Magnetic core-shell nanoparticles for drug delivery by nebulization

BACKGROUND: Aerosolized therapeutics hold great potential for effective treatment of various diseases including lung cancer. In this context, there is an urgent need to develop novel nanocarriers suitable for drug delivery by nebulization. To address this need, we synthesized and characterized a biocompatible drug delivery vehicle following surface coating of Fe(3)O(4) magnetic nanoparticles (MNPs) with a polymer poly(lactic-co-glycolic acid) (PLGA). The polymeric shell of these engineered nanoparticles was loaded with a potential anti-cancer drug quercetin and their suitability for targeting lung cancer cells via nebulization was evaluated. RESULTS: Average particle size of the developed MNPs and PLGA-MNPs as measured by electron microscopy was 9.6 and 53.2 nm, whereas their hydrodynamic swelling as determined using dynamic light scattering was 54.3 nm and 293.4 nm respectively. Utilizing a series of standardized biological tests incorporating a cell-based automated image acquisition and analysis procedure in combination with real-time impedance sensing, we confirmed that the developed MNP-based nanocarrier system was biocompatible, as no cytotoxicity was observed when up to 100 μg/ml PLGA-MNP was applied to the cultured human lung epithelial cells. Moreover, the PLGA-MNP preparation was well-tolerated in vivo in mice when applied intranasally as measured by glutathione and IL-6 secretion assays after 1, 4, or 7 days post-treatment. To imitate aerosol formation for drug delivery to the lungs, we applied quercitin loaded PLGA-MNPs to the human lung carcinoma cell line A549 following a single round of nebulization. The drug-loaded PLGA-MNPs significantly reduced the number of viable A549 cells, which was comparable when applied either by nebulization or by direct pipetting. CONCLUSION: We have developed a magnetic core-shell nanoparticle-based nanocarrier system and evaluated the feasibility of its drug delivery capability via aerosol administration. This study has implications for targeted delivery of therapeutics and poorly soluble medicinal compounds via inhalation route

Trial Forge Guidance 4 : A guideline for reporting the results of randomised Studies Within A Trial (SWATs)

Acknowledgements We would like to thank those members of the PROMETHEUS programme who are not explicitly named as authors of this publication, but who provided valuable input to the delivery and conduct of the programme within which the guideline development sat. PROMETHEUS programme members include co-authors CA, LK, AP, DB, CC, DD, SG, KG, CH, CS, DT, and ST and P Bower (University of Manchester), L Culliford (University of Bristol), L Doherty (University of York), and R Emsley (Kings College London). We would like to thank public contributors who provided input and comment on earlier versions of this work. We would also like to thank the authors of the previous guidelines for reporting of embedded recruitment trials for their advice and input in the early stages of guideline development and to the independent reviewers and trialists who offered comments and piloting of the draft guideline. Funding Development of the SWAT reporting guideline was initiated as part of The PROMoting THE Use of SWATs (PROMETHEUS) programme, funded by the Medical Research Council (MRC) [grant number MR/R013748/1].Peer reviewe

The People's Trial : supporting the public's understanding of randomised trials

Acknowledgements The People’s Trial team members acknowledge with gratitude the study participants. We would also like to acknowledge and thank Simone Lepage, Aoife O’Shaughnessy, and Louise Foley for their support with the research project. We would also like to thank Rob & Paul Digital Design™, Galway, Ireland. In addition, we would like to thank Marina Zaki for her support of The People’s Trial, in particular her expertise in promoting The People’s Trial through social media channels. Funding This research was funded by the Health Research Board in Ireland, through the Health Research Board – Trials Methodology Research Network as part of a Knowledge Exchange and Dissemination Scheme Award (grant reference KEDS-2018-012) 2018. The funder of the study had no role in the study design, data collection, data analysis, data interpretation or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit.Peer reviewedPublisher PD

Does reading a book in bed make a difference to sleep in comparison to not reading a book in bed? : The People's Trial- an online, pragmatic, randomised trial

Acknowledgements The People’s Trial team members acknowledge with gratitude the study participants. We would also like to acknowledge and thank Claire O’Connell, Simone Lepage, Aoife O’Shaughnessy and Louise Foley for their support with the research project. Trial funder This research was funded by the Health Research Board in Ireland, through the Health Research Board – Trials Methodology Research Network as part of a Knowledge Exchange and Dissemination Scheme Award 2018 (grant reference KEDS-2018-012). The funder of the study had no role in the study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit.Peer reviewedPublisher PD

Undertaking Studies Within A Trial to evaluate recruitment and retention strategies for randomised controlled trials : lessons learnt from the PROMETHEUS research programme

Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 13/55/80) and is published in full in Health Technology Assessment; Vol. 28, No. 2. See the NIHR Funding and Awards website for further award information.Peer reviewedPublisher PD

Clinical Profile of Cardiac Involvement in Danon Disease: A Multicenter European Registry.

Background: The X-linked Danon disease manifests by severe cardiomyopathy, myopathy, and neuropsychiatric problems. We designed this registry to generate a comprehensive picture of clinical presentations and outcome of patients with Danon disease in cardiomyopathy centers throughout Europe. Methods: Clinical and genetic data were collected in 16 cardiology centers from 8 European countries. Results: The cohort comprised 30 male and 27 female patients. The age at diagnosis was birth to 42 years in men and 2 to 65 in women. Cardiac involvement was observed in 96%. Extracardiac manifestations were prominent in men but not in women. Left ventricular (LV) hypertrophy was reported in 73% of male and 74% of female patients. LV systolic dysfunction was reported in 40% of men (who had LV ejection fraction, 34±11%) and 59% of women (LV ejection fraction, 28±13%). The risk of arrhythmia and heart failure was comparable among sexes. The age of first heart failure hospitalization was lower in men (18±6 versus 28±17 years; P<0.003). Heart failure was the leading cause of death (10 of 17; 59%), and LV systolic dysfunction predicted an adverse outcome. Eight men and 8 women (28%) underwent heart transplantation or received an LV assist device. Our cohort suggests better prognosis of female compared with male heart transplant recipients. Conclusions: Danon disease presents earlier in men than in women and runs a malignant course in both sexes, due to cardiac complications. Cardiomyopathy features, heart failure and arrhythmia, are similar among the sexes. Clinical diagnosis and management is extremely challenging in women due to phenotypic diversity and the absence of extracardiac manifestations.pre-print507 K

Identifying and managing patients at risk of severe allergic reactions to food: report from two iFAAM workshops

Food allergy affects a small but important number of children and adults. Much of the morbidity associated with food allergy is driven by the fear of a severe reaction, and fatalities continue to occur. Foods are the commonest cause of anaphylaxis. One of the aims of the European Union funded Integrated Approaches to Food Allergen and Allergy Risk Management (iFAAM) project was to improve the identification and management of children and adults at risk of experiencing a severe reaction. A number of interconnected studies within the project have focused on quantifying the severity of allergic reactions; the impact of food matrix, immunological factors on severity of reactions; the impact of co‐factors such as medications on the severity of reactions; utilising single dose challenges to understand threshold and severity of reactions; and community studies to understand the experience of patients suffering real‐life allergic reactions to food. Associated studies have examined population thresholds, and co‐factors such as exercise and stress. This paper summarises two workshops focused on the severity of allergic reactions to food. It outlines the related studies being undertaken in the project indicating how they are likely to impact on our ability to identify individuals at risk of severe reactions and improve their management

Trial Forge Guidance 1 : what is a Study Within A Trial (SWAT)?

Randomised trials are a central component of all evidence-informed health care systems and the evidence coming from them helps to support health care users, health professionals and others to make more informed decisions about treatment. The evidence available to trialists to support decisions on design, conduct and reporting of randomised trials is, however, sparse. Trial Forge is an initiative that aims to increase the evidence base for trial decision-making and in doing so, to improve trial efficiency.One way to fill gaps in evidence is to run Studies Within A Trial, or SWATs. This guidance document provides a brief definition of SWATs, an explanation of why they are important and some practical 'top tips' that come from existing experience of doing SWATs. We hope the guidance will be useful to trialists, methodologists, funders, approvals agencies and others in making clear what a SWAT is, as well as what is involved in doing one

Undertaking studies within a trial to evaluate recruitment and retention strategies for RCTs : lessons learnt from the PROMETHEUS research programme

Background Randomised controlled trials (‘trials’) are susceptible to poor participant recruitment and retention. Studies Within A Trial (SWATs) are the strongest methods for testing the effectiveness of strategies to improve recruitment and retention. However, relatively few of these have been conducted. Aims PROMoting THE USE of Studies Within A Trial (PROMETHEUS) aimed to facilitate at least 25 SWATs evaluating recruitment or retention strategies. We share our experience of delivering the PROMETHEUS programme, and the lessons learnt for undertaking randomised SWATs. Design A network of 10 Clinical Trials Units (CTUs) and one primary care research centre committed to conducting randomised controlled SWATs of recruitment and/or retention strategies was established. Promising recruitment and retention strategies were identified from various sources including Cochrane systematic reviews, the SWAT Repository, and existing prioritisation exercises, which were reviewed by patient and public (PPI) members to create an initial priority list of seven recruitment and eight retention interventions. Host trial teams could apply for funding and receive support from the PROMETHEUS team to undertake SWATs. We also tested the feasibility of undertaking coordinated SWATs, across multiple host trials simultaneously. Setting CTU-based trials recruiting or following up participants in any setting in the UK were eligible. Participants CTU-based teams undertaking trials in any clinical context in the UK. Interventions Funding of up to £5,000 and support from the PROMETHEUS team to design, implement, and report SWATs. Main outcome measures Number of host trials funde