Widespread dysregulation of MiRNAs by MYCN amplification and chromosomal imbalances in neuroblastoma: association of miRNA expression with survival

MiRNAs regulate gene expression at a post-transcriptional level and their dysregulation can play major roles in the pathogenesis of many different forms of cancer, including neuroblastoma, an often fatal paediatric cancer originating from precursor cells of the sympathetic nervous system. We have analyzed a set of neuroblastoma (n = 145) that is broadly representative of the genetic subtypes of this disease for miRNA expression (430 loci by stem-loop RT qPCR) and for DNA copy number alterations (array CGH) to assess miRNA involvement in disease pathogenesis. The tumors were stratified and then randomly split into a training set (n = 96) and a validation set (n = 49) for data analysis. Thirty-seven miRNAs were significantly over-or under-expressed in MYCN amplified tumors relative to MYCN single copy tumors, indicating a potential role for the MYCN transcription factor in either the direct or indirect dysregulation of these loci. In addition, we also determined that there was a highly significant correlation between miRNA expression levels and DNA copy number, indicating a role for large-scale genomic imbalances in the dysregulation of miRNA expression. In order to directly assess whether miRNA expression was predictive of clinical outcome, we used the Random Forest classifier to identify miRNAs that were most significantly associated with poor overall patient survival and developed a 15 miRNA signature that was predictive of overall survival with 72.7% sensitivity and 86.5% specificity in the validation set of tumors. We conclude that there is widespread dysregulation of miRNA expression in neuroblastoma tumors caused by both over-expression of the MYCN transcription factor and by large-scale chromosomal imbalances. MiRNA expression patterns are also predicative of clinical outcome, highlighting the potential for miRNA mediated diagnostics and therapeutics

Pampering, Well-Being And Women’s Bodies In The Therapeutic Spaces Of The Spa

This is an Author's Accepted Manuscript of an article published in Social and Cultural Geography, 2013, Vol. 14 Issue 1 pp. 41-58 © 2012 copyright Taylor & Francis, available online at: http://www.tandfonline.com/ DOI: 10.1080/14649365.2012.734846This paper develops and extends recent work in geography on therapeutic landscapes and the body in an examination of pampering practices in the contemporary spa. Drawing on feminist research on health, gender identity and the body, the paper explores the importance of escape, relaxation and other strategies to combat stress on the well-being practices and routines of women. Using original data collected from interviews in two spas in the South West of England, the paper argues that a visit to the spa is increasingly being seen as an important part of women’s wider health and bodily maintenance providing a space for relaxation and withdrawal from responsibilities of the home and workplace. The pampering treatments reinforce the therapeutic benefits of the spa creating a sense of luxury and a focus on the self. The paper locates these arguments within the twin theoretical concerns of the ‘care of the self’ and disciplining the body, suggesting that any attempts to understand the practices and therapies for maintaining bodily well-being must incorporate a recognition of their simultaneous role in regulating the size and shape of women’s bodies

Exploring haemodynamics of haemodialysis using extrema points analysis model

Background: Haemodialysis is a form of renal replacement therapy used to treat patients with end stage renal failure. It is becoming more appreciated that haemodialysis patients exhibit higher rates of multiple end organ damage compared to the general population. There is also a strong emerging evidence that haemodialysis itself causes circulatory stress. We aimed at examining haemodynamic patterns during haemodialysis using a new model and test that model against a normal control. Methods: We hypothesised that blood pressures generated by each heart beat constantly vary between local peaks and troughs (local extrema), the frequency and amplitude of which is regulated to maintain optimal organ perfusion. We also hypothesised that such model could reveal multiple haemodynamic aberrations during HD. Using a non-invasive cardiac output monitoring device (Finometer®) we compared various haemodynamic parameters using the above model between a haemodialysis patient during a dialysis session and an exercised normal control after comparison at rest. Results: Measurements yielded 29,751 data points for each haemodynamic parameter. Extrema points frequency of mean arterial blood pressure was higher in the HD subject compared to the normal control (0.761Hz IQR 0.5-0.818 vs 0.468Hz IQR 0.223-0.872, P < 0.0001). Similarly, extrema points frequency of systolic blood pressure was significantly higher in haemodialysis compared to normal. In contrary, the frequency of extrema points for TPR was higher in the normal control compared to HD (0.947 IQR 0.520-1.512 vs 0.845 IQR 0.730-1.569, P < 0.0001) with significantly higher amplitudes. Conclusion: Haemodialysis patients potentially exhibit an aberrant haemodynamic behaviour characterised by higher extrema frequencies of mean arterial blood pressure and lower extrema frequencies of total peripheral resistance. This, in theory, could lead to higher variation in organ perfusion and may be detrimental to vulnerable vascular beds

Providing Optimal Nutrition in Critical Care

Malnutrition among hospitalized patients is prevalent and associated with adverse outcomes. At the health care facility for which this quality improvement (QI) initiative was developed, patients were not consistently fed within the nationally recommended 48 hours. The purpose of this project was to facilitate the early initiation of enteral feedings to prevent malnutrition in a vulnerable patient group by development of an evidence-based enteral feeding policy, algorithm, and nursing education module. The find, organize, clarify, understand, select, plan, do, check, and act model provided a systematic approach for development of the project. Validation of the QI initiative was through the use of Likert scale which was completed by 2 nurses and a head dietician. The content validity index average was 1.0 for the QI initiative products (policy, algorithm, educational module). Ten team members completed a summative evaluation of the educational module and presentation using a 7 item, Likert scale. Basic descriptive analyses were employed to analyze the data, revealing broad support for the module and the DNP student\u27s leadership. A recommendation was made to conduct an audit using a formal software program to quantify the number of patients who were not being fed within the time frame of 48 hours. Implementing an evidence-based enteral feeding protocol can be a significant intervention that produces better patient outcomes.The implications for social change in this project relates to improvements within the critical care environment

Financial considerations in the conduct of multi-centre randomised controlled trials: evidence from a qualitative study.

National Coordinating Centre for Research Methodology; Medical Research Council, UK Department of Health; Chief Scientist OfficeNot peer reviewedPublisher PD

Lets Talk about Race: Identity, Chatbots, and AI

Why is it so hard for chatbots to talk about race? This work explores how the biased contents of databases, the syntactic focus of natural language processing, and the opaque nature of deep learning algorithms cause chatbots difficulty in handling race-talk. In each of these areas, the tensions between race and chatbots create new opportunities for people and machines. By making the abstract and disparate qualities of this problem space tangible, we can develop chatbots that are more capable of handling race-talk in its many forms. Our goal is to provide the HCI community with ways to begin addressing the question, how can chatbots handle race-talk in new and improved ways

The eClinical Care Pathway Framework: A novel structure for creation of online complex clinical care pathways and its application in the management of sexually transmitted infections.

Despite considerable international eHealth impetus, there is no guidance on the development of online clinical care pathways. Advances in diagnostics now enable self-testing with home diagnosis, to which comprehensive online clinical care could be linked, facilitating completely self-directed, remote care. We describe a new framework for developing complex online clinical care pathways and its application to clinical management of people with genital chlamydia infection, the commonest sexually transmitted infection (STI) in England.Using the existing evidence-base, guidelines and examples from contemporary clinical practice, we developed the eClinical Care Pathway Framework, a nine-step iterative process. Step 1: define the aims of the online pathway; Step 2: define the functional units; Step 3: draft the clinical consultation; Step 4: expert review; Step 5: cognitive testing; Step 6: user-centred interface testing; Step 7: specification development; Step 8: software testing, usability testing and further comprehension testing; Step 9: piloting. We then applied the Framework to create a chlamydia online clinical care pathway (Online Chlamydia Pathway).Use of the Framework elucidated content and structure of the care pathway and identified the need for significant changes in sequences of care (Traditional: history, diagnosis, information versus Online: diagnosis, information, history) and prescribing safety assessment. The Framework met the needs of complex STI management and enabled development of a multi-faceted, fully-automated consultation.The Framework provides a comprehensive structure on which complex online care pathways such as those needed for STI management, which involve clinical services, public health surveillance functions and third party (sexual partner) management, can be developed to meet national clinical and public health standards. The Online Chlamydia Pathway's standardised method of collecting data on demographics and sexual behaviour, with potential for interoperability with surveillance systems, could be a powerful tool for public health and clinical management.UKCRC Translational Infection Research (TIR) Initiative supported by the Medical Research Council, eSTI2 Consortium (Grant Number G0901608)

Multicentre randomised controlled trial: protocol for Plasma-Lyte Usage and Assessment of Kidney Transplant Outcomes in Children (PLUTO)

INTRODUCTION: Acute electrolyte and acid-base imbalance is experienced by many children following kidney transplantation. When severe, this can lead to complications including seizures, cerebral oedema and death. Relatively large volumes of intravenous fluid are administered to children perioperatively in order to establish perfusion to the donor kidney, the majority of which are from living and deceased adult donors. Hypotonic intravenous fluid is commonly used in the post-transplant period due to clinicians' concerns about the sodium, chloride and potassium content of isotonic alternatives when administered in large volumes.Plasma-Lyte 148 is an isotonic, balanced intravenous fluid that contains sodium, chloride, potassium and magnesium with concentrations equivalent to those of plasma. There is a physiological basis to expect that Plasma-Lyte 148 will reduce the incidence of clinically significant electrolyte and acid-base abnormalities in children following kidney transplantation compared with current practice.The aim of the Plasma-Lyte Usage and Assessment of Kidney Transplant Outcomes in Children (PLUTO) trial was to determine whether the incidence of clinically significantly abnormal plasma electrolyte levels in paediatric kidney transplant recipients will be different with the use of Plasma-Lyte 148 compared with intravenous fluid currently administered. METHODS AND ANALYSIS: PLUTO is a pragmatic, open-label, randomised controlled trial comparing Plasma-Lyte 148 to current care in paediatric kidney transplant recipients, conducted in nine UK paediatric kidney transplant centres.A total of 144 children receiving kidney transplants will be randomised to receive either Plasma-Lyte 148 (the intervention) intraoperatively and postoperatively, or current fluid. Apart from intravenous fluid composition, all participants will receive standard clinical transplant care.The primary outcome measure is acute hyponatraemia in the first 72 hours post-transplant, defined as laboratory plasma sodium concentration of <135 mmol/L. Secondary outcomes include symptoms of acute hyponatraemia, other electrolyte and acid-base imbalances and transplant kidney function.The primary outcome will be analysed using a logistic regression model adjusting for donor type (living vs deceased donor), patient weight (<20 kg vs ≥20 kg pretransplant) and transplant centre as a random effect. ETHICS AND DISSEMINATION: The trial received Health Research Authority approval on 20 January 2020. Findings will be presented to academic groups via national and international conferences and peer-reviewed journals. The patient and public involvement group will play an important part in disseminating the study findings to the public domain

The COVID-19 emergency response assessment study: a prospective longitudinal survey of frontline doctors in the UK and Ireland

OBJECTIVES: The psychological impact of the COVID-19 pandemic on doctors is a significant concern. Due to the emergence of multiple pandemic waves, longitudinal data on the impact of COVID-19 are vital to ensure an adequate psychological care response. The primary aim was to assess the prevalence and degree of psychological distress and trauma in frontline doctors during the acceleration, peak and deceleration of the COVID-19 first wave. Personal and professional factors associated with psychological distress are also reported. DESIGN: A prospective online three-part longitudinal survey. SETTING: Acute hospitals in the UK and Ireland. PARTICIPANTS: Frontline doctors working in emergency medicine, anaesthetics and intensive care medicine during the first wave of the COVID-19 pandemic in March 2020. PRIMARY OUTCOME MEASURES: Psychological distress and trauma measured using the General Health Questionnaire-12 and the Impact of Events-Revised. RESULTS: The initial acceleration survey distributed across networks generated a sample of 5440 doctors. Peak and deceleration response rates from the original sample were 71.6% (n=3896) and 56.6% (n=3079), respectively. Prevalence of psychological distress was 44.7% (n=1334) during the acceleration, 36.9% (n=1098) at peak and 31.5% (n=918) at the deceleration phase. The prevalence of trauma was 23.7% (n=647) at peak and 17.7% (n=484) at deceleration. The prevalence of probable post-traumatic stress disorder was 12.6% (n=343) at peak and 10.1% (n=276) at deceleration. Worry of family infection due to clinical work was the factor most strongly associated with both distress (R(2)=0.06) and trauma (R(2)=0.10). CONCLUSION: Findings reflect a pattern of elevated distress at acceleration and peak, with some natural recovery. It is essential that policymakers seek to prevent future adverse effects through (a) provision of vital equipment to mitigate physical and psychological harm, (b) increased awareness and recognition of signs of psychological distress and (c) the development of clear pathways to effective psychological care. TRIAL REGISTRATION NUMBER: ISRCTN10666798

Research priorities for cancers of the oesophagus and stomach: recommendations from a UK and Ireland patient and healthcare professional partnership exercise

Background: Cancers of the oesophagus and stomach are a major cause of morbidity and mortality. Research is crucial to improving outcomes. However, to maximise value and impact, areas of focus should be prioritised in partnership with patients. Objective: We undertook a comprehensive analysis of UK and Ireland patient and healthcare professional (HCP) priorities for research into oesophagogastric cancers across the domains of prevention, diagnosis and staging, treatment, palliative care and survivorship. Design: A scoping exercise sourced research questions from patients and HCPs. These were consolidated and then confirmed by systematic review to represent a true research uncertainty. Research questions were scored on potential impact by an interdisciplinary group of HCPs and prioritised using a weighting derived from a patient survey. Results: There were 835 (395 HCP, 440 patient) respondents to the scoping (n=455) and prioritisation (n=380) surveys. Across these, 4295 suggested research uncertainties were consolidated to 92 uncertainties that were prioritised. HCP respondents represented 25 professional groups from community and hospital settings. Patient weighting changed 22.2–46.3% of priority rankings established by HCPs. All domains were represented by the 20 highest priority questions, 5 of which focused on personalising and optimally combining treatment modalities. Two other key themes related to optimising nutrition and improving quality of life during and after treatment, including in patients not cured of their cancer. Conclusion: This work highlights the impact of patient input on HCP-ranked research priorities and provides a robust list of priorities to guide funders, policymakers and researchers to support and undertake impactful research