A randomized study of pomalidomide vs placebo in persons with myeloproliferative neoplasm-associated myelofibrosis and RBC-transfusion dependence

RBC-transfusion dependence is common in persons with myeloproliferative neoplasm (MPN)-associated myelofibrosis. The objective of this study was to determine the rates of RBC-transfusion independence after therapy with pomalidomide vs placebo in persons with MPN-associated myelofibrosis and RBC-transfusion dependence. Two hundred and fifty-two subjects (intent-to-treat (ITT) population) including 229 subjects confirmed by central review (modified ITT population) were randomly assigned (2:1) to pomalidomide or placebo. Trialists and subjects were blinded to treatment allocation. Primary end point was proportion of subjects achieving RBC-transfusion independence within 6 months. One hundred and fifty-two subjects received pomalidomide and 77 placebo. Response rates were 16% (95% confidence interval (CI), 11, 23%) vs 16% (8, 26% P=0.87). Response in the pomalidomide cohort was associated with ⩽4 U RBC/28 days (odds ratio (OR)=3.1; 0.9, 11.1), age ⩽65 (OR=2.3; 0.9, 5.5) and type of MPN-associated myelofibrosis (OR=2.6; 0.7, 9.5). Responses in the placebo cohort were associated with ⩽4 U RBC/28 days (OR=8.6; 0.9, 82.3), white blood cell at randomization >25 × 10(9)/l (OR=4.9; 0.8, 28.9) and interval from diagnosis to randomization >2 years (OR=4.9; 1.1, 21.9). Pomalidomide was associated with increased rates of oedema and neutropenia but these adverse effects were manageable. Pomalidomide and placebo had similar RBC-transfusion-independence response rates in persons with MPN-associated RBC-transfusion dependence

Determinants of excess mortality following unprotected left main stem percutaneous coronary intervention.

For percutaneous coronary intervention (PCI) to the unprotected left main stem (UPLMS), there are limited long-term outcome data. We evaluated 5-year survival for UPLMS PCI cases taking into account background population mortality.A population-based registry of 10 682 cases of chronic stable angina (CSA), non-ST-segment elevation acute coronary syndrome (NSTEACS), ST-segment elevation myocardial infarction with (STEMI+CS) and without cardiogenic shock (STEMI-CS) who received UPLMS PCI from 2005 to 2014 were matched by age, sex, year of procedure and country to death data for the UK populace of 56.6 million people. Relative survival and excess mortality were estimated.Over 26 105 person-years follow-up, crude 5-year relative survival was 93.8% for CSA, 73.1% for NSTEACS, 77.5% for STEMI-CS and 28.5% for STEMI+CS. The strongest predictor of excess mortality among CSA was renal failure (EMRR 6.73, 95% CI 4.06 to 11.15), and for NSTEACS and STEMI-CS was preprocedural ventilation (6.25, 5.05 to 7.75 and 6.92, 4.25 to 11.26, respectively). For STEMI+CS, the strongest predictor of excess mortality was preprocedural thrombolysis in myocardial infarction (TIMI) 0 flow (2.78, 1.87 to 4.13), whereas multivessel PCI was associated with improved survival (0.74, 0.61 to 0.90).Long-term survival following UPLMS PCI for CSA was high, approached that of the background populace and was significantly predicted by co-morbidity. For NSTEACS and STEMI-CS, the requirement for preprocedural ventilation was the strongest determinant of excess mortality. By contrast, among STEMI+CS, in whom survival was poor, the strongest determinant was preprocedural TIMI flow. Future cardiovascular cohort studies of long-term mortality should consider the impact of non-cardiovascular deaths

Vocation, Belongingness, and Balance: A Qualitative Study of Veterinary Student Well-Being

An elevated risk for suicide among veterinarians has stimulated research into the mental health of the veterinary profession, and more recently attention has turned to the veterinary student population. This qualitative study sought to explore UK veterinary students' perceptions and experiences of university life, and to consider how these may affect well-being. Semi-structured interviews were conducted with 18 students from a single UK school who were purposively selected to include perspectives from male, female, graduate-entry, standard-entry (straight from high school), and widening participation students across all 5 years of the program. Three main themes were identified: a deep-rooted vocation, navigating belongingness, and finding balance. Participants described a long-standing goal of becoming a veterinarian, with a determination reflected by often circuitous routes to veterinary school and little or no consideration of alternatives. Although some had been motivated by a love of animals, others were intrinsically interested in the scientific and problem-solving challenges of veterinary medicine. Most expressed strong feelings of empathy with animal owners. The issue of belongingness was central to participants' experiences, with accounts reflecting their efforts to negotiate a sense of belongingness both in student and professional communities. Participants also frequently expressed a degree of acceptance of poor balance between work and relaxation, with indications of a belief that this imbalance could be rectified later. This study helps highlight future avenues for research and supports initiatives aiming to nurture a sense of collegiality among veterinary students as they progress through training and into the profession

On the Core of Dynamic Cooperative Games

We consider dynamic cooperative games, where the worth of coalitions varies over time according to the history of allocations. When defining the core of a dynamic game, we allow the possibility for coalitions to deviate at any time and thereby to give rise to a new environment. A coalition that considers a deviation needs to take the consequences into account because from the deviation point on, the game is no longer played with the original set of players. The deviating coalition becomes the new grand coalition which, in turn, induces a new dynamic game. The stage games of the new dynamical game depend on all previous allocation including those that have materialized from the deviating time on. We define three types of core solutions: fair core, stable core and credible core. We characterize the first two in case where the instantaneous game depends on the last allocation (rather than on the whole history of allocations) and the third in the general case. The analysis and the results resembles to a great extent the theory of non-cooperative dynamic games.Comment: 25 page

How, in what contexts, and why do quality dashboards lead to improvements in care quality in acute hospitals? Protocol for a realist feasibility evaluation

Introduction: National audits are used to monitor care quality and safety and are anticipated to reduce unexplained variations in quality by stimulating quality improvement (QI). However, variation within and between providers in the extent of engagement with national audits means that the potential for national audit data to inform QI is not being realised. This study will undertake a feasibility evaluation of QualDash, a quality dashboard designed to support clinical teams and managers to explore data from two national audits, the Myocardial Ischaemia National Audit Project (MINAP) and the Paediatric Intensive Care Audit Network (PICANet). Methods and analysis: Realist evaluation, which involves building, testing and refining theories of how an intervention works, provides an overall framework for this feasibility study. Realist hypotheses that describe how, in what contexts, and why QualDash is expected to provide benefit will be tested across five hospitals. A controlled interrupted time series analysis, using key MINAP and PICANet measures, will provide preliminary evidence of the impact of QualDash, while ethnographic observations and interviews over 12 months will provide initial insight into contexts and mechanisms that lead to those impacts. Feasibility outcomes include the extent to which MINAP and PICANet data are used, data completeness in the audits, and the extent to which participants perceive QualDash to be useful and express the intention to continue using it after the study period. Ethics and dissemination: The study has been approved by the University of Leeds School of Healthcare Research Ethics Committee. Study results will provide an initial understanding of how, in what contexts, and why quality dashboards lead to improvements in care quality. These will be disseminated to academic audiences, study participants, hospital IT departments and national audits. If the results show a trial is feasible, we will disseminate the QualDash software through a stepped wedge cluster randomised trial

IgA nephropathy genetic risk score to estimate the prevalence of IgA nephropathy in UK Biobank.

This is the final version. Available fromElsevier via the DOI in this record. BACKGROUND: IgA nephropathy (IgAN) is the commonest glomerulonephritis worldwide. Its prevalence is difficult to estimate, as people with mild disease do not commonly receive a biopsy diagnosis. We aimed to generate an IgA nephropathy genetic risk score (IgAN-GRS) and estimate the proportion of people with hematuria who had IgAN in the UK Biobank (UKBB). METHODS: We calculated an IgAN-GRS using 14 single-nucleotide polymorphisms (SNPs) drawn from the largest European Genome-Wide Association Study (GWAS) and validated the IgAN-GRS in 464 biopsy-proven IgAN European cases from the UK Glomerulonephritis DNA Bank (UKGDB) and in 379,767 Europeans in the UKBB. We used the mean of IgAN-GRS to calculate the proportion of potential IgAN in 14,181 with hematuria and other nonspecific renal phenotypes from 379,767 Europeans in the UKBB. RESULTS: The IgAN-GRS was higher in the IgAN cohort (4.30; 95% confidence interval [95% CI: 4.23-4.38) than in controls (3.98; 3.97-3.98; P < 0.0001). The mean GRS in UKBB participants with hematuria (n = 12,858) was higher (4.04; 4.02-4.06) than UKBB controls (3.98; 3.97-3.98; P < 0.0001) and higher in those with hematuria, hypertension, and microalbuminuria (n = 1323) (4.07; 4.02-4.13) versus (3.98; 3.97-3.98; P = 0.0003). Using the difference in these means, we estimated that IgAN accounted for 19% of noncancer hematuria and 28% with hematuria, hypertension, and microalbuminuria in UKBB. CONCLUSIONS: We used an IgAN-GRS to estimate the prevalence of IgAN contributing to common phenotypes that are not always biopsied. The noninvasive use of polygenic risk in this setting may have further utility to identify likely etiology of nonspecific renal phenotypes in large population cohorts.Diabetes UKDiabetes UKWellcome TrustNational Institute for Health Researc

Using small molecules to facilitate exchange of bicarbonate and chloride anions across liposomal membranes

Bicarbonate is involved in a wide range of biological processes, which include respiration, regulation of intracellular pH and fertilization. In this study we use a combination of NMR spectroscopy and ion-selective electrode techniques to show that the natural product prodigiosin, a tripyrrolic molecule produced by microorganisms such as Streptomyces and Serratia, facilitates chloride/bicarbonate exchange (antiport) across liposomal membranes. Higher concentrations of simple synthetic molecules based on a 4,6-dihydroxyisophthalamide core are also shown to facilitate this antiport process. Although it is well known that proteins regulate Cl-/HCO3- exchange in cells, these results suggest that small molecules may also be able to regulate the concentration of these anions in biological systems

Positive and negative well-being and objectively measured sedentary behaviour in older adults: evidence from three cohorts

Background: Sedentary behaviour is related to poorer health independently of time spent in moderate to vigorous physical activity. The aim of this study was to investigate whether wellbeing or symptoms of anxiety or depression predict sedentary behaviour in older adults. Method: Participants were drawn from the Lothian Birth Cohort 1936 (LBC1936) (n = 271), and the West of Scotland Twenty-07 1950s (n = 309) and 1930s (n = 118) cohorts. Sedentary outcomes, sedentary time, and number of sit-to-stand transitions, were measured with a three-dimensional accelerometer (activPAL activity monitor) worn for 7 days. In the Twenty-07 cohorts, symptoms of anxiety and depression were assessed in 2008 and sedentary outcomes were assessed ~ 8 years later in 2015 and 2016. In the LBC1936 cohort, wellbeing and symptoms of anxiety and depression were assessed concurrently with sedentary behaviour in 2015 and 2016. We tested for an association between wellbeing, anxiety or depression and the sedentary outcomes using multivariate regression analysis. Results: We observed no association between wellbeing or symptoms of anxiety and the sedentary outcomes. Symptoms of depression were positively associated with sedentary time in the LBC1936 and Twenty-07 1950s cohort, and negatively associated with number of sit-to-stand transitions in the LBC1936. Meta-analytic estimates of the association between depressive symptoms and sedentary time or number of sit-to-stand transitions, adjusted for age, sex, BMI, long-standing illness, and education, were β = 0.11 (95% CI = 0.03, 0.18) and β = − 0.11 (95% CI = − 0.19, −0.03) respectively. Conclusion: Our findings indicate that depressive symptoms are positively associated with sedentary behavior. Future studies should investigate the causal direction of this association

A ‘quiet revolution’? The impact of Training Schools on initial teacher training partnerships

This paper discusses the impact on initial teacher training of a new policy initiative in England: the introduction of Training Schools. First, the Training School project is set in context by exploring the evolution of a partnership approach to initial teacher training in England. Ways in which Training Schools represent a break with established practice are considered together with their implications for the dominant mode of partnership led by higher education institutions (HEIs). The capacity of Training Schools to achieve their own policy objectives is examined, especially their efficacy as a strategy for managing innovation and the dissemination of innovation. The paper ends by focusing on a particular Training School project which has adopted an unusual approach to its work and enquires whether this alternative approach could offer a more profitable way forward. During the course of the paper, five different models of partnership are considered: collaborative, complementary, HEI-led, school-led and partnership within a partnership

An extracellular steric seeding mechanism for Eph-ephrin signaling platform assembly

Erythropoetin-producing hepatoma (Eph) receptors are cell-surface protein tyrosine kinases mediating cell-cell communication. Upon activation, they form signaling clusters. We report crystal structures of the full ectodomain of human EphA2 (eEphA2) both alone and in complex with the receptor-binding domain of the ligand ephrinA5 (ephrinA5 RBD). Unliganded eEphA2 forms linear arrays of staggered parallel receptors involving two patches of residues conserved across A-class Ephs. eEphA2-ephrinA5 RBD forms a more elaborate assembly, whose interfaces include the same conserved regions on eEphA2, but rearranged to accommodate ephrinA5 RBD. Cell-surface expression of mutant EphA2s showed that these interfaces are critical for localization at cell-cell contacts and activation-dependent degradation. Our results suggest a 'nucleation' mechanism whereby a limited number of ligand-receptor interactions 'seed' an arrangement of receptors which can propagate into extended signaling arrays