Follicular Helper and Regulatory T Cells Drive the Development of Spontaneous Epstein-Barr Virus Lymphoproliferative Disorder.

Epstein-Barr virus (EBV) is a ubiquitous herpes virus associated with various cancers. EBV establishes latency with life-long persistence in memory B-cells and can reactivate lytic infection placing immunocompromised individuals at risk for EBV-driven lymphoproliferative disorders (EBV-LPD). Despite the ubiquity of EBV, only a small percentage of immunocompromised patients (~20%) develop EBV-LPD. Engraftment of immunodeficient mice with peripheral blood mononuclear cells (PBMCs) from healthy EBV-seropositive donors leads to spontaneous, malignant, human B-cell EBV-LPD. Only about 20% of EBV+ donors induce EBV-LPD in 100% of engrafted mice (High-Incidence, HI), while another 20% of donors never generate EBV-LPD (No-Incidence, NI). Here, we report HI donors to have significantly higher basal T follicular helper (Tfh) and regulatory T-cells (Treg), and depletion of these subsets prevents/delays EBV-LPD. Transcriptomic analysis of CD4+ T cells from ex vivo HI donor PBMC revealed amplified cytokine and inflammatory gene signatures. HI vs. NI donors showed a marked reduction in IFNγ production to EBV latent and lytic antigen stimulation. In addition, we observed abundant myeloid-derived suppressor cells in HI donor PBMC that decreased CTL proliferation in co-cultures with autologous EBV+ lymphoblasts. Our findings identify potential biomarkers that may identify individuals at risk for EBV-LPD and suggest possible strategies for prevention.

Targeted Delivery of BZLF1 to DEC205 Drives EBV-Protective Immunity in a Spontaneous Model of EBV-Driven Lymphoproliferative Disease.

Epstein-Barr virus (EBV) is a human herpes virus that infects over 90% of the world's population and is linked to development of cancer. In immune-competent individuals, EBV infection is mitigated by a highly efficient virus-specific memory T-cell response. Risk of EBV-driven cancers increases with immune suppression (IS). EBV-seronegative recipients of solid organ transplants are at high risk of developing post-transplant lymphoproliferative disease (PTLD) due to iatrogenic IS. While reducing the level of IS may improve EBV-specific immunity and regression of PTLD, patients are at high risk for allograft rejection and need for immune-chemotherapy. Strategies to prevent PTLD in this vulnerable patient population represents an unmet need. We have previously shown that BZLF1-specific cytotoxic T-cell (CTL) expansion following reduced IS correlated with immune-mediated PTLD regression and improved patient survival. We have developed a vaccine to bolster EBV-specific immunity to the BZLF1 protein and show that co-culture of dendritic cells (DCs) loaded with a αDEC205-BZLF1 fusion protein with peripheral blood mononuclear cells (PMBCs) leads to expansion and increased cytotoxic activity of central-effector memory CTLs against EBV-transformed B-cells. Human-murine chimeric Hu-PBL-SCID mice were vaccinated with DCs loaded with αDEC205-BZLF1 or control to assess prevention of fatal human EBV lymphoproliferative disease. Despite a profoundly immunosuppressive environment, vaccination with αDEC205-BZLF1 stimulated clonal expansion of antigen-specific T-cells that produced abundant IFNγ and significantly prolonged survival. These results support preclinical and clinical development of vaccine approaches using BZLF1 as an immunogen to harness adaptive cellular responses and prevent PTLD in vulnerable patient populations.

Living With Rheumatoid Arthritis in Spain: A Qualitative Study of Patient Experience and the Role of Health Professionals.

The aim of this study was to explore the experience of Spanish people living with rheumatoid arthritis (RA) and the support these people received from health professionals, particularly nurses. Nineteen patients with >1 year diagnosis, disease activity moderate or severe (DAS28 > 3.2), and already treated with disease-modifying antirheumatic drugs (DMARDs) were interviewed. A thematic analysis was performed to interpret the discourses. The difficulties of symptom management; the need for home-adaptations, the difficulties of living with a deteriorating self-image; and the reluctant reliance on medication to control their disease were the main themes that emerged from the discourse analysis of this study. Nurses appeared to have a limited role in RA patients care, and focused primarily on giving information and training for biological therapies. RA patients in Spain would benefit from having contact with specialist nurses who could empower them to self-manage their disease, as happens in other countries.

Evaluating the use of patient pathway scores in medical assessments.

Aim This article describes the modification and testing of a triage tool, the patient pathway assessment score (PPAS), which could be used by all grades of nursing staff to triage patients in a medical assessment area (MAA). The aim was to increase patient satisfaction and reduce waiting times. Method Staff scored all patients using PPAS, but used the existing triage process to assign patients to one of the MAA's two pathways. Two researchers reviewed patients' notes retrospectively to determine which pathway they should have followed and compared this to the outcome that would have occurred if the PPAS score had been used. Results Full, rather than theoretical, use of the PPAS tool could have reduced patient waiting times, as 55 (24%) out of 231 patients would have been allocated to the correct pathway. Conclusion The tool could improve patients' journeys through the MAA by ensuring they are allocated to the correct pathway. It is now implemented in practice.

Emotional Intelligence and Nurse Recruitment: Rasch and confirmatory factor analysis of the trait emotional intelligence questionnaire short form.

AIM: To examine the construct validity of the Trait Emotional Intelligence Questionnaire Short form. BACKGROUND: Emotional intelligence involves the identification and regulation of our own emotions and the emotions of others. It is therefore a potentially useful construct in the investigation of recruitment and retention in nursing and many questionnaires have been constructed to measure it. DESIGN: Secondary analysis of existing dataset of responses to Trait Emotional Intelligence Questionnaire Short form using concurrent application of Rasch analysis and confirmatory factor analysis. METHOD: First year undergraduate nursing and computing students completed Trait Emotional Intelligence Questionnaire-Short Form in September 2013. Responses were analysed by synthesising results of Rasch analysis and confirmatory factor analysis. RESULTS: Participants (N = 938) completed Trait Emotional Intelligence Questionnaire Short form. Rasch analysis showed the majority of the Trait Emotional Intelligence Questionnaire-Short Form items made a unique contribution to the latent trait of emotional intelligence. Five items did not fit the model and differential item functioning (gender) accounted for this misfit. Confirmatory factor analysis revealed a four-factor structure consisting of: self-confidence, empathy, uncertainty and social connection. All five misfitting items from the Rasch analysis belonged to the 'social connection' factor. CONCLUSIONS: The concurrent use of Rasch and factor analysis allowed for novel interpretation of Trait Emotional Intelligence Questionnaire Short form. Much of the response variation in Trait Emotional Intelligence Questionnaire Short form can be accounted for by the social connection factor. Implications for practice are discussed.

Patients and nursing staff views of using the education needs assessment tool in rheumatology clinics: a qualitative study.

AIMS AND OBJECTIVES: To evaluate the usability of the educational needs assessment tool in clinical practice, from a practitioner and patient perspective and to establish whether patients perceive that they are getting an equally good or equally inadequate education service for their needs. BACKGROUND: The educational needs assessment tool was developed to enable patients with Rheumatoid Arthritis to assess their education needs prior to a consultation with a health professional. The educational needs assessment tool has been translated into nine languages and measurement properties have been established, however, its usability in clinical practice has not been studied. DESIGN: A qualitative study embedded into a multicentre RCT in which patients had been randomised into either educational needs assessment tool-focused education (Experimental Group) or usual care (control group). METHODS: Both groups were seen by a clinical nurse specialist. Sixteen patients and four clinical nurse specialists were recruited from the Rheumatology Outpatient Departments of three Acute Hospitals within the U K. Data were collected by interviews with patients and clinical nurse specialist. Analysis followed the Framework approach. RESULTS: Patients and clinical nurse specialist found completion of the educational needs assessment tool straightforward, comprehensive and easy to use. Completing the educational needs assessment tool helped patients to focus on what they needed to know from the clinical nurse specialist. Patients in both the control group and the experimental group felt supported and reassured by their clinical nurse specialist and perceived that they received a good and adequate education provision. CONCLUSION: This study provides useful insights into the ability of the educational needs assessment tool to assess the educational needs of patients with rheumatoid arthritis in routine clinical practice. RELEVANCE TO CLINICAL PRACTICE: The educational needs assessment tool would be useful as a structured guide for nurses when assessing and meeting individual patient educational needs. This has the potential to improve patient-centred care, involve patients more actively in their care and enhance the long-term effects of patient education provision.

Moving the injectable methotrexate service closer to home: a practice development initiative.

OBJECTIVE: The aim of this practice development project was to make it quicker and easier for patients to switch to subcutaneous (s/c) methotrexate and thereby introduce a nurse-led methotrexate clinic into a district general hospital, which would make the best use of the advanced knowledge and skills of the rheumatology specialist nurses; empower patients and improve their experience; and introduce cost savings for the Trust. METHODS: Over a period of four months, meetings were held with pharmacists, clinicians, administrative and support staff to formulate a plan to introduce the changes and agree the benefits to patients. A detailed plan for the practice development project addressed the procedures to follow, the safety issues for patients and the revision of current documentation. RESULTS: A review of service in the year before and after the change revealed that the number of rheumatoid arthritis patients who had switched to s/c methotrexate had increased by 80%. This was a significant difference (p = 0.049), which strongly suggested that the change in service was the reason for the increased number of patients who were able to switch their route of administration of methotrexate. CONCLUSION: This project demonstrated that not only do nurse specialists have the skills to make clinical decisions and judgements, prescribe medications and escalate therapies with no detriment to the patients, but also that this practice can lead to a more efficient and effective service, at a reduced cost to the Trust.

The outcome and cost-effectiveness of nurse-led care in people with rheumatoid arthritis: a multicentre randomised controlled trial.

OBJECTIVE: To determine the clinical effectiveness and cost-effectiveness of nurse-led care (NLC) for people with rheumatoid arthritis (RA). METHODS: In a multicentre pragmatic randomised controlled trial, the assessment of clinical effects followed a non-inferiority design, while patient satisfaction and cost assessments followed a superiority design. Participants were 181 adults with RA randomly assigned to either NLC or rheumatologist-led care (RLC), both arms carrying out their normal practice. The primary outcome was the disease activity score (DAS28) assessed at baseline, weeks 13, 26, 39 and 52; the non-inferiority margin being DAS28 change of 0.6. Mean differences between the groups were estimated controlling for covariates following per-protocol (PP) and intention-to-treat (ITT) strategies. The economic evaluation (NHS and healthcare perspectives) estimated cost relative to change in DAS28 and quality-adjusted life-years (QALY) derived from EQ5D. RESULTS: Demographics and baseline characteristics of patients under NLC (n=91) were comparable to those under RLC (n=90). Overall baseline-adjusted difference in DAS28 mean change (95% CI) for RLC minus NLC was -0.31 (-0.63 to 0.02) for PP and -0.15 (-0.45 to 0.14) for ITT analyses. Mean difference in healthcare cost (RLC minus NLC) was £710 (-£352, £1773) and -£128 (-£1263, £1006) for PP and ITT analyses, respectively. NLC was more cost-effective with respect to cost and DAS28, but not in relation to QALY utility scores. In all secondary outcomes, significance was met for non-inferiority of NLC. NLC had higher 'general satisfaction' scores than RLC in week 26. CONCLUSIONS: The results provide robust evidence to support non-inferiority of NLC in the management of RA. TRIAL REGISTRATION: ISRCTN29803766.

The perceptions of people with low back pain treated in the Spanish National Health, and their experience while undergoing a new evidence-based treatment. A focus group study.

PURPOSE: To explore the perceptions of people with low back pain (LBP) treated within the Spanish National Health Service, and their experience while undergoing a new evidence-based treatment ("neuroreflexotherapy"). METHODS: A focus group (FG) study was conducted. Participants were divided into five groups according to whether they: suffered from subacute versus chronic LBP; had undergone one versus several neuroreflexotherapy procedures; showed a clinically relevant improvement in pain and disability according to validated measuring instruments, and reported it. Thirty-two patients were selected by purposive sampling. Content analysis was undertaken by two researchers who had no contact with the clinicians. RESULTS: Subacute and chronic LBP curtails daily activities, reduces quality of life (QoL) and self-esteem, and is experienced as a stigma. Patients want to be treated with respect and empathy by clinicians who refrain from judging them. New treatments trigger hope, but also fear and mistrust. Most patients experiencing a clinically relevant improvement resume daily activities, and report improvement in QoL, self-esteem and emotional wellbeing. CONCLUSION: Southern European LBP patients have similar perceptions to those in other cultural settings. LBP jeopardizes patients' QoL and self-esteem. When pain improves significantly, patients are happy to acknowledge it and resume their normal life. Implications for Rehabilitation People with low back pain (LBP) want to be treated with respect and empathy by clinicians who inspire confidence and refrain from judging them. When faced with a new evidence based treatment, people with subacute and chronic LBP are hopeful, but apprehensive. Most of those who experience a clinically meaningful improvement after treatment are happy to acknowledge it and resume an active and fulfilling life. People who report no improvements after being treated, should be believed.

Psychosocial effects of Tai Chi exercise on people with rheumatoid arthritis.

AIMS AND OBJECTIVES: To investigate the perceived psychosocial effects of participating in taught sessions of Tai Chi on people diagnosed with rheumatoid arthritis (RA). BACKGROUND: Tai Chi is thought to be psychologically as well as physically beneficial for people with arthritis. DESIGN: This study adopted a qualitative approach to follow-up participants who had previously demonstrated physical and psychological benefits from a specifically modified Tai Chi programme in an attempt to explore perceived psychosocial improvements. METHODS: Nineteen semi-structured, audio-taped, interviews were carried out with participants who had taken part in, twice weekly, group-based Tai Chi sessions for 12 weeks. Data from transcripts were analysed using thematic analysis. RESULTS: Analysis suggests that participating in shared Tai Chi sessions provides increased awareness of the links between mind and body; reduces anxiety and depression; and improves self-esteem, self-efficacy and motivation. It was particularly striking to find that the highly structured nature of Tai Chi was felt to improve memory and seemed to offer aesthetic experiences through developing graceful, 'fluid' moves rather than the 'jarring' movements often imposed by having RA. Such group sessions were found to provide social support and help improve participants' sense of perspective. CONCLUSION: Although small scale, this study suggests that Tai Chi has the potential to offer psychosocial benefits for people with RA. RELEVANCE TO CLINICAL PRACTICE: Offering Tai Chi alongside traditional treatments for RA could promote psychological health and well-being, help inform clinical decision-making and prove cost-effective.

Tai Chi exercise and auricular acupressure for people with rheumatoid arthritis: an evaluation study.

AIMS AND OBJECTIVES: (i) To assess the effectiveness of Tai Chi exercise in people with rheumatoid arthritis (RA). (ii) To ascertain if Tai Chi and auricular acupressure have a potentiation effect in controlling pain. (iii) To evaluate the acceptability and enjoyment of the classes. BACKGROUND: Tai Chi has been suggested as a suitable exercise for people with arthritis and specific programmes have been developed. Auricular acupressure is a therapeutic method by which points on the ear are stimulated to treat various disorders. DESIGN: A pragmatic non-randomised before/after study to compare the effects of the interventions. METHODS: People with RA (n=21) were recruited and allocated into two groups. Both groups followed a Tai Chi exercise programme, twice a week for 12 weeks, but one group (n=14) had, in addition, the auricular acupressure. Physical symptoms and function, pain, quality of life and self-efficacy were measured in both groups before and after the programme. Acceptability and enjoyment were assessed at the end. RESULTS: At 12 weeks, both groups had achieved statistically significant improvements in balance, grip strength, pinch strength, 50 foot walk time self reported joint pain, swollen joint count, tender joint count and in self efficacy in relation to pain control. All participants stated that they enjoyed the classes. There was no evidence to suggest that the auricular acupressure enhanced the effects of the Tai Chi intervention. CONCLUSION: The classes appeared to be mentally as well as physically helpful to participants. RELEVANCE TO CLINICAL PRACTICE: People with a chronic debilitating disease such as RA should be encouraged to undertake gentle strengthening exercise such as Tai Chi because of its potential for physical and psychological improvements.

The effectiveness of nurse-led care in people with rheumatoid arthritis: a systematic review.

OBJECTIVES: The objective of this systematic review was to determine the effectiveness of nurse-led care in rheumatoid arthritis. DESIGN: Systematic review of effectiveness. DATA SOURCES: Electronic databases (AMED, CENTRAL, CINAHL, EMBASE, HMIC, HTA, MEDLINE, NHEED, Ovid Nursing and PsycINFO) were searched from 1988 to January 2010 with no language restrictions. Inclusion criteria were: randomised controlled trials, nurse-led care being part of the intervention and including patients with RA. REVIEW METHODS: Data were extracted by one reviewer and checked by a second reviewer. Quality assessment was conducted independently by two reviewers using the Cochrane Collaboration's Risk of Bias Tool. For each outcome measure, the effect size was assessed using risk ratio or ratio of means (RoM) with corresponding 95% confidence intervals (CI) as appropriate. Where possible, data from similar outcomes were pooled in a meta-analysis. RESULTS: Seven records representing 4 RCTs with an overall low risk of bias (good quality) were included in the review. They included 431 patients and the interventions (nurse-led care vs usual care) lasted for 1-2years. Most effect sizes of disease activity measures were inconclusive (DAS28 RoM=0.96, 95%CI [0.90-1.02], P=0.16; plasma viscosity RoM=1 95%CI [0.8-1.26], p=0.99) except the Ritchie Articular Index (RoM=0.89, 95%CI [0.84-0.95], P<0.001) which favoured nurse-led care. Results from some secondary outcomes (functional status, stiffness and coping with arthritis) were also inconclusive. Other outcomes (satisfaction and pain) displayed mixed results when assessed using different tools making them also inconclusive. Significant effects of nurse-led care were seen in quality of life (RAQoL RoM=0.83, 95%CI [0.75-0.92], P<0.001), patient knowledge (PKQ RoM=4.39, 95%CI [3.35-5.72], P<0.001) and fatigue (median difference=-330, P=0.02). CONCLUSIONS: The estimates of the primary outcome and most secondary outcomes showed no significant difference between nurse-led care and the usual care. While few outcomes favoured nurse-led care, there is insufficient evidence to conclude whether this is the case. More good quality RCTs of nurse-led care effectiveness in rheumatoid arthritis are required.

A randomised, controlled study of outcome and cost effectiveness for RA patients attending nurse-led rheumatology clinics: study protocol of an ongoing nationwide multi-centre study.

BACKGROUND: The rise in the number of patients with arthritis coupled with understaffing of medical services has seen the deployment of Clinical Nurse Specialists in running nurse-led clinics alongside the rheumatologist clinics. There are no systematic reviews of nurse-led care effectiveness in rheumatoid arthritis. Few published RCTs exist and they have shown positive results for nurse-led care but they have several limitations and there has been no economic assessment of rheumatology nurse-led care in the UK. OBJECTIVE: This paper outlines the study protocol and methodology currently being used to evaluate the outcomes and cost effectiveness for patients attending rheumatology nurse-led clinics. DESIGN AND METHODS: A multi-centred, pragmatic randomised controlled trial with a non-inferiority design; the null hypothesis being that of 'inferiority' of nurse-led clinics compared to physician-led clinics. The primary outcome is rheumatoid arthritis disease activity (measured by DAS28 score) and secondary outcomes are quality of life, self-efficacy, disability, psychological well-being, satisfaction, pain, fatigue and stiffness. Cost effectiveness will be measured using the EQ-5D, DAS28 and cost profile for each centre. POWER CALCULATIONS: In this trial, a DAS28 change of 0.6 is considered to be the threshold for clinical distinction of 'inferiority'. A sample size of 180 participants (90 per treatment arm) is needed to reject the null hypothesis of 'inferiority', given 90% power. Primary analysis will focus on 2-sided 95% confidence interval evaluation of between-group differences in DAS28 change scores averaged over 4 equidistant follow up time points (13, 26, 39 and 52 weeks). Cost effectiveness will be evaluated assessing the joint parameterisation of costs and effects. RESULTS: The study started in July 2007 and the results are expected after July 2011. TRIAL REGISTRATION: The International Standard Randomised Controlled Trial Number ISRCTN29803766.

A review of design and reporting issues in self-reported prevalence studies of leg ulceration.

OBJECTIVE: The aim of this review was to examine design and reporting issues that affect prevalence estimates of leg ulceration obtained using self-report and outline strategies to strengthen the validity and reliability of research in this area. STUDY DESIGN AND SETTING: We identified leg ulcer prevalence studies and evaluated them against the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) statement. The authors draw upon the wider literature and their own empirical work in discussing strategies to overcome design and reporting issues. RESULTS: Common deficiencies in the design and reporting of studies include wide variations in diagnostic criteria and age parameters for participant selection, a lack of description of efforts to address bias/study size rationale, and low participation rates in clinical examination stages. These factors and differences in statistical methods of analysis affect the validity and reliability of findings and hinder interpretation, making comparisons across populations difficult. Opportunities for subgroup analyses are frequently missed. CONCLUSION: Self-report is a valuable means of capturing leg ulcer prevalence, but the future design and reporting of studies need to be strengthened, including addressing weaknesses in validation strategies. Capture-recapture analysis or a multiple-methods approach has the potential to yield the most valid and reliable prevalence estimates.

The predictors of foot ulceration in patients with rheumatoid arthritis: a preliminary investigation.

We explored the predictors of foot ulceration in patients with rheumatoid arthritis (RA). The cases were 15 patients with RA reporting foot ulceration in response to a postal survey of patients sampled from a diagnostic register in secondary care (n = 1,130). The controls were 66 patients with RA randomly sampled from the survey respondents (n = 883) after matching for age, sex and disease duration. Patients with co-existent diabetes were excluded. Clinical examination included the assessment of known risk factors for foot ulceration in diabetes including: neuropathy (insensitivity to 10 g monofilament), peripheral vascular disease (ankle brachial pressure index [ABPI]), foot deformity (Platto indices) and raised plantar pressure (PressureStat readings). A 44 swollen-joint count, the presence of pre-ulcerative lesions and current steroid therapy were identified through univariate analysis as additional potential predictors in patients with RA. Forward step-wise logistic regression analysis showed that the following variables were significant predictors of ulceration: steroid therapy (OR = 9.70, 95%CI = 2.09-45.11, p = 0.004), abnormal ABPI (OR = 13.45, 95%CI = 1.19-151.43, p = 0.035), the presence of pre-ulcerative lesions (OR = 7.40, 95%CI = 1.51-36.30, p = 0.014) and swollen-joint count (OR = 1.25, 95%CI = 1.02-1.53, p = 0.034). Abnormal sensation, foot deformity and raised plantar pressures were not significant predictors of ulceration. The wide confidence intervals for ABPI were due to sparse data with very few abnormal values, and the results of exact logistic regression (more accurate where data is sparse and case matching employed) found that ABPI was no longer a significant predictor (p = 0.054). The significance of the other predictors did not differ substantially. In this preliminary study, abnormal sensation, foot deformity and raised plantar pressures were not significantly associated with foot ulceration but active disease and current steroid therapy were. The contribution of peripheral vascular disease to risk is unclear and further investigation is needed in a larger cohort.

The prevalence of foot ulceration in patients with rheumatoid arthritis.

OBJECTIVE: To establish the prevalence of foot ulceration in patients with rheumatoid arthritis (RA) in secondary care. METHODS: A postal survey of all patients with RA (n = 1,130) under the care of rheumatologists in Bradford, West Yorkshire, UK was performed. The prevalence data were validated through clinical examination, case-note review, and contact with health professionals. The false-negative rate was investigated in a subsample of patients (n = 70) who denied any history of ulceration. RESULTS: The postal survey achieved a 78% response rate. Following validation, the point prevalence of foot ulceration was 3.39% and the overall prevalence was 9.73%. The false-positive rate was initially high at 21.21%, but use of diagrammatic questionnaire data to exclude leg ulceration reduced the rate to 10.76%. The false-negative rate was 11.76%. The most common sites for ulceration were the dorsal aspect of hammer toes, the metatarsal heads, and the metatarsophalangeal joint in patients with hallux abducto valgus, with 33% of patients reporting multiple sites of ulceration. Patients with open-foot and healed-foot ulceration had significantly longer RA disease duration, reported significantly greater use of special footwear, and had a higher prevalence of foot surgery than ulcer-free patients. CONCLUSION: Foot ulceration affects a significant proportion of patients with RA. Further work is needed to establish risk factors for foot ulceration in RA and to target foot health provision more effectively.