Serial prophylactic exchange blood transfusion in pregnant women with sickle cell disease (TAPS-2): statistical and qualitative analysis plan for a randomised controlled feasibility trial.

BACKGROUND: There are significant knowledge gaps regarding the effectiveness of serial prophylactic exchange blood transfusion (SPEBT) for pregnant women with sickle cell disease (SCD). The protocol for the randomised feasibility trial assessing SPEBT versus usual care in women with SCD (TAPS2 trial) has previously been published. This publication outlines the statistical and qualitative analysis plan for the study. METHODS AND DESIGN: TAPS2 is a randomised two-arm phase 2 feasibility trial with a nested qualitative study and health economic evaluation. Up to 50 pregnant women with SCD and a singleton pregnancy will be recruited and individually randomised to either SPEBT approximately every 6-10 weeks until delivery (intervention arm) or to usual care (control arm). Information will be collected on a range of feasibility and clinical outcomes. RESULTS: Due to the impact of COVID-19 on study recruitment, the initial study period of 24 months was extended to 48 months. Other protocol updates designed to mitigate the impact of COVID-19-related disruption included allowing for remote consent and conducting all qualitative interviews by telephone. The primary outcome for the trial is the overall recruitment rate. The number of women screened, eligible, consented, randomised and withdrawn will be summarised as a CONSORT flow diagram. Differences in clinical outcomes will additionally be presented as an initial assessment of efficacy and to inform sample size calculations for a future definitive trial. Qualitative interviews with trial participants and clinicians will be analysed using reflexive thematic analysis; data from interviews with participants who declined to participate in the trial will be extracted and incorporated into summary tables to report key findings. The health economic analysis plan is not covered by this update. CONCLUSION: The publication of this analysis plan is designed to aid transparency and to reduce the potential for reporting bias. TRIAL REGISTRATION: NIH registry ( www. CLINICALTRIALS: gov ), registration number NCT03975894 (registered 05/06/19); ISRCTN ( www.isrctn.com ), registration number ISRCTN52684446 (retrospectively registered 02/08/19).

Serial prophylactic exchange blood transfusion in pregnant women with sickle cell disease (TAPS-2): study protocol for a randomised controlled feasibility trial.

BACKGROUND: Pregnancies in women with sickle cell disease (SCD) are associated with a higher risk of sickle and pregnancy complications. Limited options exist for treating SCD during pregnancy. Serial prophylactic exchange blood transfusion (SPEBT) has been shown to be effective in treating SCD outside pregnancy, but evidence is lacking regarding its use during pregnancy. The aim of this study is to assess the feasibility and acceptability of conducting a future phase 3 randomised controlled trial (RCT) to establish the clinical and cost effectiveness of SPEBT in pregnant women with SCD. METHODS: The study is an individually randomised, two-arm, feasibility trial with embedded qualitative and health economic studies. Fifty women, 18 years of age and older, with SCD and a singleton pregnancy at ≤ 18 weeks' gestation will be recruited from six hospitals in England. Randomisation will be conducted using a secure online database and minimised by centre, SCD genotype and maternal age. Women allocated to the intervention arm will receive SPEBT commencing at ≤ 18 weeks' gestation, performed using automated erythrocytapheresis every 6-10 weeks until the end of pregnancy, aiming to maintain HbS% or combined HbS/HbC% below 30%. Women in the standard care arm will only receive transfusion when clinically indicated. The primary outcome will be the recruitment rate. Additional endpoints include reasons for refusal to participate, attrition rate, protocol adherence, and maternal and neonatal outcomes. Women will be monitored throughout pregnancy to assess maternal, sickle, and foetal complications. Detailed information about adverse events (including hospital admission) and birth outcomes will be extracted from medical records and via interview at 6 weeks postpartum. An embedded qualitative study will consist of interviews with (a) 15-25 trial participants to assess experiences and acceptability, (b) 5-15 women who decline to participate to identify barriers to recruitment and (c) 15-20 clinical staff to explore fidelity and acceptability. A health economic study will inform a future cost effectiveness and cost-utility analysis. DISCUSSION: This feasibility study aims to rigorously evaluate SPEBT as a treatment for SCD in pregnancy and its impact on maternal and infant outcomes. TRIAL REGISTRATION: NIH registry (www.clinicaltrials.gov), registration number NCT03975894 (registered 05/06/19); ISRCTN (www.isrctn.com), registration number ISRCTN52684446 (retrospectively registered 02/08/19).

The NC3Rs gateway: Accelerating scientific discoveries with new 3Rs models and technologies.

This editorial introduces the NC3Rs gateway, which publishes articles and reviews on new models and technologies emerging from NC3Rs-funded research. The aim is to raise awareness about these approaches, increase confidence in their capability, and provide sufficient information to facilitate their uptake by others.

A Systematic Review of End-of-Life Care Communication Skills Training for Generalist Palliative Care Providers: Research Quality and Reporting Guidance.

CONTEXT: End-of-life care (EoLC) communication skills training for generalist palliative care providers is recommended in policy guidance globally. Although many training programs now exist, there has been no comprehensive evidence synthesis to inform future training delivery and evaluation. OBJECTIVES: To identify and appraise how EoLC communication skills training interventions for generalist palliative care providers are developed, delivered, evaluated, and reported. METHODS: Systematic review. Ten electronic databases (inception to December 2015) and five relevant journals (January 2004 to December 2015) were searched. Studies testing the effectiveness of EoLC communication skills training for generalists were included. Two independent authors assessed study quality. Descriptive statistics and narrative synthesis are used to summarize the findings. RESULTS: From 11,441 unique records, 170 reports were identified (157 published, 13 unpublished), representing 160 evaluation studies of 153 training interventions. Of published papers, eight were of low quality, 108 medium, and 41 high. Few interventions were developed with service user involvement (n = 7), and most were taught using a mixture of didactics (n = 123), reflection and discussion (n = 105), and role play (n = 86). Evaluation designs were weak: <30% were controlled, <15% randomized participants. Over half (n = 85) relied on staff self-reported outcomes to assess effectiveness, and 49% did not cite psychometrically validated measures. Key information (e.g., training duration, participant flow) was poorly reported. CONCLUSIONS: Despite a proliferation of EoLC communication skills training interventions in the literature, evidence is limited by poor reporting and weak methodology. Based on our findings, we present a CONSORT statement supplement to improve future reporting and encourage more rigorous testing.

The Effect of Communication Skills Training for Generalist Palliative Care Providers on Patient-Reported Outcomes and Clinician Behaviors: A Systematic Review and Meta-analysis.

CONTEXT: As most end-of-life care is provided by health care providers who are generalists rather than specialists in palliative care, effective communication skills training for generalists is essential. OBJECTIVES: To determine the effect of communication training interventions for generalist palliative care providers on patient-reported outcomes and trainee behaviors. METHODS: Systematic review from searches of 10 databases to December 2015 (MEDLINE, EMBASE, PsycINFO, ERIC, CINAHL, CENTRAL, Web of Science, ICTRP, CORDIS, and OpenGrey) plus hand searching. Randomized controlled trials of training interventions intended to enhance generalists' communication skills in end-of-life care were included. Two authors independently assessed eligibility after screening, extracted data, and graded quality. Data were pooled for meta-analysis using a random-effects model. PRISMA guidelines were followed. RESULTS: Nineteen of 11,441 articles were eligible, representing 14 trials. Eleven were included in meta-analyses (patients n = 3144, trainees n = 791). Meta-analysis showed no effect on patient outcomes (standardized mean difference [SMD] = 0.10, 95% CI -0.05 to 0.24) and high levels of heterogeneity (chi-square = 21.32, degrees of freedom [df] = 7, P = 0.003; I2 = 67%). The effect on trainee behaviors in simulated interactions (SMD = 0.50, 95% CI 0.19-0.81) was greater than in real patient interactions (SMD = 0.21, 95% CI -0.01 to 0.43) with moderate heterogeneity (chi-square = 8.90, df = 5, P = 0.11; I2 = 44%; chi-square = 5.96, df = 3, P = 0.11; I2 = 50%, respectively). Two interventions with medium effects on showing empathy in real patient interactions included personalized feedback on recorded interactions. CONCLUSIONS: The effect of communication skills training for generalists on patient-reported outcomes remains unclear. Training can improve clinicians' ability to show empathy and discuss emotions, at least in simulated consultations. Personalized feedback on recorded patient interactions may be beneficial. REGISTRATION NUMBER: CRD42014014777.

Primary care physicians' educational needs and learning preferences in end of life care: A focus group study in the UK.

BACKGROUND: Primary care physicians (General Practitioners (GPs)) play a pivotal role in providing end of life care (EoLC). However, many lack confidence in this area, and the quality of EoLC by GPs can be problematic. Evidence regarding educational needs, learning preferences and the acceptability of evaluation methods is needed to inform the development and testing of EoLC education. This study therefore aimed to explore GPs' EoLC educational needs and preferences for learning and evaluation. METHODS: A qualitative focus group study was conducted with qualified GPs and GP trainees in the UK. Audio recordings were transcribed and analysed thematically. Expert review of the coding frame and dual coding of transcripts maximised rigour. RESULTS: Twenty-eight GPs (10 fully qualified, 18 trainees) participated in five focus groups. Four major themes emerged: (1) why education is needed, (2) perceived educational needs, (3) learning preferences, and (4) evaluation preferences. EoLC was perceived as emotionally and clinically challenging. Educational needs included: identifying patients for palliative care; responsibilities and teamwork; out-of-hours care; having difficult conversations; symptom management; non-malignant conditions; and paediatric palliative care. Participants preferred learning through experience, working alongside specialist palliative care staff, and discussion of real cases, to didactic methods and e-learning. 360° appraisals and behavioural assessment using videoing or simulated interactions were considered problematic. Self-assessment questionnaires and patient and family outcome measures were acceptable, if used and interpreted correctly. CONCLUSIONS: GPs require education and support in EoLC, particularly the management of complex clinical care and counselling. GPs value mentoring, peer-support, and experiential learning alongside EoLC specialists over formal training.

'End of life could be on any ward really': A qualitative study of hospital volunteers' end-of-life care training needs and learning preferences.

BACKGROUND: Over half of all deaths in Europe occur in hospital, a location associated with many complaints. Initiatives to improve inpatient end-of-life care are therefore a priority. In England, over 78,000 volunteers provide a potentially cost-effective resource to hospitals. Many work with people who are dying and their families, yet little is known about their training in end-of-life care. AIMS: To explore hospital volunteers' end-of-life care training needs and learning preferences, and the acceptability of training evaluation methods. DESIGN: Qualitative focus groups. SETTING/PARTICIPANTS: Volunteers from a large teaching hospital were purposively sampled. RESULTS: Five focus groups were conducted with 25 hospital volunteers (aged 19-80 years). Four themes emerged as follows: preparation for the volunteering role, training needs, training preferences and evaluation preferences. Many described encounters with patients with life-threatening illness and their families. Perceived training needs in end-of-life care included communication skills, grief and bereavement, spiritual diversity, common symptoms, and self-care. Volunteers valued learning from peers and end-of-life care specialists using interactive teaching methods including real-case examples and role plays. A chance to 'refresh' training at a later date was suggested to enhance learning. Evaluation through self-reports or observations were acceptable, but ratings by patients, families and staff were thought to be pragmatically unsuitable owing to sporadic contact with each. CONCLUSION: Gaps in end-of-life care training for hospital volunteers indicate scope to maximise on this resource. This evidence will inform development of training and evaluations which could better enable volunteers to make positive, cost-effective contributions to end-of-life care in hospitals.

Improving confidence and competence of healthcare professionals in end-of-life care: an evaluation of the 'Transforming End of Life Care' course at an acute hospital trust.

BACKGROUND: UK policymakers, clinicians and public wish to see improvements in end-of-life care (EoLC). However, healthcare professionals' skills and knowledge to deliver high-quality care are often lacking. Since May 2012, palliative care staff in an inner-city tertiary hospital have run a 2-day Transforming End of Life Care (TEoLC) course to improve EoLC confidence, and competence among hospital and community staff. AIM: To evaluate course participants' self-rated confidence, competence and knowledge of EoLC topics. EVALUATION DESIGN: A before-and-after design using self-completion questionnaires, precourse and postcourse. 14 self-assessment questions examined confidence, understanding and knowledge of EoLC topics. Mean change scores and paired t tests were calculated and free-text responses analysed thematically. PARTICIPANTS: 236 staff members completed the course between May 2012 and April 2014. 42% worked in hospitals and 55% in the community; the most frequent staff roles were qualified nurses (49%), senior nurses (16%) and general practitioners (15%). RESULTS: All 14 self-assessment topics improved significantly (p<0.001); most improved was 'understanding and implementing Fast Track discharge'. Qualitative data showed increased knowledge and confidence in EoLC, particularly in communication, commitment to team work and holistic care. Overall, 217 (92%) participants would recommend the course and 215 (98%) indicated it would influence their practice. CONCLUSIONS: The TEoLC course improved participants' self-rated confidence, competence and knowledge in EoLC. Findings have utility beyond the UK in light of the international policy recommendations to improve the palliative care skills of generalist healthcare providers.

Pioneering better science through the 3Rs: an introduction to the national centre for the replacement, refinement, and reduction of animals in research (NC3Rs).

The National Centre for the Replacement, Refinement, and Reduction of Animals in Research (NC3Rs) is an independent scientific organization that is based in the United Kingdom, which was set up by the government to lead the discovery and application of new technologies and approaches that minimize the use of animals in research and improve animal welfare. The NC3Rs uses a range of strategies to improve and advance science through application of the 3Rs. These include funding basic research, open innovation (CRACK IT), and programs run by inhouse scientists. We present several case studies from the NC3Rs portfolio, featuring asthma research, the use of nonhuman primates in monoclonal antibody development, and CRACK IT. Finally, we anticipate the future, as we use our experience to move into new research fields and expand toward international collaboration. Here we highlight how equipping scientists with relevant and emerging 3Rs tools can help overcome the challenges and limitations of the use of animals in research to the benefit of the whole bioscience community.

Why assisted suicide must remain illegal in the UK.

Many people with life-limiting disease are vulnerable to emotional distress associated with physical, spiritual, psychological and social stressors. Psychological stress and affective disorders have the potential to influence decision making, particularly at the end of life. This article discusses the main reasons why assisted suicide and physician-assisted suicide (PAS) should remain illegal in the UK. In particular, it explores the problems associated with safeguarding 'vulnerable' patient groups and assessing mental capacity. The article also examines guidance for nurses regarding what to do if a patient asks for assistance to die or for information on assisted suicide and PAS.

Adjusting to the caregiving role: the importance of coping and support.

BACKGROUND: Although informal end-of-life care is associated with significant physical and psychological morbidity for caregivers, few interventions have been developed to meet these needs. This study aimed to identify existing coping and support mechanisms among informal cancer caregivers in order to inform intervention development. METHOD: One-to-one semi-structured qualitative interviews were undertaken with 20 informal cancer caregivers of home palliative care patients. RESULTS: Caregivers' existing coping strategies included distraction, mental stimulation, emotional release, looking for the positive aspects of caregiving, and disengaging from stressful thoughts. The majority of the participants described the importance of support and understanding form family and friends. CONCLUSIONS: The data suggests that feasible and acceptable interventions will be those that are targeted to caregivers to assist them in optimising existing coping strategies and support from family and friends.

The importance of anniversaries.

This year marks a number of important anniversaries for the Three Rs and those organisations involved in their advancement. These include the 50th anniversary of the publication of Russell and Burch's book, The Principles of Humane Experimental Technique, the 40th anniversary of FRAME, and the 5th anniversary for the UK's National Centre for the 3Rs. These anniversaries provide an important opportunity to reflect on past achievements and future challenges.

Preclinical development of monoclonal antibodies: considerations for the use of non-human primates.

The development of mAbs remains high on the therapeutic agenda for the majority of pharmaceutical and biotechnology companies. Often, the only relevant species for preclinical safety assessment of mAbs are non-human primates (NHPs), and this raises important scientific, ethical and economic issues. To investigate evidence-based opportunities to minimize the use of NHPs, an expert working group with representatives from leading pharmaceutical and biotechnology companies, contract research organizations and institutes from Europe and the USA, has shared and analyzed data on mAbs for a range of therapeutic areas. This information has been applied to hypothetical examples to recommend scientifically appropriate development pathways and study designs for a variety of potential mAbs. The addendum of ICHS6 provides a timely opportunity for the scientific and regulatory community to embrace strategies which minimize primate use and increase efficiency of mAb development.

Evaluation of a short-term group intervention for informal carers of patients attending a home palliative care service.

Despite evidence of high psychological distress and unmet needs, evaluated interventions for informal caregivers in palliative care are few. This study involved an observational outcome evaluation of attendees, and a comparison group, in specialist home palliative care. The measures included carer psychological status and patient physical status at baseline, 8 weeks, and 20 weeks. Qualitative data were collected regarding content, satisfaction with, and impact of intervention. Process data described the uptake, resources, and group activity. The intervention combined informal multiprofessional teaching with facilitated peer exchange and support, and was delivered over 6 sessions of 90 minutes per week. The uptake rate was 25%; carers were less likely to accept if they were in paid employment (OR=0.26, P=0.06), and more likely to accept if they utilized avoidance coping (OR=1.13, P=0.04) or their patient had worse physical status (OR=2.1, P=0.03). Attendees described significant support and knowledge gains from the multiprofessional input and peer group. Most relied on social comparison processes to appraise their situation. Potential detection of significant effects on global psychological scores (i.e. anxiety, depression, and burden) using multivariate analysis was disallowed due to attrition. This acceptable and accessible intervention provided information and support; further outcome studies are needed for a range of interventions. Short-term interventions are unlikely to affect global psychological scores, and future evaluations should include additional time points of data collection to demonstrate support during attendance.

Refinement and reduction in the production of genetically modified mice: sixth report of the BVAAWF/FRAME/RSPCA/UFAW Joint Working Group on Refinement.

This paper introduces the sixth report of the BVAAWF/FRAME/RSPCA/UFAW Joint Working Group on Refinement (JWGR), which addresses reduction and refinement in the generation, management and care of genetically modified (GM) mice. The report provides a comprehensive review of the potential for reduction and refinement at all stages of the generation and maintenance of GM animals. The issues covered include scientific, procedural and practical issues. The need for good training in all of these areas is emphasised. The report concludes with a section on the need to develop comprehensive criteria for welfare assessments for GM mice and a preliminary list of criteria is provided. The full report has been published in Laboratory Animals.