A Split-Lung Ex Vivo Perfusion Model for Time- and Cost-Effective Evaluation of Therapeutic Interventions to the Human Donor Lung.

With the ongoing shortage of donor lungs, ex vivo lung perfusion (EVLP) offers the opportunity for objective assessment and potential therapeutic repair of marginal organs. There is a need for robust research on EVLP interventions to increase the number of transplantable organs. The use of human lungs, which have been declined for transplant, for these studies is preferable to animal organs and is indeed essential if clinical translation is to be achieved. However, experimental human EVLP is time-consuming and expensive, limiting the rate at which promising interventions can be assessed. A split-lung EVLP model, which allows stable perfusion and ventilation of two single lungs from the same donor, offers advantages scientifically, financially and in time to yield results. Identical parallel circuits allow one to receive an intervention and the other to act as a control, removing inter-donor variation between study groups. Continuous hemodynamic and airway parameters are recorded and blood gas, perfusate, and tissue sampling are facilitated. Pulmonary edema is assessed directly using ultrasound, and indirectly using the lung tissue wet:dry ratio. Evans blue dye leaks into the tissue and can quantify vascular endothelial permeability. The split-lung ex vivo perfusion model offers a cost-effective, reliable platform for testing therapeutic interventions with relatively small sample sizes.

Nurture Early for Optimal Nutrition (NEON) participatory learning and action women's groups to improve infant feeding and practices in South Asian infants: pilot randomised trial study protocol.

INTRODUCTION: Feeding practices developed in early life can impact a child's nutrition, growth, dental health, cognitive development and lifetime risk of chronic diseases. Substantial evidence suggests ethnic health inequalities, and non-recommended complementary infant feeding practices among UK's South Asian (SA) population. Nurture Early for Optimal Nutrition aims to use women's group participatory learning and action (PLA) cycles to optimise infant feeding, care and dental hygiene practices in SA infants <2 years in East London. METHODS AND ANALYSIS: A three-arm pilot feasibility cluster randomised controlled trial will assess feasibility, acceptability, costs and explore preliminary effectiveness for proposed primary outcome (ie, reporting on body mass index (BMI) z-score). Multilingual SA community facilitators will deliver the intervention, group PLA Cycle, to mothers/carers in respective ethnic/language groups. 12 wards are randomised to face-to-face PLA, online PLA and usual care arms in 1:1:1 ratio. Primary outcomes are feasibility and process measures (ie, BMI z-score, study records, feedback questionnaires, direct observation of intervention and sustainability) for assessment against Go/Stop criteria. Secondary outcomes are cluster-level and economic outcomes (ie, eating behaviour, parental feeding practices, network diffusion, children development performance, level of dental caries, general practitioner utilisation, costs, staff time). Outcomes are measured at baseline, every 2 weeks during intervention, 14 weeks and at 6 months by blinded outcome assessors where possible. This study will use concurrent mixed-methods evaluation. Quantitative analyses include descriptive summary with 95% CI and sample size calculation for the definitive trial. The intervention effect with CI will be estimated for child BMI z-score. Implementation will be evaluated qualitatively using thematic framework analysis. ETHICS AND DISSEMINATION: Ethics approval was obtained from University College London (UCL), National Health Service (Health Research Authority (HRA) and Health and Care Research Wales (HRCW)). Results will be published in peer-reviewed journals, presented at scientific conferences/workshops with commissioners, partners and participating communities. Plain language summaries will be disseminated through community groups, websites and social media. TRIAL REGISTRATION NUMBER: IRAS-ID-296259 (ISRCTN10234623).

Dissecting the Therapeutic Mechanisms of Sphingosine-1-Phosphate Receptor Agonism during Ischaemia and Reperfusion.

Sphingosine 1-phosphate (S1P) and S1P receptors (S1PR) regulate many cellular processes, including lymphocyte migration and endothelial barrier function. As neutrophils are major mediators of inflammation, their transendothelial migration may be the target of therapeutic approaches to inflammatory conditions such as ischaemia-reperfusion injury (IRI). The aim of this project was to assess whether these therapeutic effects are mediated by S1P acting on neutrophils directly or indirectly through the endothelial cells. First, our murine model of peritoneum cell recruitment demonstrated the ability of S1P to reduce CXCL8-mediated neutrophil recruitment. Mechanistic in vitro studies revealed that S1P signals in neutrophils mainly through the S1PR1 and 4 receptors and induces phosphorylation of ERK1/2; however, this had no effect on neutrophil transmigration and adhesion. S1P treatment of endothelial cells significantly reduced TNF-α-induced neutrophil adhesion under flow (p < 0.01) and transendothelial migration towards CXCL8 during in vitro chemotaxis assays (p < 0.05). S1PR1 agonist CYM5442 treatment of endothelial cells also reduced neutrophil transmigration (p < 0.01) and endothelial permeability (p < 0.005), as shown using in vitro permeability assays. S1PR3 agonist had no effects on chemotaxis or permeability. In an in vivo mouse model of renal IRI, S1PR agonism with CYM5442 reduced endothelial permeability as shown by reduced Evan's Blue dye extravasation. Western blot was used to assess phosphorylation at different sites on vascular endothelial (VE)-cadherin and showed that CYM5442 reduced VEGF-mediated phosphorylation. Taken together, the results of this study suggest that reductions in neutrophil infiltration during IRI in response to S1P are mediated primarily by S1PR1 signalling on endothelial cells, possibly by altering phosphorylation of VE-cadherin. The results also demonstrate the therapeutic potential of S1PR1 agonist during IRI.

Developing a community facilitator-led participatory learning and action women's group intervention to improve infant feeding, care and dental hygiene practices in South Asian infants: NEON programme.

INTRODUCTION: The Nurture Early for Optimal Nutrition (NEON) study is a multiphase project that aims to optimize feeding, care and dental hygiene practices in South Asian children <2 years in East London, United Kingdom. The multiphase project uses a participatory learning and action (PLA) approach facilitated by a multilingual community facilitator. In this paper, we elaborate on the process and results of the Intervention Development Phase in the context of the wider NEON programme. METHODS: Qualitative community-based participatory intervention codevelopment and adaptation. SETTING: Community centres in East London and online (Zoom) meetings and workshops. PARTICIPANTS: In total, 32 participants registered to participate in the Intervention Development Phase. Four Intervention Development workshops were held, attended by 25, 17, 20 and 20 participants, respectively. RESULTS: Collaboratively, a culturally sensitive NEON intervention package was developed consisting of (1) PLA group facilitator manual, (2) picture cards detailing recommended and nonrecommended feeding, care and dental hygiene practices with facilitators/barriers to uptake as well as solutions to address these, (3) healthy infant cultural recipes, (4) participatory Community Asset Maps and (5) list of resources and services supporting infant feeding, care and dental hygiene practices. CONCLUSION: The Intervention Development Phase of the NEON programme demonstrates the value of a collaborative approach between researchers, community facilitators and the target population when developing public health interventions. We recommend that interventions to promote infant feeding, care and dental hygiene practices should be codeveloped with communities. Recognizing and taking into account both social and cultural norms may be of particular value for infants from ethnically diverse communities to develop interventions that are both effective in and accepted by these communities. PATIENT AND PUBLIC INVOLVEMENT AND ENGAGEMENT: Considerable efforts were placed on Patient/Participant and Public Involvement and Engagement. Five community facilitators were identified, each of which represented one ethnic/language group: (i) Bangladeshi/Bengali and Sylheti, (ii) Pakistani/Urdu, (iii) Indian/Gujrati, (iv) Indian/Punjabi and (v) Sri Lankan/Tamil. The community facilitators were engaged in every step of the study, from the initial drafting of the protocol and study design to the Intervention Development and refinement of the NEON toolkit, as well as the publication and dissemination of the study findings. More specifically, their role in the Intervention Development Phase of the NEON programme was to: 1. Support the development of the study protocol, information sheets and ethics application. 2. Ensure any documents intended for community members are clear, appropriate and sensitively worded. 3. Develop strategies to troubleshoot any logistical challenges of project delivery, for example, recruitment shortfalls. 4. Contribute to the writing of academic papers, in particular reviewing and revising drafts. 5. Develop plain language summaries and assist in dissemination activities, for example, updates on relevant websites. 6. Contribute to the development of the NEON intervention toolkit and recruitment of the community members. 7. Attend and contribute to Intervention Development workshops, ensuring the participant's voices were the focus of the discussion and workshop outcomes.

Normothermic machine perfusion of donor-lungs ex-vivo: promoting clinical adoption.

PURPOSE OF REVIEW: Lung transplantation offers the only realistic therapeutic option for patients with end-stage lung disease. However, this is impacted by a shortfall in availability of suitable donor-lungs. Normothermic machine perfusion of donor-lungs outside the donor body also known as ex-vivo lung perfusion (EVLP) offers a potential solution through objective assessment, reconditioning and treatment of donor-lungs initially deemed unsuitable for use. This review discusses key advances and challenges in the wider clinical adoption of this technology. RECENT FINDINGS: This review will summarize key research within the following areas: recent clinical trials utilizing EVLP, logistical challenges, EVLP protocol innovations, novel assessment methods and current research into therapeutic modulation of lung function during EVLP. SUMMARY: Normothermic machine perfusion of donor-lungs ex-vivo offers a promising platform to assess and modulate donor-lung quality prior to transplantation. Consensus on how and when to best utilize EVLP is yet to be reached, meaning that widespread clinical adoption of the technology has not yet become a reality. Further work is needed on agreed indications, perfusion protocols and organization of services before becoming a regularly used procedure prior to lung transplantation.