Clinical and epigenetic factors underlying treatment refractory Rheumatoid Arthritis

Rheumatoid Arthritis (RA) is a chronic, progressive, multisystem inflammatory disorder for which there is, at present, no cure. It affects up to 1% of the population resulting in chronic pain, disability and, through loss of function, may lead to loss of employment. It is associated with major co-morbidities that account for premature mortality. There is now extensive published research that suggests early treatment with disease modifying drugs can retard joint damage and improve outcome. In a proportion, drug- free remission is possible. However, there remain both individuals with persistently active disease despite standard drug treatments and those with longstanding disease not exposed to effective early treatment that remain relatively unresponsive to therapy. There is a growing literature that epigenetic modifications may underpin, or at least accelerate the development of many autoimmune disorders. These include alterations in DNA methylation patterns, histone tail modifications, post-translational mRNA regulation by microRNA and combinations therein. Having established the human genome project and underlying human DNA sequence, the recognition of dynamic epigenetic regulation of the genome has added further complexity. Few data however are currently available in ‘real-world’ cohorts of patients. In order to explore the hypothesis that specific epigenetic changes may underpin differences in response to therapy, I first examined the characteristics of a cohort of fifty RA patients with longstanding and active disease (DAS28 >3.2) despite receipt of standard therapies (disease modifying drugs (DMARD) and biologic therapies. This included a detailed examination of clinical characteristics, immune profile, inflammatory markers and burden of co-morbid complications such as vascular disease and depression. Outcomes such as disability, quality of life assessments and fatigue were evaluated by means of previously validated questionnaires. These groups were assessed at baseline, three months and six months. I then measured one of the many epigenetic marks, namely microRNA, of this cohort. We analyzed the accessible profile of peripheral RA CD14+ cell microRNAs in treatment resistant RA patients, in healthy controls, DMARD inadequate responders and DMARD good responders in order to determine the presence of a microRNA profile indicative of biologic resistance. An analysis of the serum cytokine profile of the biologic resistant and DMARD resistant groups was also performed. Finally, to extend the analysis beyond conventional clinical and novel molecular biomarkers the influence of additional patient factors such as coping and illness perception were evaluated by questionnaire to determine subjective disease severity in discrete patient groups. Active inflammatory disease was present as judged by the DAS28 score and there was some improvements seen over the six-month assessment period reflecting treatment changes in all groups. Substantial disability and impaired quality of life was found particularly in the therapeutic resistant group but also in those with inadequate response to DMARD, and remained relatively unresponsive to treatment escalation. Clinical variables, deprivation, quality of life and fatigue were strongly correlated with mood suggesting close interactions and resultant increase in disease activity as measured by the DAS28. Multiple cardiovascular risk factors were determined and, having applied cardiovascular risk scoring systems, unmet treatment of modifiable risk was demonstrated. Exploratory analysis of candidate microRNA -34a, -27b and -125a showed no correlation with clinical or biochemical variables other than swollen joint counts but differential expression between study groups. Exploratory microarray profiling between the four study groups demonstrated a number of differentially regulated microRNA. Of these, a unique microRNA profile of the biologic resistant group was found. MicroRNA-423 and -1275 showed higher expression in the biologic resistant group and fell in parallel with the DAS28 reduction between study visits raising their potential utility as biomarkers. MicroRNA-3178 showed higher relative expression in the biologic resistant group. Cytokine profiles demonstrated significant differences vs healthy controls but biologic resistant, DMARD resistant and DMARD good responder groups were less distinct and individual cytokines failed to discriminate in these study groups. Cytokine profiling did not correlate with observed clinical variables, inflammatory markers nor central processes such as mood or fatigue. Finally, those coping strategies favoured were adaptive and problem based. These were unaffected by the high prevalence of mood disturbance. Conversely, illness perception was influenced by mood and both affected subjective disease assessments. The strong influence of mood and fatigue raise the hypothesis that blunted treatment response may be partially driven by these variables. Ultimately we seek to explain, identify and target those patients with aggressive disease as early intervention may prevent established disease and it's accompanying co-morbid conditions. Undoubtedly, a personalised assessment of disease variables and co-morbid conditions is necessary where treatment response is being evaluated. In such a way, significant cardiovascular morbidity and mortality may be prevented. The question of true biologic resistance remains open. Undoubtedly residual inflammation exists in longstanding RA but significant ‘disease activity’ may be explained at least in part by those subjective clinical variables influenced by both external and internal factors. The identification of a ‘biologic resistant’ microRNA profile could act both as a biomarker of treatment response in longstanding disease, superior to the DAS28 scoring system and, through target identification, better understanding of the regulation of the molecular pathways of inflammation operating in such patients. In this way novel pathways of treatment resistance may be exposed and novel treatment targets revealed. However, mood and thus illness perception also contribute to resistance to therapy and should be sought, characterized, and directly addressed to add to the global improvements in outcome that we seek in a holistic model of care in the rheumatic diseases

Mortality Among Adults With Intellectual Disability in England: Comparisons With the General Population.

OBJECTIVES: To describe mortality among adults with intellectual disability in England in comparison with the general population. METHODS: We conducted a cohort study from 2009 to 2013 using data from 343 general practices. Adults with intellectual disability (n = 16 666; 656 deaths) were compared with age-, gender-, and practice-matched controls (n = 113 562; 1358 deaths). RESULTS: Adults with intellectual disability had higher mortality rates than controls (hazard ratio [HR] = 3.6; 95% confidence interval [CI] = 3.3, 3.9). This risk remained high after adjustment for comorbidity, smoking, and deprivation (HR = 3.1; 95% CI = 2.7, 3.4); it was even higher among adults with intellectual disability and Down syndrome or epilepsy. A total of 37.0% of all deaths among adults with intellectual disability were classified as being amenable to health care intervention, compared with 22.5% in the general population (HR = 5.9; 95% CI = 5.1, 6.8). CONCLUSIONS: Mortality among adults with intellectual disability is markedly elevated in comparison with the general population, with more than a third of deaths potentially amenable to health care interventions. This mortality disparity suggests the need to improve access to, and quality of, health care among people with intellectual disability. (Am J Public Health. Published online ahead of print June 16, 2016: e1-e8. doi:10.2105/AJPH.2016.303240)

Graduate attributes: implications for higher education practice and policy: Introduction

The higher education landscape is shifting under neo-liberal forces that are increasingly aligning the goals of business, government and education. This shift is engendering debate around the world about the role of higher education institutions in producing employable graduates to feed national prosperity in the emerging knowledge economy. As this evolution continues, we need to consider how we enhance generic graduate capabilities as well as the disciplinary expertise of our undergraduate students. Our graduates should possess the knowledge, skills and values to enable them to cope with dynamic employment opportunities, but they must also understand, through the benefits and constraints of their disciplinary perspectives, who they are and how they might contribute positively to the heterogeneity they will encounter in their local, regional and global communities

Translating novel strategies for cardioprotection: the Hatter Workshop Recommendations

Ischemic heart disease (IHD) is the leading cause of death worldwide. Novel cardioprotective strategies are therefore required to improve clinical outcomes in patients with IHD. Although a large number of novel cardioprotective strategies have been discovered in the research laboratory, their translation to the clinical setting has been largely disappointing. The reason for this failure can be attributed to a number of factors including the inadequacy of the animal ischemia–reperfusion injury models used in the preclinical cardioprotection studies and the inappropriate design and execution of the clinical cardioprotection studies. This important issue was the main topic of discussion of the UCL-Hatter Cardiovascular Institute 6th International Cardioprotection Workshop, the outcome of which has been published in this article as the “Hatter Workshop Recommendations”. These have been proposed to provide guidance on the design and execution of both preclinical and clinical cardioprotection studies in order to facilitate the translation of future novel cardioprotective strategies for patient benefit

Variability in a young, L/T transition planetary-mass object

As part of our ongoing NTT SoFI survey for variability in young free-floating planets and low-mass brown dwarfs, we detect significant variability in the young, free-floating planetary-mass object PSO J318.5-22, likely due to rotational modulation of inhomogeneous cloud cover. A member of the 23 ± 3 Myr β Pic moving group, PSO J318.5-22 has Teff = K and a mass estimate of 8.3 ± 0.5 MJup for a 23 ± 3 Myr age. PSO J318.5-22 is intermediate in mass between 51 Eri b and β Pic b, the two known exoplanet companions in the β Pic moving group. With variability amplitudes from 7% to 10% in JS at two separate epochs over 3-5 hr observations, we constrain the rotational period of this object to >5 hr. In KS, we marginally detect a variability trend of up to 3% over a 3 hr observation. This is the first detection of weather on an extrasolar planetary-mass object. Among L dwarfs surveyed at high photometric precision (<3%), this is the highest amplitude variability detection. Given the low surface gravity of this object, the high amplitude preliminarily suggests that such objects may be more variable than their high-mass counterparts, although observations of a larger sample are necessary to confirm this. Measuring similar variability for directly imaged planetary companions is possible with instruments such as SPHERE and GPI and will provide important constraints on formation. Measuring variability at multiple wavelengths can help constrain cloud structure.Peer reviewe

Interaction of Risk Factors, Comorbidities, and Comedications with Ischemia/Reperfusion Injury and Cardioprotection by Preconditioning, Postconditioning, and Remote Conditioning

Pre-, post-, and remote conditioning of the myocardium are well described adaptive responses that markedly enhance the ability of the heart to withstand a prolonged ischemia/reperfusion insult and provide therapeutic paradigms for cardioprotection. Nevertheless, more than 25 years after the discovery of ischemic preconditioning, we still do not have established cardioprotective drugs on the market. Most experimental studies on cardioprotection are still undertaken in animal models, in which ischemia/reperfusion is imposed in the absence of cardiovascular risk factors. However, ischemic heart disease in humans is a complex disorder caused by, or associated with, cardiovascular risk factors and comorbidities, including hypertension, hyperlipidemia, diabetes, insulin resistance, heart failure, altered coronary circulation, and aging. These risk factors induce fundamental alterations in cellular signaling cascades that affect the development of ischemia/reperfusion injury per se and responses to cardioprotective interventions. Moreover, some of the medications used to treat these risk factors, including statins, nitrates, and antidiabetic drugs, may impact cardioprotection by modifying cellular signaling. The aim of this article is to review the recent evidence that cardiovascular risk factors and their medication may modify the response to cardioprotective interventions. We emphasize the critical need to take into account the presence of cardiovascular risk factors and concomitant medications when designing preclinical studies for the identification and validation of cardioprotective drug targets and clinical studies. This will hopefully maximize the success rate of developing rational approaches to effective cardioprotective therapies for the majority of patients with multiple risk factors

The 10th Biennial Hatter Cardiovascular Institute workshop: cellular protection—evaluating new directions in the setting of myocardial infarction, ischaemic stroke, and cardio-oncology

Due to its poor capacity for regeneration, the heart is particularly sensitive to the loss of contractile cardiomyocytes. The onslaught of damage caused by ischaemia and reperfusion, occurring during an acute myocardial infarction and the subsequent reperfusion therapy, can wipe out upwards of a billion cardiomyocytes. A similar program of cell death can cause the irreversible loss of neurons in ischaemic stroke. Similar pathways of lethal cell injury can contribute to other pathologies such as left ventricular dysfunction and heart failure caused by cancer therapy. Consequently, strategies designed to protect the heart from lethal cell injury have the potential to be applicable across all three pathologies. The investigators meeting at the 10th Hatter Cardiovascular Institute workshop examined the parallels between ST-segment elevation myocardial infarction (STEMI), ischaemic stroke, and other pathologies that cause the loss of cardiomyocytes including cancer therapeutic cardiotoxicity. They examined the prospects for protection by remote ischaemic conditioning (RIC) in each scenario, and evaluated impasses and novel opportunities for cellular protection, with the future landscape for RIC in the clinical setting to be determined by the outcome of the large ERIC-PPCI/CONDI2 study. It was agreed that the way forward must include measures to improve experimental methodologies, such that they better reflect the clinical scenario and to judiciously select combinations of therapies targeting specific pathways of cellular death and injury

Evaluating an intervention to improve the safety and experience of transitions from hospital to home for older people (Your Care Needs You) : a protocol for a cluster randomised controlled trial and process evaluation

Background Older patients often experience safety issues when transitioning from hospital to home. The ‘Your Care Needs You’ (YCNY) intervention aims to support older people to‘know more’ and‘do more’ whilst in hospital so that they are better prepared for managing at home. Methods A multi-centre cluster randomised controlled trial (cRCT) will evaluate the efectiveness and cost-efectiveness of the YCNY intervention. Forty acute hospital wards (clusters) in England from varying medical specialities will be randomised to deliver YCNY or care-as-usual on a 1:1 basis. The primary outcome will be unplanned hospital readmission rates within 30 days of discharge. This will be extracted from routinely collected data of at least 5440 patients (aged 75 years and older) discharged to their own homes during the 4- to 5-month YCNY intervention period. A nested cohort of up to 1000 patients will be recruited to the study to collect secondary outcomes via follow-up questionnaires at 5-, 30-and 90-day post-discharge. These will include measures of patient experience of transitions, patient-reported safety events, quality of life and healthcare resource use. Unplanned hospital readmission rates at 60 and 90 days of discharge will be collected from routine data. A process evaluation (primarily interviews and observations with patients, carers and staff) will be conducted to understand the implementation of the intervention and the contextual factors that shape this, as well as the inter- vention’s underlying mechanisms of action. Fidelity of intervention delivery will also be assessed across all intervention wards