future definitive parallel-group randomised controlled trial (RCT) and economic evaluation of an enhanced rehabilitation package for hip fracture.SETTING: Recruitment from 3 acute hospitals in North Wales. Intervention delivery in the community.PARTICIPANTS: Older adults (aged ≥65) who received surgical treatment for hip fracture, lived independently prior to fracture, had mental capacity (assessed by clinical team) and received rehabilitation in the North Wales area.INTERVENTION: Remote randomisation to usual care (control) or usual care+enhanced rehabilitation package (intervention), including six additional home-based physiotherapy sessions delivered by a physiotherapist or technical instructor, novel information workbook and goal-setting diary.PRIMARY AND SECONDARY OUTCOME MEASURES: Primary: Barthel Activities of Daily Living (BADL). Secondary measures included Nottingham Extended Activities of Daily Living scale (NEADL), EQ-5D, ICECAP capability, a suite of self-efficacy, psychosocial and service-use measures and costs. Outcome measures were assessed at baseline and 3-month follow-up by blinded researchers.RESULTS: 62 participants were recruited, 61 randomised (control 32; intervention 29) and 49 (79%) completed 3-month follow-up. Minimal differences occurred between the 2 groups for most outcomes, including BADL (adjusted mean difference 0.5). The intervention group showed a medium-sized improvement in the NEADL relative to the control group, with an adjusted mean difference between groups of 3.0 (Cohen's d 0.63), and a trend for greater improvement in self-efficacy and mental health, but with small effect sizes. The mean cost of delivering the intervention was £231 per patient. There was a small relative improvement in quality-adjusted life year in the intervention group. No serious adverse events relating to the intervention were reported.CONCLUSIONS: The trial methods were feasible in terms of eligibility, recruitment and retention. The effectiveness and cost-effectiveness of the rehabilitation package should be tested in a phase III RCT.TRIAL REGISTRATION NUMBER: ISRCTN22464643; Results.

BackgroundCardiac arrest is the final common step in the dying process. In the right context, resuscitation can reverse the dying process, yet success rates are low. However, cardiopulmonary resuscitation (CPR) is a highly invasive medical treatment, which, if applied in the wrong setting, can deprive the patient of dignified death. Do-not-attempt-cardiopulmonary-resuscitation (DNACPR) decisions provide a mechanism to withhold CPR. Recent scientific and lay press reports suggest that the implementation of DNACPR decisions in NHS practice is problematic.Aims and objectivesThis project sought to identify reasons why conflict and complaints arise, identify inconsistencies in NHS trusts’ implementation of national guidelines, understand health professionals’ experience in relation to DNACPR, its process and ethical challenges, and explore the literature for evidence to improve DNACPR policy and practice.MethodsA systematic review synthesised evidence of processes, barriers and facilitators related to DNACPR decision-making and implementation. Reports from NHS trusts, the National Reporting and Learning System, the Parliamentary and Health Service Ombudsman, the Office of the Chief Coroner, trust resuscitation policies and telephone calls to a patient information line were reviewed. Multiple focus groups explored service-provider perspectives on DNACPR decisions. A stakeholder group discussed the research findings and identified priorities for future research.ResultsThe literature review found evidence that structured discussions at admission to hospital or following deterioration improved patient involvement and decision-making. Linking DNACPR to overall treatment plans improved clarity about goals of care, aided communication and reduced harms. Standardised documentation improved the frequency and quality of recording decisions. Approximately 1500 DNACPR incidents are reported annually. One-third of these report harms, including some instances of death. Problems with communication and variation in trusts’ implementation of national guidelines were common. Members of the public were concerned that their wishes with regard to resuscitation would not be respected. Clinicians felt that DNACPR decisions should be considered within the overall care of individual patients. Some clinicians avoid raising discussions about CPR for fear of conflict or complaint. A key theme across all focus groups, and reinforced by the literature review, was the negative impact on overall patient care of having a DNACPR decision and the conflation of ‘do not resuscitate’ with ‘do not provide active treatment’.LimitationsThe variable quality of some data sources allows potential overstatement or understatement of findings. However, data source triangulation identified common issues.ConclusionThere is evidence of variation and suboptimal practice in relation to DNACPR decisions across health-care settings. There were deficiencies in considering, discussing and implementing the decision, as well as unintended consequences of DNACPR decisions being made on other aspects of patient care.Future workRecommendations supported by the stakeholder group are standardising NHS policies and forms, ensuring cross-boundary recognition of DNACPR decisions, integrating decisions with overall treatment plans and developing tools and training strategies to support clinician and patient decision-making, including improving communication.Study registrationThis study is registered as PROSPERO CRD42012002669.FundingThe National Institute for Health Research Health Services and Delivery Research programme.

Summary Reasons for performing study: There is a lack of objective information on the value of ancillary diagnostic techniques used to investigate equine sinus disease, and also on which sinus compartments are commonly affected in this disorder. Objectives: To record the ancillary diagnostic findings used to investigate equine sinus disease and to document which compartments are affected. Materials and methods: The clinical case records of 200 consecutive cases of sinus disease, including subacute ( 2 months' duration) primary (n = 37); dental (n = 40); traumatic (n = 13); sinus cyst (n = 26); sinus neoplasia (n = 10); dental related oromaxillary fistula (n = 8); mycotic sinusitis (n = 7) and intra-sinus progressive ethmoid haematoma (n = 7) were retrospectively examined. Results: Nasal endoscopy showed exudate draining from the sino-nasal ostia in 88% of cases and a sino-nasal fistula was present in 15% of cases. Sinoscopy was performed in 79% of cases and was of great diagnostic value. More recently, 22% of cases had fenestration of the ventral conchal bulla performed to allow sinoscopy of the rostral sinus compartments. Radiography was performed in 97% of cases and showed intra-sinus fluid lines to be common (69% prevalence) in subacute primary sinusitis. Radiographic dental apical changes were not specific to dental sinusitis, e.g. 29% of chronic primary sinusitis cases had radiographic dental changes. Scintigraphy was performed in 20% of cases and was helpful in identifying dental apical changes when radiography was inconclusive. Overall, the caudal maxillary (78% involvement) and rostral maxillary (61%) sinuses were most commonly affected, with the ventral conchal sinus (VCS) (54% involvement) and conchofrontal sinuses (48%) less so. The VCS showed the greatest tendency to contain inspissated pus (present in 46% of all affected VCS). Conclusions: Nasal endoscopy, sinoscopy and skull radiography are of great value in diagnosing the presence and causes of equine sinus disease.

Summary Reasons for performing study: There is limited objective information available on the treatment and the long-term response to treatment of the different types of equine sinus disease. Objectives: To document the treatments and long-term response to these treatments in 200 cases of equine sinus disease (1997–2009). Methods: The treatments of horses affected with subacute primary sinusitis (n = 52); chronic primary sinusitis (n = 37); dental sinusitis (n = 40); sinus cyst (n = 26); traumatic (n = 13); dental-related oromaxillary fistula (n = 8); sinus neoplasia (n = 10); mycotic sinus disease (n = 7); and intrasinus progressive ethmoid haematoma (n = 7) and the long-term response to these treatments were retrospectively reviewed. Results: Treatments evolved throughout the study and latterly were as conservative as possible, including sinoscopic lavage and standing sinusotomy, with a maxillary sinusotomy approach preferred for the mainly mature horses treated in this study. Removal of intrasinus inspissated pus, including transendoscopically (by sinusotomy and via existing sinonasal fistulae), was the main treatment for chronic primary sinusitis and sinonasal fistulation was seldom performed latterly. Attempted oral extraction of infected cheek teeth, even if unsuccessful, facilitated subsequent dental repulsion, resulting in few post operative problems. Sinus cyst removal carried an excellent prognosis. Except for cases of sinus neoplasia (only 22% cured), an excellent long-term response to treatment (91% fully cured, 7% partially cured) was obtained for all other types of sinus disease following a median of one treatment. Conclusions: More conservative treatments, including removal of intrasinus inspissated pus by sinoscopy, pre-existing sinonasal fistula or sinusotomy, are effective for chronic primary sinus disease. Standing sinusotomy, mainly using a small maxillary site, was suitable for most cases of sinus disease in mature horses.

Basal and triple-negative breast cancer phenotypes are characterised by unfavourable biological behaviour and outcome. Although certain studies have examined their pathological and molecular profile, the vascular characteristics of lymphatic and blood vessels have not been examined. Immunohistochemical staining with podoplanin, CD34 and CD31 was used to examine lymphatic and microvessel density, as well as vascular invasion in 197 basal-like and in 99 triple-negative breast tumours and compared against 200 non-basal and 334 non-triple-negative cases. All specimens were lymph node negative. Vascular invasion was identified as blood or lymphatic vascular invasion by the differential expression of markers. All measurements were correlated with clinicopathological features and prognosis. No significant difference was detected between the basal and triple-negative groups in terms of lymphatic or microvessel density or vascular invasion. However, both the basal and the triple-negative groups showed significantly higher microvessel density than did the non-basal and non-triple-negative groups (P=0.017 and P

Summary Palatal dysfunction is very common in performance horses. At present, relatively little is known about its aetiology and pathogenesis, although several theories have been proposed. As a result, a multitude of treatments, both conservative and surgical, have been advocated for dorsal displacement of the soft palate (DDSP). This tutorial article aims to provide a comprehensive review of the disorder, discussing aetiopathogenesis, diagnosis and management in turn.

Summary Reasons for performing study: Dysfunction of the muscles is implicated in the pathogenesis of intermittent dorsal displacement of the soft palate (DDSP) in exercising horses. The histological features of normal equine soft palate muscles have not been previously described. Objective: To describe the histological and morphometric features of normal equine soft palate muscles. Methods: The palatinus, palatopharyngeus, levator veli palatini and tensor veli palatini muscles of 6 Thoroughbred type horses were examined histologically and histochemically to assess their general morphology, fibre-type distribution and mean fibre diameter. Results: The muscles of all 6 specimens showed very similar characteristics, including a low proportion of type 1 muscle fibres in the 4 different muscles examined, with the 3 muscles innervated by the pharyngeal branch of the vagus (i.e. palatopharyngeus, palatinus and levator veli palatini) having significantly fewer (P 250 and the latter also having high levels of endomysial connective tissue. The palatinus had least variation in fibre size. Conclusion and clinical relevance: Morphological characterisation of the normal soft palate muscles may provide reference values for future comparative studies with samples obtained from horses with palatal dysfunction. The palatinus appears to be the best muscle to histologically examine for evidence of muscle abnormality.