Epeleuton, a novel synthetic ω-3 fatty acid, reduces hypoxia/ reperfusion stress in a mouse model of sickle cell disease

Inflammatory vasculopathy is critical in sickle cell disease (SCD)-associated organ damage. An imbalance between pro-inflammatory and pro-resolving mechanisms in response to different triggers such as hypoxia/reoxygenation or infections has been proposed to contribute to the progression of SCD. Administration of specialized pro-resolving lipid mediators may provide an effective therapeutic strategy to target inflammatory vasculopathy and to modulate inflammatory response. Epeleuton (15 hydroxy eicosapentaenoic acid ethyl ester) is a novel, orally administered, second-generation ω-3 fatty acid with a favorable clinical safety profile. In this study we show that epeleuton re-programs the lipidomic pattern of target organs for SCD towards a pro-resolving pattern. This protects against systemic and local inflammatory responses and improves red cell features, resulting in reduced hemolysis and sickling compared with that in vehicle-treated SCD mice. In addition, epeleuton prevents hypoxia/reoxygenation-induced activation of nuclear factor-κB with downregulation of the NLRP3 inflammasome in lung, kidney, and liver. This was associated with downregulation of markers of vascular activation in epeleuton-treated SCD mice when compared to vehicle-treated animals. Collectively our data support the potential therapeutic utility of epeleuton and provide the rationale for the design of clinical trials to evaluate the efficacy of epeleuton in patients with SCD

Children’s unscheduled primary and emergency care in Ireland: a multimethod approach to understanding decision making, trends, outcomes and parental perspectives (CUPID): project protocol

Introduction: The aim of this project is to determine the patterns, decision-making processes and parental preferences associated with unscheduled paediatric healthcare utilisation in Ireland. Unscheduled paediatric healthcare is outpatient care provided within primary care settings by general practitioners (GPs), emergency departments (EDs) located in paediatric and general hospitals, and out-of-hours services provided by cooperatives of GPs operating on a regional basis. This project will take a multimethod approach to analysing the utilisation of unscheduled paediatric healthcare nationally within the context of a significant change to the provision of healthcare for young children in Ireland-the introduction of free at the point of delivery GP care for all children aged under 6. Methods and analysis: A multimethod approach consisting of three work packages will be employed. Using patient-level data, work package 1 will describe patterns of attendance at primary care, out-of-hours medical services and at EDs. Applying a difference-in-difference methodology, the impact of the introduction of free GP care for children under 6 on attendance will be assessed. Work package 2 will explore geospatial trends of attendance at EDs, identifying disparities in ED attendance by local area and demographic characteristics. Work package 3 will employ two discrete choice experiments to examine parental preferences for unscheduled paediatric healthcare and GP decision making when referring a child to the ED. The insights gained by each of the work packages individually and collectively will inform evidence-based health policy for the organisation of paediatric care and resource allocation. Ethics and dissemination: Ethical approval for this research has been granted by University College Dublin, The Irish College of General Practitioners and the five participating hospitals. Results will be disseminated via publication in peer-reviewed journals, national and international conferences, and to relevant stakeholders and interest groups

Developing outcome, process and balancing measures for an emergency department longitudinal patient monitoring system using a modified Delphi

Background: Early warning score systems have been widely recommended for use to detect clinical deterioration in patients. The Irish National Emergency Medicine Programme has developed and piloted an emergency department specific early warning score system. The objective of this study was to develop a consensus among frontline healthcare staff, quality and safety staff and health systems researchers regarding evaluation measures for an early warning score system in the Emergency Department.Methods: Participatory action research including a modified Delphi consensus building technique with frontline hospital staff, quality and safety staff, health systems researchers, local and national emergency medicine stakeholders was the method employed in this study. In Stage One, a workshop was held with the participatory action research team including frontline hospital staff, quality and safety staff and health systems researchers to gather suggestions regarding the evaluation measures. In Stage Two, an electronic modified-Delphi study was undertaken with a panel consisting of the workshop participants, key local and national emergency medicine stakeholders. Descriptive statistics were used to summarise the characteristics of the panellists who completed the questionnaires in each round. The mean Likert rating, standard deviation and 95% bias-corrected bootstrapped confidence interval for each variable was calculated. Bonferroni corrections were applied to take account of multiple testing. Data were analysed using Stata 14.0 SE.Results: Using the Institute for Healthcare Improvement framework, 12 process, outcome and balancing metrics for measuring the effectiveness of an ED-specific early warning score system were developed.Conclusion: There are currently no published measures for evaluating the effectiveness of an ED early warning score system. It was possible in this study to develop a suite of evaluation measures using a modified Delphi consensus approach. Using the collective expertise of frontline hospital staff, quality and safety staff and health systems researchers to develop and categorise the initial set of potential measures was an innovative and unique element of this study.Keywords: Emergency department, Early warning score system, Longitudinal patient monitoring, Evaluation measure

Epeleuton, a novel synthetic ω-3 fatty acid, reduces hypoxia/ reperfusion stress in a mouse model of sickle cell disease

Inflammatory vasculopathy is critical in sickle cell disease (SCD)-associated organ damage. An imbalance between pro-inflammatory and pro-resolving mechanisms in response to different triggers such as hypoxia/reoxygenation or infections has been proposed to contribute to the progression of SCD. Administration of specialized pro-resolving lipid mediators may provide an effective therapeutic strategy to target inflammatory vasculopathy and to modulate inflammatory response. Epeleuton (15 hydroxy eicosapentaenoic acid ethyl ester) is a novel, orally administered, second-generation ω-3 fatty acid with a favorable clinical safety profile. In this study we show that epeleuton re-programs the lipidomic pattern of target organs for SCD towards a pro-resolving pattern. This protects against systemic and local inflammatory responses and improves red cell features, resulting in reduced hemolysis and sickling compared with that in vehicle-treated SCD mice. In addition, epeleuton prevents hypoxia/reoxygenation-induced activation of nuclear factor-κB with downregulation of the NLRP3 inflammasome in lung, kidney, and liver. This was associated with downregulation of markers of vascular activation in epeleuton-treated SCD mice when compared to vehicle-treated animals. Collectively our data support the potential therapeutic utility of epeleuton and provide the rationale for the design of clinical trials to evaluate the efficacy of epeleuton in patients with SCD

The co-design, implementation and evaluation of a serious board game ‘PlayDecide patient safety’ to educate junior doctors about patient safety and the importance of reporting safety concerns

Background: We believe junior doctors are in a unique position in relation to reporting of incidents and safety culture. They are still in training and are also ‘fresh eyes’ on the system providing valuable insights into what they perceive as safe and unsafe behaviour. The aim of this study was to co-design and implement an embedded learning intervention – a serious board game – to educate junior doctors about patient safety and the importance of reporting safety concerns, while at the same time shaping a culture of responsiveness from senior medical staff. Methods: A serious game based on the PlayDecide framework was co-designed and implemented in two large urban acute teaching hospitals. To evaluate the educational value of the game voting on the position statements was recorded at the end of each game by a facilitator who also took notes after the game of key themes that emerged from the discussion. A sample of players were invited on a voluntary basis to take part in semi-structured interviews after playing the game using Flanagan’s Critical Incident Technique. A paper-based questionnaire on ‘Safety Concerns’ was developed and administered to assess pre-and post-playing the game reporting behaviour. Dissemination workshops were held with senior clinicians to promote more inclusive leadership behaviours and responsiveness to junior doctors raising of safety concerns from senior clinicians. Results: The game proved to be a valuable patient safety educational tool and proved effective in encouraging deep discussion on patient safety. There was a significant change in the reporting behaviour of junior doctors in one of the hospitals following the intervention. Conclusion: In healthcare, limited exposure to patient safety training and narrow understanding of safety compromise patients lives. The existing healthcare system needs to value the role that junior doctors and others could play in shaping a positive safety culture where reporting of all safety concerns is encouraged. Greater efforts need to be made at hospital level to develop a more pro-active safe and just culture that supports and encourages junior doctors and ultimately all doctors to understand and speak up about safety concerns.Health Research BoardHealth Service ExecutiveMedical Council of Ireland - Medical Education Research Grant (MERG) Award

Effects of Epeleuton, a Novel Synthetic Second-Generation n-3 Fatty Acid, on Non-Alcoholic Fatty Liver Disease, Triglycerides, Glycemic Control, and Cardiometabolic and Inflammatory Markers.

Background Epeleuton is 15-hydroxy eicosapentaenoic acid ethyl ester, a second-generation synthetic n-3 fatty acid derivative of eicosapentaenoic acid. The primary objective was to assess the effect of epeleuton on markers of nonalcoholic fatty liver disease (NAFLD) with post hoc analyses of cardiometabolic markers. Methods and Results In a multicenter, randomized, double-blind, placebo-controlled trial, 96 adults with nonalcoholic fatty liver disease and body mass index 25 to 40 were randomized in a 1:1:1 ratio to receive epeleuton 2 g/day, epeleuton 1 g/day, or placebo for 16 weeks. A total of 27% of patients had diabetes mellitus. Primary end points of changes in alanine aminotransferase and liver stiffness did not improve at week 16. Secondary and post hoc analyses investigated changes in cardiometabolic markers. Epeleuton 2 g/day significantly decreased triglycerides, very-low-density lipoprotein cholesterol, and total cholesterol without increasing low-density lipoprotein cholesterol. Despite a low mean baseline hemoglobin A1C (HbA; 6.3±1.3%), epeleuton 2 g/day significantly decreased HbA (-0.4%; =0.026). Among patients with baseline HbA >6.5%, epeleuton 2 g/day decreased HbA by 1.1% (=0.047; n=26). Consistent dose-dependent reductions were observed for fasting plasma glucose, insulin, and insulin resistance indices. Epeleuton 2 g/day decreased circulating markers of cardiovascular risk and endothelial dysfunction. Epeleuton was well tolerated, with a safety profile not different from placebo. Conclusions While epeleuton did not meet its primary end points on alanine aminotransferase or liver stiffness, it significantly decreased triglycerides, HbA, plasma glucose, and inflammatory markers. These data suggest epeleuton may have potential for cardiovascular risk reduction and nonalcoholic fatty liver disease by simultaneously targeting hypertriglyceridemia, hyperglycemia, and systemic inflammation. Further trials are planned. Registration URL: https://www.clini​caltr​ials.gov; Unique identifier: NCT02941549

Factors that influence family and parental preferences and decision making for unscheduled paediatric healthcare: a systematic review protocol

There is a plethora of factors that dictate where parents and families choose to seek unscheduled healthcare for their child; and the complexity of these decisions can present a challenge for policy makers and healthcare planners as these behaviours can have a significant impact on resources in the health system. The systematic review will seek to identify the factors that influence parents' and families' preferences and decision making when seeking unscheduled paediatric healthcare.  Five databases will be searched for published studies (CINAHL, PubMed, SCOPUS, PsycInfo, EconLit) and grey literature will also be searched. Inclusion and exclusion criteria will be applied and articles assessed for quality. A narrative approach will be used to synthesise the evidence that emerges from the review. By collating the factors that influence decision-making and attendance at these services, the review can inform future health policies and strategies seeking to expand primary care to support the provision of accessible and responsive care. The systematic review will also inform the design of a discrete choice experiment (DCE) which will seek to determine parental and family preferences for unscheduled paediatric healthcare. Policies such as Sláintecare that seek to expand primary care and reduce hospital admissions from emergency departments need to be cognisant of the nuanced and complex factors that govern patients' behaviour