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Objective\ud Thyroid status in the months following radioiodine treatment for Graves’ disease can be unstable.Our objective was to quantify frequency of abnormal thyroid function post-radioiodine and compare effectiveness of common management strategies.\ud \ud Design\ud Retrospective, multi-centre, observational study.\ud \ud Patients\ud Adult patients with Graves’ disease treated with radioiodine with 12 months’ follow-up.\ud \ud Measurements\ud Euthyroidism was defined as both serum thyrotropin (TSH) and free thyroxine (FT4) within their reference ranges or, when only one was available, it was within its reference range; hypothyroidism as TSH ≥ 10 mu/L, or subnormal FT4 regardless of TSH; hyperthyroidism as TSH below and FT4 above their reference ranges; dysthyroidism as the sum of hypo- and hyperthyroidism; subclinical hypothyroidism as normal FT4 and TSH between the upper limit of normal and

Introduction: Epidemiological studies in acromegaly have shown increased mortality rates from vascular, respiratory and malignant diseases. We aimed to use a large national cohort of subjects with acromegaly to determine mortality rates due to the above disease categories and to determine whether suppressing post treatment growth hormone (GH) levels to < 1 ng/ml improved survival compared with GH levels of 1-2.5 ng/ml.Methods: We identified 1845 cases from the UK Acromegaly database diagnosed 1970-2016 (31,768 person-yrs.), determined population mortality rates (for the period in question, age and sex of the study population) based on historic data, and death certification data for the study population from NHS digital. We were then able to determine standardized mortality rates (SMR) for the above conditions and determine whether they were associated with with age at diagnosis, duration of disease, post treatment (last recorded random or mean of profile) and mean GH levels (day weighted average of all GH measurements). Data presented as SMR, 95% CI and P value.Results: Overall standardised mortality rate (SMR) was increased, Observed 556 vs. Expected 412.74, 1.35 (1.24 -1.46, P 10yrs.1.13 (1.03-1.25) P

Essentials Near-patient testing improves coagulopathy diagnosis in cardiac surgery patients with severe bleeding. We investigated how well pre-emptive near-patient testing predicted severe bleeding. Severe bleeding could be predicted using both near-patient tests and patient clinical characteristics. Near-patient test results gave little additional predictive value over clinical characteristics alone. Background Coagulopathic bleeding is common after cardiac surgery and is associated with increased morbidity, mortality and healthcare costs. Implementation of blood management algorithms in which patients with severe bleeding undergo near-patient coagulation testing results in less overall bleeding and transfusion. However, it is unknown whether there is additional value from pre-emptive near-patient testing to predict whether severe bleeding will occur. Objectives To evaluate how well a comprehensive panel of 28 near-patient platelet and viscoelastometry tests predict bleeding after cardiac surgery, compared to prediction using baseline clinical characteristics alone. Methods Single-center, prospective cohort study in adults undergoing a range of cardiac surgery procedures. The primary outcome was clinical concern about bleeding (CCB), a composite of high blood loss (chest drain volume >600 mL within 6 hours), re-operation for bleeding or administration of a pro-haemostatic treatment directed by clinician judgement. Results In 1833 patients recruited between March 2010 and August 2012, the median number of abnormal near-patient test results was 5/28 per patient (range 0-18). CCB occurred in 449/1833 patients (24.5%). The c-statistic for a predictive model for CCB using only baseline clinical characteristics (baseline-only model) was 0.72 (95% CI 0.69-0.75). Addition of near-patient test results to this model (baseline-plus-test model) improved the prediction of CCB (c-statistic 0.75 [0.72-0.77]), but increased the number of correctly classified patients by only 18 (0.98%). Conclusions Near-patient coagulation testing predicts bleeding in cardiac surgery patients, but offers little improvement in prediction compared to baseline clinical characteristics alone. trial registration: ISRNCTN 20778544 (http://www.isrctn.com/).

Background: Patient education is an important part of the management of rheumatic and other diseases. Since patients do not have the same needs, it is crucial to assess needs of a targeted group to be able to tailor educational interventions. Objectives: To assess educational needs of a large cohort of patients with different rheumatic and musculoskeletal diseases attending a health facility in Austria.

ObjectivesTo see if a group course delivered by rheumatology teams using cognitive-behavioural approaches, plus usual care, reduced RA fatigue impact more than usual care alone.MethodsMulticentre, 2-year randomised controlled trial in RA adults (fatigue severity>6/10, no recent major medication changes). RAFT (Reducing Arthritis Fatigue: clinical Teams using CB approaches) comprises seven sessions, codelivered by pairs of trained rheumatology occupational therapists/nurses. Usual care was Arthritis Research UK fatigue booklet. Primary 26-week outcome fatigue impact (Bristol RA Fatigue Effect Numerical Rating Scale, BRAF-NRS 0–10). Intention-to-treat regression analysis adjusted for baseline scores and centre.Results308/333 randomised patients completed 26 week data (156/175 RAFT, 152/158 Control). Mean baseline variables were similar. At 26 weeks, the adjusted difference between arms for fatigue impact change favoured RAFT (BRAF-NRS Effect −0.59, 95% CI –1.11 to -0.06), BRAF Multidimensional Questionnaire (MDQ) Total −3.42 (95% CI –6.44 to -0.39), Living with Fatigue −1.19 (95% CI –2.17 to -0.21), Emotional Fatigue −0.91 (95% CI –1.58 to -0.23); RA Self-Efficacy (RASE, +3.05, 95% CI 0.43 to 5.66) (14 secondary outcomes unchanged). Effects persisted at 2 years: BRAF-NRS Effect −0.49 (95% CI −0.83 to -0.14), BRAF MDQ Total −2.98 (95% CI −5.39 to -0.57), Living with Fatigue −0.93 (95% CI −1.75 to -0.10), Emotional Fatigue −0.90 (95% CI −1.44, to -0.37); BRAF-NRS Coping +0.42 (95% CI 0.08 to 0.77) (relevance of fatigue impact improvement uncertain). RAFT satisfaction: 89% scored > 8/10 vs 54% controls rating usual care booklet (pConclusionMultiple RA fatigue impacts can be improved for 2 years by rheumatology teams delivering a group programme using cognitive behavioural approaches.Trial registration numberISRCTN52709998.

Background: Complex interventions are widely used in modern health care practice and are defined as those having potentially interacting components. Evaluation can be challenging due to difficulties in logistics, standardisation and delivery. In addition, there can be difficulty recruiting to time and to target (particularly in multicentre studies) and minimising attrition and data loss. We report how the RAFT study [a seven-centre randomized controlled trial (RCT) comparing a complex group cognitive-behavioural (CB) intervention with standard care for the reduction of fatigue impact in patients with RA) is implementing successful strategies to meet recruitment, intervention delivery and retention targets. The study requires patients to make a substantial commitment over a 2 year period and for the intervention to be delivered by routine clinical staff trained for this purpose. Methods: The following strategies were agreed upon during the planning and design phase: Maximising recruitment: Funded research nurse time at all seven sites; mailshot option for approach; recruitment posters for clinics; flexible and pragmatic approach to session attendance; telephone, email and postal contact; newsletter and regular knowledge exchange between the central trial management team and sites; weekly recruitment updates and reviews. Ensuring intervention delivery: Flexible course dates and times set by each site, regular communication with the central management team to discuss foreseeable issues and preventative actions, provision of real-time clinical supervision and full-time telephone/email support. Minimising attrition and data loss: Primary outcome collection by telephone, ensuring regular personal contact; secondary data collection by postal questionnaire, reducing the number of hospital visits; telephone reminders; partial withdrawal options; personalized letters and thank you cards. Patient involvement: We had a number of acceptability and feasibility consultations with our two patient partners. Both partners had prior experience attending the intervention, were co-applicants on the grant proposal and continue to provide a patient perspective as members of the trial management group. Results: Our target was to recruit 300 participants with no recent medication changes and a fatigue level ≥6 (on a 1–10 scale where 10 is totally exhausted). During the 2 year recruitment phase, 333 participants were randomized (11% over target). All 28 programmes successfully delivered, with 7/7 sites and 14/15 tutors remaining fully engaged with the study. Retention at 6 months is currently 92.5% (sample size allows for 20% attrition). Data returned by those reaching the 6 month time point are 100% for the primary outcome and 97% for secondary outcomes. Conclusion: Advanced planning and consistent application of these strategies has ensured success so far. A flexible and pragmatic approach, regular communication between local and central teams, personal contact with participants and extensive patient partner input are key components.

Introduction: Near-patient haemostasis tests assist diagnosis and treatment of blood clotting abnormalities in bleeding patients after cardiac surgery. Aim: To quantify the predictive value of routine near-patient haemostasis tests for coagulopathic bleeding in a large clinical trial. Methods: We performed a prospective cohort study of the patient characteristics and the results of 23 near-patient platelet and viscoelastometry tests in adults undergoing a range of cardiac surgery procedures. The primary outcome was clinical concern about bleeding (CCB), defined as a composite of high blood loss or pro-haemostatic treatment or re-operation for bleeding. A multivariable predictive model for CCB was developed based on the pre-operative characteristics of 1833 patients at a single cardiac centre recruited between March 2010 and August 2012. This model was validated using data for 1611 patients recruited at 16 other UK cardiac surgery centres between July 2009 and February 2013. The additional predictive value of near-patient test results was estimated in the development cohort. Results: CCB occurred in 449 (24.5%) patients in the development cohort. Male sex, absence of diabetes, complex procedure, anti-platelet treatment, short interval since withdrawal of anti-platelet treatment, reduced BMI, reduced pre-operative haematocrit and reduced pre-operative platelet count were independently associated with increased risk of CCB (area under RoC curve (AUR)=0.72 (0.69 to 0.75)). At 75% sensitivity, the specificity of the model was 57%. In the validation cohort, the AUR of the patient characteristics model was 0.63 (0.60 to 0.66). Adding the results of the most predictive near-patient tests performed immediately after surgery improved prediction of CCB in the development cohort (AUR 0.74; 0.72 to 0.77), but at 75% sensitivity this increased the specificity by only 4%. Adding the results of near-patient platelet tests performed before surgery did not further improve prediction of CCB (AUR 0.75; 0.72 to 0.77). Conclusions: Routine near-patient haemostasis tests offer little improvement in the prediction of CCB after cardiac surgery compared to pre-operative patient characteristics alone.

BackgroundDespite improved myocardial protection strategies, cardioplegic arrest and ischemia still result in reperfusion injury. We have previously published a study describing the effects of propofol (an anesthetic agent commonly used in cardiac surgery) on metabolic stress, cardiac function, and injury in a clinically relevant animal model. We concluded that cardioplegia supplementation with propofol at a concentration relevant to the human clinical setting resulted in improved hemodynamic function, reduced oxidative stress, and reduced reperfusion injury when compared to standard cardioplegia. ObjectiveThe Propofol cardioplegia for Myocardial Protection Trial (ProMPT) aims to translate the successful animal intervention to the human clinical setting. We aim to test the hypothesis that supplementation of the cardioplegic solution with propofol will be cardioprotective for patients undergoing isolated coronary artery bypass graft or aortic valve replacement surgery with cardiopulmonary bypass. MethodsThe trial is a single-center, placebo-controlled, randomized trial with blinding of participants, health care staff, and the research team. Patients aged between 18 and 80 years undergoing nonemergency isolated coronary artery bypass graft or aortic valve replacement surgery with cardiopulmonary bypass at the Bristol Heart Institute are being invited to participate. Participants are randomly assigned in a 1:1 ratio to either cardioplegia supplementation with propofol (intervention) or cardioplegia supplementation with intralipid (placebo) using a secure, concealed, Internet-based randomization system. Randomization is stratified by operation type and minimized by diabetes mellitus status. Biomarkers of cardiac injury and metabolism are being assessed to investigate any cardioprotection conferred. The primary outcome is myocardial injury, studied by measuring myocardial troponin T. The trial is designed to test hypotheses about the superiority of the intervention within each surgical stratum. The sample size of 96 participants has been chosen to achieve 80% power to detect standardized differences of 0.5 at a significance level of 5% (2-tailed) assuming equal numbers in each surgical stratum. ResultsA total of 96 patients have been successfully recruited over a 2-year period. Results are to be published in late 2014. ConclusionsDesigning a practicable method for delivering a potentially protective dose of propofol to the heart during cardiac surgery was challenging. If our approach confirms the potential of propofol to reduce damage during cardiac surgery, we plan to design a larger multicenter trial to detect differences in clinical outcomes. Trial RegistrationInternational Standard Randomized Controlled Trial Number (ISRCTN): 84968882; http://www.controlled-trials.com/ISRCTN84968882/ProMPT (Archived by WebCite at http://www.webcitation.org/6Qi8A51BS).

Background Emergency operations, cancellations, changing operating theatre schedules, day of surgery arrivals and an aging population are all challenges facing the recruitment of cardiac surgery patients into studies. The observational Coagulation and Platelet Function Testing in Cardiac Surgery (COPTIC) study, which required patients to consent to give blood samples at the start and end of surgery, is the largest of its kind and the largest single study conducted at our hospital. We describe our experience of recruitment and retention and share our successful strategy.

Background Complex interventions are widely used in modern health care practice and are defined as those having potentially interacting components. Evaluation can be challenging due to difficulties in logistics, standardisation, delivery, recruiting to time and target (particularly in multi-centre studies) and minimising attrition and data loss. We report how the RAFT study (a 7-centre randomised controlled trial comparing a complex, group cognitive-behavioural intervention with standard care, for the reduction of fatigue impact in patients with rheumatoid arthritis) is implementing successful strategies to meet targets. The study requires patients to make a substantial commitment over a two year period and for the intervention to be delivered by routine clinical staff trained for this purpose. Objectives To recruit to time and target, ensure intervention delivery, minimise attrition and maximise retention. Methods Maximising recruitment: Funded research nurse time at all 7 sites, mailshot approach option, recruitment posters, flexible/pragmatic approach to session attendance, telephone, email and postal contact, newsletter and regular knowledge exchange between the central management team and sites, weekly recruitment review. Ensuring intervention delivery: Flexible course dates and times, regular discussions around foreseeable issues and preventative actions, provision of real-time clinical supervision and full-time telephone/email support. Minimising attrition and data loss: Primary outcome collected by telephone ensuring regular personal contact. Secondary data collected by postal questionnaire reducing the number of hospital visits. Telephone reminders, partial withdrawal options, personalised letters and thank you cards. Patient involvement: Acceptability and feasibility consultations with our 2 patient partners. Both have experience of attending the intervention, were co-applicants on the grant proposal and continue to provide the patient perspective as members of the trial management group. Results Recruitment: Target of 300 participants with no recent medication changes and a fatigue level of ≥6 (on a 1–10 scale where 10 is totally exhausted). During the 2 year recruitment phase 333 participants were randomised (11% over target). Intervention delivery: 28/28 programmes successfully delivered with 7/7 sites and 14/15 tutors remaining fully engaged with the study. Attrition and data loss: Retention at 6 months is currently 92.5% (sample size allows for 20% attrition). Data returned by those reaching the 6 month time point is 100% for the primary outcome and 97% for secondary outcomes. Conclusions Advanced planning and consistent application of these strategies has ensured success so far. A flexible and pragmatic approach, regular communication between local and central teams, personal contact with participants and extensive patient partner input are key components. Acknowledgement This work is funded by the NIHR HTA commissioned call [project number 11/112/01] Disclosure of Interest None declared

Background Protein 4.1R is an important component of die red cell membrane skeleton. It imparts structural integrity and has transmembrane signaling roles by direct interactions with transmembrane proteins and other membrane skeletal components, notably p55 and calmodulin. Design and Methods Spontaneous and ligation-induced phosphatidylserine exposure on erythrocytes from two patients with 4.1R deficiency were studied, using CD47 glycoprotein and glycophorin C as ligands We also looked for protein abnormalities in the 4.1R - based multiprotein complex. Results Phosphatidylserine exposure was significantly increased in 4.1R-deficient erythrocytes obtained from the two different individuals when ligands to CD47 glycoprotein were bound. Spontaneous phosphatidylserine exposure was normal. 4.1R, glycophorin C and p55 were missing or sharply reduced. Furthermore there was an alteration or deficiency of CD47 glycoprotein and a lack of CD44 glycoprotein. Based on a recent study in 4.1R-deficient mice, we found that there are clear functional differences between interactions of human red cell 4.1R and its murine counterpart Conclusions Glycophorin C is known to bind 4.1R, and we have defined previously that it also binds CD47 From our evidence, we suggest that 4.1R plays a role in the phosphatidylserine exposure signaling pathway that is of Fundamental importance in red cell turnover The linkage of CD44 to 4.1R may be relevant to this process

Non-invasive prenatal diagnosis (NIPD) offers the opportunity to eliminate completely the risky procedures of amniocentesis and chorionic villus sampling. The development of NIPD tests has largely centred around the isolation and analysis of fetal cells in the maternal circulation and the analysis of free fetal DNA in maternal plasma. Both of these techniques offer difficult technical challenges, and at the current moment in time the use of free fetal DNA is the simplest and most effective method of defining paternally inherited fetal genes for diagnosis. Post-genomics technologies that explore the proteins (proteomics) and transcripts (transcriptomics) released by the placenta into the maternal circulation offer new opportunities to identify genes and their protein products that are key diagnostic markers of disease (in particular Down syndrome), and might replace the current screening markers in use for prediction of risk of Down syndrome. In the ideal situation, these markers are sufficiently diagnostic not to require invasive sampling of fetal genetic material. Post-genomics techniques might also offer better opportunities for defining fetal cell-specific markers that might enhance their isolation from maternal blood samples. This review describes progress in these studies, particularly those funded by the Special Non-invasive Advances in Fetal and Neonatal Evaluation (SAFE) Network of Excellence.

OBJECTIVES: Cardiac surgery with cardiopulmonary bypass and cardioplegic arrest is an effective treatment for coronary artery and aortic valve diseases. However, the myocardium sustains reperfusion injury after ischemic cardioplegic arrest. Our objective was to assess the benefits of supplementing cardioplegia solution with the general anesthetic propofol in patients undergoing either coronary artery bypass grafting (CABG) or aortic valve replacement (AVR).METHODS: A single-center, double-blind randomized controlled trial was carried out to compare cardioplegia solution supplemented with propofol (concentration 6 μg/mL) versus intralipid (placebo). The primary outcome was cardiac troponin T release over the first 48 hours after surgery.RESULTS: We recruited 101 participants (51 in the propofol group, 50 in the intralipid group); 61 underwent CABG and 40 underwent AVR. All participants were followed to 3 months. Cardiac troponin T release was on average 15% lower with propofol supplementation (geometric mean ratio, 0.85; 95% confidence interval [CI], 0.73-1.01; P = .051). There were no differences for CABG participants but propofol-supplemented participants undergoing AVR had poorer postoperative renal function (geometric mean ratio, 1.071; 95% CI, 1.019-1.125; P = .007), with a trend toward longer intensive care stay (median, 89.5 vs 47.0 hours; hazard ratio, 0.58; 95% CI, 0.31-1.09; P = .09) and fewer with perfect health (based on the EQ-5D health utility index) at 3 months (odds ratio, 0.26; 95% CI, 0.06-1.05; P = .058) compared with the intralipid group. Safety profiles were similar. There were no deaths.CONCLUSIONS: Propofol supplementation in cardioplegia appears to be cardioprotective. Its influence on early clinical outcomes may differ between CABG and AVR surgery. A larger, multicenter study is needed to confirm or refute these suggestions.

Introduction Rheumatoid arthritis (RA) fatigue is distressing, leading to unmanageable physical and cognitive exhaustion impacting on health, leisure and work. Group cognitive–behavioural (CB) therapy delivered by a clinical psychologist demonstrated large improvements in fatigue impact. However, few rheumatology teams include a clinical psychologist, therefore, this study aims to examine whether conventional rheumatology teams can reproduce similar results, potentially widening intervention availability. Methods and analysis This is a multicentre, randomised, controlled trial of a group CB intervention for RA fatigue self-management, delivered by local rheumatology clinical teams. 7 centres will each recruit 4 consecutive cohorts of 10–16 patients with RA (fatigue severity ≥6/10). After consenting, patients will have baseline assessments, then usual care (fatigue self-management booklet, discussed for 5–6 min), then be randomised into control (no action) or intervention arms. The intervention, Reducing Arthritis Fatigue by clinical Teams (RAFT) will be cofacilitated by two local rheumatology clinicians (eg, nurse/occupational therapist), who will have had brief training in CB approaches, a RAFT manual and materials, and delivered an observed practice course. Groups of 5–8 patients will attend 6×2 h sessions (weeks 1–6) and a 1 hr consolidation session (week 14) addressing different self-management topics and behaviours. The primary outcome is fatigue impact (26 weeks); secondary outcomes are fatigue severity, coping and multidimensional impact, quality of life, clinical and mood status (to week 104). Statistical and health economic analyses will follow a predetermined plan to establish whether the intervention is clinically and cost-effective. Effects of teaching CB skills to clinicians will be evaluated qualitatively. Ethics and dissemination Approval was given by an NHS Research Ethics Committee, and participants will provide written informed consent. The copyrighted RAFT package will be freely available. Findings will be submitted to the National Institute for Health and Care Excellence, Clinical Commissioning Groups and all UK rheumatology departments. Trial registration number ISRCTN: 52709998; Protocol v3 09.02.2015.

CD47 is a 47–50kDa membrane glycoprotein with 5 known isoforms. The role of CD47 within the erythrocyte membrane remains the subject of much research and debate though we recently provided evidence that CD47 may function as an inducer of eryptosis (Head et al, 2005). As both a cytoskeletal linked fraction and a smaller membrane diffuse fraction of CD47 exists, it is most likely that there are a number of protein species that are able to bind to CD47 at its cytoplasmic face. Our research has focused on a study of the molecular interactions of erythrocyte CD47 with erythrocyte membrane skeletal proteins protein 4.1R (p4.1R), protein 4.2 (p4.2) and p55. Here we demonstrate the ubiquitous expression of all CD47 isoforms in haemopoietic cells and tissues using basic and real-time PCR. Via immunoprecipitation of CD47 from mature erythrocyte membranes using the anti-CD47 mAb BRIC-126, yeast two-hybrid analysis and in vitro co-immunoprecipitation of 35[S] labelled peptides in a cell-free translation procedure, a novel ternary complex involving CD47, p55 and p4.1R has been indicated. More specifically, the potential interaction between p55/p4.1R and the cytoplasmic face of CD47 has been localised to the PDZ and FERM domain of these proteins respectively. Though research suggests p4.2 provides the major cytoskeletal attachment of CD47 (Bruce et al, 2002; Mouro-Chanteloup et al, 2003), a direct interaction between CD47 and p4.2 was not suggested by our study and remains undemonstrated. We continue to further the evidence for a functional role of CD47 in eryptosis. We propose p4.1R links CD47 to the apoptotic machinery of the cell and suggest a mechanism whereby cytoskeletal rearrangement and PS exposure occurs. 4.1null cells have been obtained and are currently being investigated. Further characterisation of the eryptotic pathway may offer insight into potential therapies for erythroleukaemia characterised by resistance of the erythroid lineage to apoptosis. This work has equal significance in the stabilization of red cell preparations in the blood transfusion setting.