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Background: Liver disease is the third leading cause of premature death in the UK. Transplantation is the only successful treatment for end-stage liver disease but is limited by a shortage of suitable donor organs. As a result, up to 20% of patients on liver transplant waiting lists die before receiving a transplant. A third of donated livers are not suitable for transplant, often due to steatosis. Hepatic steatosis, which affects 33% of the UK population, is strongly associated with obesity, an increasing problem in the potential donor pool. We have recently tested defatting interventions during normothermic machine perfusion (NMP) in discarded steatotic human livers that were not transplanted. A combination of therapies including forskolin (NKH477) and L-carnitine to defat liver cells and lipoprotein apheresis filtration were investigated. These interventions resulted in functional improvement during perfusion and reduced the intrahepatocellular triglyceride (IHTG) content. We hypothesise that defatting during NMP will allow more steatotic livers to be transplanted with improved outcomes., Methods: In the proposed multi-centre clinical trial, we will randomly assign 60 livers from donors with a high-risk of hepatic steatosis to either NMP alone or NMP with defatting interventions. We aim to test the safety and feasibility of the defatting intervention and will explore efficacy by comparing ex-situ and post-reperfusion liver function between the groups. The primary endpoint will be the proportion of livers that achieve predefined functional criteria during perfusion which indicate potential suitability for transplantation. These criteria reflect hepatic metabolism and injury and include lactate clearance, perfusate pH, glucose metabolism, bile composition, vascular flows and transaminase levels. Clinical secondary endpoints will include proportion of livers transplanted in the two arms, graft function; cell-free DNA (cfDNA) at follow-up visits; patient and graft survival; hospital and ITU stay; evidence of ischemia-reperfusion injury (IRI); non-anastomotic biliary strictures and recurrence of steatosis (determined on MRI at 6 months)., Discussion: This study explores ex-situ pharmacological optimisation of steatotic donor livers during NMP. If the intervention proves effective, it will allow the safe transplantation of livers that are currently very likely to be discarded, thereby reducing waiting list deaths., Trial Registration: ISRCTN ISRCTN14957538. Registered in October 2022., (© 2024. The Author(s).)

Background: Applications of causal inference methods to randomised controlled trial (RCT) data have usually focused on adjusting for compliance with the randomised intervention rather than on using RCT data to address other, non-randomised questions. In this paper we review use of causal inference methods to assess the impact of aspects of patient management other than the randomised intervention in RCTs., Methods: We identified papers that used causal inference methodology in RCT data from Medline, Premedline, Embase, Cochrane Library, and Web of Science from 1986 to September 2014, using a forward citation search of five seminal papers, and a keyword search. We did not include studies where inverse probability weighting was used solely to balance baseline characteristics, adjust for loss to follow-up or adjust for non-compliance to randomised treatment. Studies where the exposure could not be assigned were also excluded., Results: There were 25 papers identified. Nearly half the papers (11/25) estimated the causal effect of concomitant medication on outcome. The remainder were concerned with post-randomisation treatment regimens (sequential treatments, n =5 ), effects of treatment timing (n = 2) and treatment dosing or duration (n = 7). Examples were found in cardiovascular disease (n = 5), HIV (n = 7), cancer (n = 6), mental health (n = 4), paediatrics (n = 2) and transfusion medicine (n = 1). The most common method implemented was a marginal structural model with inverse probability of treatment weighting., Conclusions: Examples of studies which exploit RCT data to address non-randomised questions using causal inference methodology remain relatively limited, despite the growth in methodological development and increasing utilisation in observational studies. Further efforts may be needed to promote use of causal methods to address additional clinical questions within RCTs to maximise their value.

Background: Depressive symptoms are usually managed within primary care and antidepressant medication constitutes the first-line treatment. It remains unclear at present which people are more likely to benefit from antidepressant medication. This paper describes the protocol for a randomised controlled trial (PANDA) to investigate the severity and duration of depressive symptoms that are associated with a clinically significant response to sertraline compared to placebo, in people presenting to primary care with depression., Methods/design: PANDA is a randomised, double blind, placebo controlled trial in which participants are individually randomised to sertraline or placebo. Eligible participants are those who are between the ages of 18 to 74; have presented to primary care with depression or low mood during the past 2 years; have not received antidepressant or anti-anxiety medication in the 8 weeks prior to enrolment in the trial and there is clinical equipoise about the benefits of selective serotonin reuptake inhibitor (SSRI) medication. Participants who consent to participate in the trial are randomised to receive either sertraline or matching placebo, starting at 50 mg daily for 1 week, increasing to 100 mg daily for up to 11 weeks (with the option of increasing to 150 mg if required). Participants, general practitioners (GPs) and the research team will be blind to treatment allocation. The primary outcome will be depressive symptoms measured by the Patient Health Questionnaire-9 (PHQ-9) at 6 weeks post randomisation, measured as a continuous outcome. Secondary outcomes include depressive symptoms measured with the PHQ-9 at 2 and 12 weeks as a continuous outcome and at 2, 6 and 12 weeks as a binary outcome; follow-up scores on depressive symptoms measured with the Beck Depression Inventory-II, anxiety symptoms measured by the Generalized Anxiety Disorder-7 and quality of life measured with the Euroqol-5D-5L and Short Form-12; emotional processing task scores measured at baseline, 2 and 6 weeks; and costs associated with healthcare use, time off work and personal costs., Discussion: The PANDA trial uses a simple self-administered measure to establish the severity and duration of depressive symptoms associated with a clinically significant response to sertraline. The evidence from the trial will inform primary care prescribing practice by identifying which patients are more likely to benefit from antidepressants., Trial Registration: Controlled Trials ISRCTN Registry, ISRCTN84544741 . Registered on 20 March 2014. EudraCT Number: 2013-003440-22; Protocol Number: 13/0413 (version 6.1).