FAecal micRobiota transplantation in primary sclerosinG chOlangitis (FARGO): study protocol for a randomised, multicentre, phase IIa, placebo-controlled trial

Introduction
Primary sclerosing cholangitis (PSC) is the classical hepatobiliary manifestation of inflammatory bowel disease (IBD). The strong association between gut and liver inflammation has driven several pathogenic hypotheses to which the intestinal microbiome is proposed to contribute. Pilot studies of faecal microbiota transplantation (FMT) in PSC and IBD are demonstrated to be safe and associated with increased gut bacterial diversity. However, the longevity of such changes and the impact on markers of disease activity and disease progression have not been studied. The aim of this clinical trial is to determine the effects of repeated FMT as a treatment for PSC-IBD.

Methods and analysis
FAecal micRobiota transplantation in primary sclerosinG chOlangitis (FARGO) is a phase IIa randomised placebo-controlled trial to assess the efficacy and safety of repeated colonic administration of FMT in patients with non-cirrhotic PSC-IBD. Fifty-eight patients will be recruited from six sites across England and randomised in a 1:1 ratio between active FMT or FMT placebo arms. FMT will be manufactured by the University of Birmingham Microbiome Treatment Centre, using stool collected from rigorously screened healthy donors. A total of 8 weekly treatments will be delivered; the first through colonoscopic administration (week 1) and the remaining seven via once-weekly enema (up to week 8). Participants will then be followed on a 12-weekly basis until week 48 from the first treatment visit. The primary efficacy outcome will be to determine the effect of FMT on serum alkaline phosphatase values over time (end of study at 48 weeks). Key secondary outcomes will be to evaluate the impact of FMT on other liver biochemical parameters, PSC risk scores, circulating and imaging markers of liver fibrosis, health-related quality of life measures, IBD activity and the incidence of PSC-related clinical events. Key translational objectives will be to identify mucosal metagenomic, metatranscriptomic, metabolomic and immunological pathways associated with the administration of FMT.

Ethics and dissemination
The protocol was approved by the South Central—Hampshire B Research Ethics Committee (REC 23/SC/0147). Participants will be required to provide written informed consent. The results of this trial will be disseminated through national and international presentations and peer-reviewed publications.

Trial registration number
The trial was registered at ClinicalTrials.gov on 23 February 2024 (NCT06286709). Weblink: Study Details | FAecal Microbiota Transplantation in primaRy sclerosinG chOlangitis | ClinicalTrials.gov.

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Endometriosis and Ovarian Cancer

To the Editor As noted by Dr Barnard and colleagues, existing evidence confirms that endometriosis is associated with an elevated risk of ovarian cancer with differences by histotype. However, despite the varying presentations of endometriosis—most notably 3 macrosurgically visualized subphenotypes (endometriomas, superficial peritoneal, and/or deep lesions)—identifying women with endometriosis who are at high risk remains elusive. To address this question, the investigators leveraged data from the Utah Population Database and defined endometriosis subphenotypes by International Classification of Diseases (ICD) codes documented from 1992 to 2019 in more than 450 000 women. A consistent challenge in registry-based studies has been the selection of a comparison group. As demonstrated by Hermens et al in the Dutch nationwide registry, women diagnosed with ovarian cancer may be concurrently diagnosed with endometriosis, biasing estimated risk compared with members of the general population, who typically have not had pelvic surgery and whose endometriosis is more likely to remain undetected, leading to an observed 29 (95% CI, 20.7-40.9) times greater risk of endometrioid ovarian cancer (incident rate per 100 000 person-years, 29.7) when they included concurrent endometriosis diagnosis, but a much lower 2.6 (95% CI, 1.5-4.5)–fold greater risk when they excluded endometriosis diagnosed within 1 year of a diagnosis of ovarian cancer (incident rate per 100 000 person-years, 4.1). Unfortunately, Barnard and colleagues did not exclude concurrent diagnoses of ovarian cancer and endometriosis (17% of endometriosis and ovarian cancer diagnoses were within 5 mm under the peritoneal surface). Furthermore, since deep lesions were combined with endometriomas, the reader is unable to distinguish the true ovarian cancer risk for women with endometriomas vs deep lesions. Ultimately, the results may encourage clinicians to advise women with endometriomas or deep endometriosis toward prophylactic bilateral oophorectomy based on an overestimation of the true risk. Such an approach disregards the growing evidence of harm caused by inducing early menopause unnecessarily, including elevated risk of cardiovascular disease, bone fracture, and Alzheimer disease. As this is an essential question for women’s health, a reanalysis of the data are needed to guide women and clinicians in understanding a realistic estimation of their ovarian cancer risk and valid attribution to an accurately defined endometriosis subtype.

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Intestinal Microbiota Transplant Prior to Allogeneic Stem Cell Transplant (MAST) trial: study protocol for a multicentre, double-blinded, placebo-controlled, phase IIa trial

Introduction
Lower diversity of the gut microbiome prior to allogeneic haematopoietic cell transplantation (HCT) correlates with reduced survival after the intervention. Most patients undergoing HCT for a haematological malignancy have previously received intensive chemotherapy, resulting in prolonged neutropenic episodes requiring broad-spectrum antibiotics; use of these has been linked to reduced microbiome diversity. Intestinal microbiota transplant (IMT) is a novel treatment approach that restores this diversity. We hypothesised that IMT performed prior to initiation of HCT conditioning restores microbiome diversity during the early stages of HCT, leading to decreased frequency of complications and improved outcomes of HCT.

Methods and analysis
50 adult patients receiving allogeneic HCT will be recruited into this phase IIa trial and randomised 1:1 to receive capsulised IMT or matched placebo shortly prior to initiation of HCT conditioning and followed for up to 12 months. The primary outcome will be to assess the increase in alpha diversity between pre-IMT and that measured at ~42 days after IMT administration (day +28 of HCT), comparing the difference between patients receiving IMT compared with placebo. Secondary outcomes will include tolerability, the dynamics of gut microbiome diversity metrics and taxonomy over all time points assessed, as well as clinical outcomes (including burden of invasive infections, days of fever, admission to intensive care, development of graft-vs-host disease and mortality).

Ethics and dissemination
This study was approved by a UK Research Ethics Committee (REC reference: 23/NE/0105). Dissemination of results will be in concert with patient and public involvement group input and is expected to be primarily via abstract presentation at conferences and manuscripts in peer-reviewed journals.

Trial registration numbers
NCT6355583; EudraCT: 2022-003617-10.

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Acute effect of a Mediterranean-style dietary pattern (MDP) on mood, anxiety and cognition in UK adults with mild to moderate anxiety and depression: the MediMood randomised controlled trial protocol

Introduction
Psychological disorders including depression and anxiety are significant public health concerns. A Mediterranean-style dietary pattern (MDP) has been associated with improved mental well-being in observational studies. Evidence of the acute (defined as postprandial to 1 week) effects of an MDP on brain function, mood, cognition and important modulators, including sleep and the gut microbiota is limited. The current intervention aims to examine whether an MDP, compared with a Western diet (WD), improves mood, cognition and anxiety symptoms, postprandially, at 24-hour and after 5 days in adults with mild to moderate anxiety and depression.

Methods and analysis
Twenty-five UK adults (aged 18 or over) with mild to moderate anxiety and/or depression and low adherence to an MDP were recruited to a cross-over randomised controlled trial. Each participant undergoes a 5 day MDP and a 5 day WD in a randomised order with all meals provided. The co-primary outcomes are mood and anxiety, with secondary outcomes including cognitive function, brain perfusion (as assessed by MRI), sleep quality, blood pressure, plasma glucose, insulin, lipids, C-reactive protein, cortisol, brain-derived neurotrophic factor, gut microbiota speciation and microbial metabolites including short chain fatty acids. A linear mixed model and/or paired analysis will be used to compare the effects of treatments over time.

Ethics and dissemination
The study has received a favourable ethics opinion from the National Health Service London Queen Square Research Ethics Committee (22/LO/0796). The results will be disseminated through scientific journals and conferences.

Trial registration number
NCT05927376.

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Advancement in predictive biomarkers for gestational diabetes mellitus diagnosis and related outcomes: a scoping review

Objective
Gestational diabetes mellitus (GDM) is a metabolic disorder associated with adverse maternal and neonatal outcomes. While GDM is diagnosed by oral glucose tolerance testing between 24–28 weeks, earlier prediction of risk of developing GDM via circulating biomarkers has the potential to risk-stratify women and implement targeted risk reduction before adverse obstetric outcomes. This scoping review aims to collate biomarkers associated with GDM development, associated perinatal outcome and medication requirement in GDM.

Design
The Preferred Reporting Items for Systematic Reviews and Meta-Analysis extension for scoping reviews was used to guide the study.

Data sources
This review searched for articles on PubMed, Embase, Scopus, Cochrane Central Register of Controlled Trials, the Cumulative Index to Nursing and Allied Health Literature and the Web of Science from January 2013 to February 2023.

Eligibility criteria
The eligibility criteria included analytical observational studies published in English, focusing on pregnant women with maternal plasma or serum biomarkers collected between 6 and 24 weeks of gestation. Studies were excluded if they evaluated drug effects, non-GDM diabetes types or involved twin pregnancies, microbiota, genetic analyses or non-English publications.

Data extraction and synthesis
Two independent reviewers extracted data. One reviewer extracted data from papers included in the scoping review using Covidence. From the 8837 retrieved records, 137 studies were included.

Results
A total of 278 biomarkers with significant changes in individuals with GDM compared with controls were identified. The univariate predictive biomarkers exhibited insufficient clinical sensitivity and specificity for predicting GDM, perinatal outcomes, and the necessity of medication. Multivariable models combining maternal risk factors with biomarkers provided more accurate detection but required validation for use in clinical settings.

Conclusion
This review recommends further research integrating novel omics technology for building accurate models for predicting GDM, perinatal outcome, and the necessity of medication while considering the optimal testing time.

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