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Calo embriogênico tem sido o tecido-alvo mais utilizado para transformação genética de cereais. O objetivo deste trabalho foi investigar o estabelecimento de calos embriogênicos e a regeneração de plantas in vitro a partir de embriões maduros de genótipos de aveia (Avena sativa L.). Embriões maduros foram retirados das sementes e colocados em meio MS (Murashige & Skoog), contendo 30,0 g L-1 de sacarose e 2,0 mg L-1 de ácido 2,4-diclorofenoxiacético (2,4-D). Após o período de indução de calos, agregados embriogênicos foram isolados e subcultivados a cada 21 dias para meio fresco. Os calos embriogênicos foram então transferidos para meio de indução de parte aérea, e, na seqüência, as partes aéreas foram transferidas para meio de indução de raízes. Houve diferenças entre genótipos quanto à capacidade de embriogênese somática e regeneração de plantas in vitro a partir de embrião maduro. Este explante permitiu a indução de calos embriogênicos, que se multiplicaram, e que regeneraram in vitro um grande número de plantas de genótipos como UFRGS 7 e UFRGS 19, o que o faz passível de ser utilizado na transformação genética da aveia.

A regeneração de plantas in vitro é uma limitação encontrada na maioria dos cereais. Uma forma de minimizar essa dificuldade tem sido a busca de fontes alternativas de tecidos com habilidade para esse fim. O objetivo deste trabalho foi investigar o potencial e o período necessário para regeneração de plantas in vitro de genótipos brasileiros de aveia (Avena sativa L.) a partir de segmentos da base da folha. Segmentos de 1-2mm retirados do coleóptilo de genótipos de aveia foram cultivados por 21 dias em meio MS (MURASHIGE & SKOOG, 1962) suplementado com 2,0mg L-1 de 2,4-D (ácido 2,4-diclorofenoxiacético) e, posteriormente, transferidos para meio de regeneração de plantas. Não foi encontrada variabilidade entre os genótipos quanto à capacidade de induzir calos embriogênicos e regenerar plantas a partir de segmentos da base da folha, tendo sido possível regenerar genótipos de aveia antes considerados sem habilidade para o cultivo in vitro. O uso desse explante possibilitou reduzir o tempo de regeneração de plantas de aveia para cinco meses e a não correlação entre a percentagem de embriogênese somática e regeneração de plantas indica que a embriogênese não é o único caminho de regeneração a partir desse explante.

Abstract Background Increasing evidence has underscored the role of carcinoma associated fibroblasts (CAF) in tumor growth. However, there are controversial data regarding the persistence of inoculated CAF within the tumors. We have developed a model in which murine metastatic ductal mammary carcinomas expressing estrogen and progesterone receptors transit through different stages of hormone dependency. Hormone dependent (HD) tumors grow only in the presence of progestins, whereas hormone independent (HI) variants grow without hormone supply. We demonstrated previously that CAF from HI tumors (CAF-HI) express high levels of FGF-2 and that FGF-2 induced HD tumor growth in vivo. Our main goal was to investigate whether inoculated CAF-HI combined with purified epithelial (EPI) HD cells can induce HD tumor growth. Methods Purified EPI cells of HD and HI tumors were inoculated alone, or together with CAF-HI, into female BALB/c mice and tumor growth was evaluated. In another set of experiments, purified EPI-HI alone or combined with CAF-HI or CAF-HI-GFP were inoculated into BALB/c or BALB/c-GFP mice. We assessed whether inoculated CAF-HI persisted within the tumors by analyzing inoculated or host CAF in frozen sections of tumors growing in BALB/c or BALB/c-GFP mice. The same model was used to evaluate early stages of tumor development and animals were euthanized at 2, 7, 12 and 17 days after EPI-HI or EPI-HI+CAF-HI inoculation. In angiogenesis studies, tumor vessels were quantified 5 days after intradermal inoculation. Results We found that admixed CAF-HI failed to induce epithelial HD tumor growth, but instead, enhanced HI tumor growth (p < 0.001). Moreover, inoculated CAF-HI did not persist within the tumors. Immunofluorescence studies showed that inoculated CAF-HI disappeared after 13 days. We studied the mechanisms by which CAF-HI increased HI tumor growth, and found a significant increase in angiogenesis (p < 0.05) in the co-injected mice at early time points. Conclusions Inoculated CAF-HI do not persist within the tumor mass although they play a role during the first stages of tumor formation promoting angiogenesis. This angiogenic environment is unable to replace the hormone requirement of HD tumors that still need the hormone to recruit the stroma from the host.

Abstract Background Severe post tracheostomy (PT) and post intubation (PI) tracheal stenosis is an uncommon clinical entity that often requires interventional bronchoscopy before surgery is considered. We present our experience with severe PI and PT stenosis in regards to patient characteristics, possible risk factors, and therapy. Methods We conducted a retrospective chart review of 31 patients with PI and PT stenosis treated at Lahey Clinic over the past 8 years. Demographic characteristics, body mass index, co-morbidities, stenosis type and site, procedures performed and local treatments applied were recorded. Results The most common profile of a patient with tracheal stenosis in our series was a female (75%), obese (66%) patient with a history of diabetes mellitus (35.4%), hypertension (51.6%), and cardiovascular disease (45.1%), who was a current smoker (38.7%). Eleven patients (PI group) had only oro-tracheal intubation (5.2 days of intubation) and developed web-like stenosis at the cuff site. Twenty patients (PT group) had undergone tracheostomy (54.5 days of intubation) and in 17 (85%) of them the stenosis appeared around the tracheal stoma. There was an average of 2.4 procedures performed per patient. Rigid bronchoscopy with Nd:YAG laser and dilatation (mechanical or balloon) were the preferred methods used. Only 1(3.2%) patient was sent to surgery for re-stenosis after multiple interventional bronchoscopy treatments. Conclusion We have identified putative risk factors for the development of PI and PT stenosis. Differences in lesions characteristics and stenosis site were noted in our two patient groups. All patients underwent interventional bronchoscopy procedures as the first-line, and frequently the only treatment approach.

Competing Interests: RJM acknowledges research support from Open Targets, Wellcome Trust, European Bioinformatics Institute (EMBL-EBI), Genentech, GlaxoSmithKline, Merck Sharp and Dohme, Pfizer, and Sanofi; and support for educational meeting attendance from Ferring. CAL was Secretary of the Inflammatory Bowel Disease Section Committee of the British Society of Gastroenterology 2021 to 2024; sits on the Steering Committee and Board of IBD UK, acknowledges research support from the NIHR Newcastle Biomedical Research Centre, Medical Research Council, The Leona M and Harry B Helmsley Charitable Trust, Crohn's & Colitis UK, EU Innovative Medicines Initiative, Wellcome Trust, Open Targets, EMBL-EBI, Janssen, Takeda, AbbVie, AstraZeneca, Eli Lilly, Orion, Pfizer, Roche, Sanofi Aventis, UCB, Biogen, Genentech, Bristol Myers Squibb, GlaxoSmithKline, and Merck Sharp and Dohme; has undertaken consultancy for Janssen and Bristol Myers Squibb; has received honoraria for development or delivery of education, or both, from Takeda, Ferring, Janssen, Dr Falk, and Nordic Pharma; and has received conference attendance support from Tillotts Pharma UK, Janssen, British Society of Gastroenterology, International Organisation of IBD (IOIBD), and the European Crohn's & Colitis Organisation (ECCO).

Competing Interests: CT and AG have lived experience of inflammatory bowel disease. CAL is Secretary of the Inflammatory Bowel Disease Section Committee of the British Society of Gastroenterology; sits on the Steering Committee of IBD UK; acknowledges research support from the National Institute of Health and Care Research (NIHR), Newcastle Biomedical Research Centre, Medical Research Council, The Leona M and Harry B Helmsley Charitable Trust, Crohn's & Colitis UK, EU Innovative Medicines Initiative, Wellcome Trust, Open Targets, Janssen, Takeda, AbbVie, AstraZeneca, Eli Lilly, Orion, Pfizer, Roche, Sanofi Aventis, UCB, Biogen, Genentech, Bristol Myers Squibb, GlaxoSmithKline, and Merck Sharp & Dohme; has undertaken consultancy for Janssen and Bristol Myers Squibb; has received honoraria for development and delivery of education from Ferring, Takeda, Janssen, Dr Falk, and Nordic Pharma; and has received conference attendance support from Tillotts Pharma UK, Janssen, the British Society of Gastroenterology, and the European Crohn's & Colitis Organisation. CT has received conference travel support from the European Crohn's & Colitis Organisation. RB has received grants or research support from the Asian Healthcare Foundation and The Leona M and Harry B Helmsley Charitable Trust; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Takeda, Johnson & Johnson, Pfizer, Cipla, Abbott, Ferring Pharmaceuticals, Sun Pharmaceuticals, and Zydus; support for attending meetings from Takeda and Johnson & Johnson; and participation on data safety monitoring or advisory boards from Pfizer, Takeda, Johnson & Johnson, and Cipla. DTR has received grant support from The Leona M and Harry B Helmsley Charitable Trust, the Gastrointestinal Research Foundation, and Takeda; has served as a consultant for AbbVie, Altrubio, Apex, Avalo Therapeutics, Bristol Myers Squibb, Buhlmann Diagnostics Corp, Celgene, Chronicles Health, ClostraBio, Connect BioPharma, Image Analysis Group, Index Pharmaceuticals, Intouch Group, Iterative Health, Janssen Pharmaceuticals, Lilly, Odyssey Therapeutics, Pfizer, Prometheus Biosciences (now Merck Sharp & Dohme), Reistone, Samsung Neurologica, Sangamo, Shanghai Pharm Biotherapeutics, Takeda, Tissium, and Trellus Health; has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AbbVie, Bristol Myers Squibb, and Janssen; serves on the Board of Trustees for the Crohn's & Colitis Foundation; is on the Board of Directors for Cornerstones Health; and holds stock options in Iterative Health (artificial intelligence computational tools in gastroenterology), AltruBio (biotechnology research), and Datos Health (remote patient monitoring). ALH sits on the Governing Board of European Crohn's & Colitis Organisation; declares consultancy fees from AbbVie, Bristol Myers Squibb, Celltrion, Galapagos, Johnson & Johnson, Takeda, Pfizer, and Lilly; has received honoraria from AbbVie, Bristol Myers Squibb, Celltrion, Galapogos, Johnson & Johnson, Takeda, Pfizer, Lilly; and has received support for attending meetings or travel from AbbVie, Bristol Myers Squibb, Celltrion, Galapagos, Johnson & Johnson, Takeda, Pfizer, and Lilly. All other authors declare no competing interests.

The lipid metabolism adaptations of estrogen and progesterone receptor-positive breast cancer tumors from a mouse syngeneic model are investigated in relation to differences across the transition from hormone-dependent (HD) to hormone-independent (HI) tumor growth and the acquisition of endocrine therapy (ET) resistance (HIR tumors). Results are articulated with reported polar metabolome results to complete a metabolic picture of the above transitions and suggest markers of tumor progression and aggressiveness. Untargeted nuclear magnetic resonance metabolomics was used to analyze tumor and mammary tissue lipid extracts. Tumor progression (HD-HI-HIR) was accompanied by increased nonesterified cholesterol forms and phospholipids (phosphatidylcholine, phosphatidylethanolamine, sphingomyelins, and plasmalogens) and decreased relative contents of triglycerides and fatty acids. Predominating fatty acids became shorter and more saturated on average. These results were consistent with gradually more activated cholesterol synthesis, β-oxidation, and phospholipid biosynthesis to sustain tumor growth, as well as an increase in cholesterol (possibly oxysterol) forms. Particular compound levels and ratios were identified as potential endocrine tumor HD-HI-HIR progression markers, supporting new hypotheses to explain acquired ET resistance.

Background: Checkpoint inhibitors (CPIs) are widely used in cancer treatment, with transformative impacts on survival. They nonetheless carry a significant risk of toxicity in the form of immune-related adverse events (IrAEs), which may be sustained and life-altering. IrAEs may require high-dose and/or prolonged steroid use and represent a significant healthcare burden. They mimic immune-mediated inflammatory diseases (IMIDs) but understanding of their pathogenesis is limited. The MEDALLION project aims to determine targetable mechanisms of immune dysregulation in IrAE development, employing an immune monitoring approach to determine changes in circulating and tissue resident cells of CPI recipients who do/do not develop them and assessing the contribution of the microbiome in parallel., Methods: MEDALLION is a non-randomised longitudinal cohort study aiming to recruit 66 cancer patient recipients of anti-PD1/PD-L1, anti-CTLA-4 or combination therapy. Eligible participants include those with malignant melanoma in the adjuvant or metastatic setting, mesothelioma and non-small cell lung carcinoma (NSCLC) treated in the metastatic setting. Comprehensive clinical evaluation is carried out alongside blood, skin swab and stool sampling at the time of CPI initiation (baseline) and during subsequent routine hospital visits on 6 occasions over a 10-month follow-up period. It is conservatively anticipated that one third of enrolled patients will experience a "significant IrAE" (SirAE), defined according to pre-determined criteria specific to the affected tissue/organ system. Those developing such toxicity may optionally undergo a biopsy of affected tissue where appropriate, otherwise being managed according to standard of care. Peripheral blood mononuclear cells will be analysed using multi-parameter flow cytometry to investigate immune subsets, their activation status and cytokine profiles. Stool samples and skin swabs will undergo DNA extraction for 16 S ribosomal RNA (rRNA) sequencing and internal transcribed spacer (ITS) gene sequencing to determine bacterial and fungal microbiome diversity, respectively, including species associated with toxicity. Stored tissue biopsies will be available for in situ and single-cell transcriptomic evaluation. Analysis will focus on the identification of biological predictors and precursors of SirAEs., Discussion: The pathogenesis of IrAEs will be assessed through the MEDALLION cohort, with the potential to develop tools for their prediction and/or strategies for targeted prevention or treatment., Trial Registration: The study was registered on 18/09/2023 in the ISRCTN registry (43,419,676)., (© 2024. The Author(s).)

Background and Aims: This study compares the effectiveness of different biologic therapies and sequences in patients with inflammatory bowel disease [IBD] using real-world data from a large cohort with long exposure., Methods: Demographic, disease, treatment, and outcome data were retrieved for patients in the UK IBD BioResource. Effectiveness of treatment was based on persistence free of discontinuation or failure, analysed by Kaplan-Meier survival analysis with inverse probability of treatment weighting to adjust for differences between groups., Results: In total, 13 222 evaluable patients received at least one biologic. In ulcerative colitis [UC] first-line vedolizumab [VDZ] demonstrated superior effectiveness over 5 years compared to anti-tumour necrosis factor [anti-TNF] agents [p = 0.006]. VDZ was superior to both infliximab [IFX] and adalimumab [ADA] after ADA and IFX failure respectively [p < 0.001 and p < 0.001]. Anti-TNF therapy showed similar effectiveness when used as first-line treatment, or after failure of VDZ. In Crohn's disease [CD] we found significant differences between first-line treatments over 10 years [p = 0.045], with superior effectiveness of IFX compared to ADA in perianal CD. Non-anti-TNF biologics were superior to a second anti-TNF after first-line anti-TNF failure in CD [p = 0.035]. Patients with UC or CD experiencing TNF failure due to delayed loss of response or intolerance had superior outcomes when switching to a non-anti-TNF biologic, rather than a second anti-TNF., Conclusions: We provide real-world evidence to guide biologic selection and sequencing in a range of common scenarios. Our findings challenge current guidelines regarding drug selection after loss of response to first anti-TNF treatment., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)

Adult polycystic kidney disease (APKD) is a genetic disorder leading to premature renal dysfunction and failure. The prevalence of malignant renal tumors occurring in the APKD setting has been rarely reported., Objective: To better characterize malignant renal tumors in nephrectomy specimens of APKD and apply modern pathologic evaluation., Methods: We reviewed our database of APKD specimens over the past 11 years (from 2012 to 2023) for primary malignant tumors within the kidneys of APKD., Results: Of 48 nephrectomy specimens with APKD evaluated, 10 malignant renal tumors were identified, indicating a prevalence of 20.8 % (10/48). These included three clear cell (cc) renal cell carcinomas (RCC) (ranging from 1 mm to 6.7 cm), three papillary RCCs (2.5, 3.5, and 14 cm with lymph node metastasis), two cases of clear cell papillary (CCP) RCC, one acquired cystic disease (ACD) with associated RCC (4 mm), and one urothelial adenocarcinoma. The urothelial adenocarcinoma was found near a tubulovillous adenoma in a collecting duct and stained positively for GATA3 and Uroplakin-2 but was negative for PAX8 & CDX2. The tumor showed extensive invasion into perirenal fatty tissue and the rectum. Next generating sequencing (NGS) analysis of the tumor showed mutations in TERT, RB1, TP53, ERBB2, and TET1 genes, further supporting its urothelial origin., Conclusions: We found a prevalence of 20.8%, which was higher than in previous reports of malignant renal tumors in patients who underwent resections for APKD. Renal tumors were mostly from damaged proximal tubular origins (clear cell or papillary RCC), but less commonly were from distal tubular or urothelial cells as well (clear cell papillary RCC and urothelial adenocarcinoma)., (© 2024 by the Association of Clinical Scientists, Inc.)

Introduction: Characterised by chronic inflammation of the gastrointestinal tract, inflammatory bowel disease (IBD) symptoms including diarrhoea, abdominal pain and fatigue can significantly impact patient's quality of life. Therapeutic developments in the last 20 years have revolutionised treatment. However, clinical trials and real-world data show primary non-response rates up to 40%. A significant challenge is an inability to predict which treatment will benefit individual patients.Current understanding of IBD pathogenesis implicates complex interactions between host genetics and the gut microbiome. Most cohorts studying the gut microbiota to date have been underpowered, examined single treatments and produced heterogeneous results. Lack of cross-treatment comparisons and well-powered independent replication cohorts hampers the ability to infer real-world utility of predictive signatures.IBD-RESPONSE will use multi-omic data to create a predictive tool for treatment response. Future patient benefit may include development of biomarker-based treatment stratification or manipulation of intestinal microbial targets. IBD-RESPONSE and downstream studies have the potential to improve quality of life, reduce patient risk and reduce expenditure on ineffective treatments., Methods and Analysis: This prospective, multicentre, observational study will identify and validate a predictive model for response to advanced IBD therapies, incorporating gut microbiome, metabolome, single-cell transcriptome, human genome, dietary and clinical data. 1325 participants commencing advanced therapies will be recruited from ~40 UK sites. Data will be collected at baseline, week 14 and week 54. The primary outcome is week 14 clinical response. Secondary outcomes include clinical remission, loss of response in week 14 responders, corticosteroid-free response/remission, time to treatment escalation and change in patient-reported outcome measures., Ethics and Dissemination: Ethical approval was obtained from the Wales Research Ethics Committee 5 (ref: 21/WA/0228). Recruitment is ongoing. Following study completion, results will be submitted for publication in peer-reviewed journals and presented at scientific meetings. Publications will be summarised at www.ibd-response.co.uk., Trial Registration Number: ISRCTN96296121., Competing Interests: Competing interests: TA reports personal grants from F. Hoffmann-La Roche, Biogen, AbbVie, Janssen, Celltrion, Galapagos, Immunodiagnostik and Takeda, outside the submitted work; personal fees for educational development/delivery from Pfizer, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Pfizer, Takeda and F. Hoffman-La Roche; support for attending meetings from Celltrion, Tillotts and Pfizer. CAA reports grants from the Wellcome Sanger Institute Quinquennial Review 2021–2026, Crohn’s and Colitis Foundation (USA), the Medical Research Council, Open Targets UK and the Helmsley Charitable Trust; consulting fees from BridgeBio, Genomics and Brigham & Women’s Hospital Boston; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from GlaxoSmithKline; support for attending meetings and/or travel membership from the Wellcome Sanger Institute Quinquennial Review 2021–2026; (Chair) of the Board of Trustees for the Sanger Prize; other interests as Director of Anderson Genomics Consultancy. MB reports partial personal salary funding from the Medical Research Council. ALH reports personal consulting fees from AbbVie, BMS, Celltrion, Falk, Galapagos, Janssen, Pfizer, Takeda and Roche; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from BMS, Celltrion, Falk, Galapagos, Janssen, Pfizer, Takeda, Roche and AbbVie; support for attending meetings and/or travel from BMS, Celltrion, Falk, Galapagos, Janssen, Pfizer, Takeda, Roche and AbbVie. PI reports personal grants from Celltrion, Galapagos and Pfizer, outside the submitted work; personal consulting fees from AbbVie, Takeda, BMS, Janssen, Arena, Pfizer, Galapagos, Lilly, Boehringer-Ingelheim and Celgene; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AbbVie, Takeda, Janssen, Lilly, BMS, Pfizer and Galapagos; support for attending meetings and/or travel from AbbVie and Tillotts. LJ-D reports grants from the Wellcome Trust, the Royal Society, the Kennedy Trust for Rheumatology Research, the Helmsley Charitable Trust and the Medical Research Council; grants from Novartis Pharmaceutical, outside the submitted work; consulting fees from Nightingale Health and Genomics. CK reports partial salary funding from the Medical Research Council. NAK reports grants from AbbVie, Biogen, Celltrion, Galapagos and Immunodiagnostik; consulting fees from AbbVie, Bristol-Meyers Squibb and Dr Falk; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AbbVie, Dr Falk, Tillotts, Galapagos and Takeda; support for attending meetings and/or travel from Tillotts; participation (Chair) on the Board of the British Society of Gastroenterology IBD Clinical Research Group. CAL reports grants from and/or consultancy for Janssen, Takeda, AbbVie, AstraZeneca, Eli Lilly, Orion, Pfizer, Roche, Sanofi Aventis, UCB, Biogen, GSK, Bristol-Myers Squibb and Genentech; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Ferring, Takeda, Janssen, Nordic Pharma and Dr Falk; participation (Secretary) on the British Society of Gastroenterology IBD Section; participation on the Steering Committee of IBD UK. CWL reports grants from UKRI Future Leaders Fellowship; personal consulting fees from AbbVie, Pfizer, Janssen, Takeda, Galapagos, Fresnius Kabi, Novartis/Sandoz, BMS and Celltrion; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AbbVie, Pfizer, Janssen, Takeda, Galapagos, Fresnius Kabi, Novartis/Sandoz, BMS, Ferring, Dr Falk and Celltrion. JOL reports grants from AbbVie, and Gilead; personal consulting fees from Allergan, AbbVie, Bristol-Myers Squibb, Celgene, Cornerstones US, Galapagos, Gilead, GSK, Lilly, MSD UK, Shire UK, Shire International, Ferring UK, Ferring International, Celltrion, Takeda, Pfizer and Janssen; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AbbVie, Bristol-Myers Squibb, Cornerstones US, Galapagos, Ferring UK, Ferring International, Celltrion, Takeda, Pfizer and Janssen; support to attend meetings and/or travel from AbbVie and Janssen. RHM reports that she is an independent membership on the Trial Steering Committee for the National Institute for Health and Care Research funded ALLEGRO trial. JRM reports personal consulting fees from EnteroBiotix and Cultech; patent held (without financial gain) on Clostridium difficile therapy (WO2019197836A1), participation (Chair) on the IDMC Board. NMcG reports partial (10%) salary funding from the Medical Research Council. REM reports personal salary funding from the Wellcome Sanger Institute. JO reports stock held in Novartis. MP reports grants from Pfizer and Gilead; personal consulting fees from Galapagos; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Janssen. NP reports grants from Bristol-Myers Squibb, Takeda and Pfizer; consulting fees from AbbVie, Allergan, AstraZeneca, Bristol-Myers Squibb, Celgene, Celltrion, Galapagos, GSK, Takeda and Vifor; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AbbVie, Bristol-Myers Squibb, Ferring, Galapagos, Janssen, Roche, Pfizer, Takeda and Tillotts; support for attending meetings and/or travel from AbbVie, Allergan, Celltrion, Janssen and Takeda; participation on a data safety monitoring board or advisory board for AbbVie, Allergan, AstraZeneca, Bristol-Myers Squibb, Celgene, Celltrion, Galapagos, GSK, Takeda and Vifor. TR reports personal grants from AbbVie; personal consulting fees from AbbVie, Arena, Aslan, AstraZeneca, Boehringer-Ingelheim, BMS, Celgene, Ferring, Galapagos, Gilead, GSK, Heptares, LabGenius, Janssen, Mylan, MSD, Novartis, Pfizer, Roche, Sandoz, Takeda, UCB and XAP therapeutics; participation on the board of UCB, membership (Chair) of the ECCO Guidelines Committee, membership of the UEG Scientific Committee. JS reports grants from Crohn’s and Colitis UK, the Helmsley Charitable Trust, ECCO, the European Commission, CCFA and Action Medical Research; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Roche; participation on a Data Safety Monitoring Board or Advisory Board for the MODULATE trial and the TRIBUTE trial; leadership or fiduciary role as the Director of the Royal College of Physicians IBD Registry, and Governing Body Fellow at Green Templeton College. AS reports personal consulting fees from GSK; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Falk, and AbbVie; payment of conference fees to attend the British Society of Gastroenterology Annual Conference 2022 from Celltrion; participation on a Data Safety Monitoring Board or Advisory Board for the IBD-RESPONSE study (unpaid), and AbbVie; participation on the British Society of Gastroenterology IBD Section Committee. CJS reports personal consultancy fees from Astarte Medical; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Nestle Nutrition Institute. JW reports grants from Intercept; consulting fees from Worg and UCB; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Janssen; participation on a Data Safety Monitoring Board or Advisory Board for Roche. KW reports grants from the Helsmsley Charitable Trust, Crohn’s and Colitis UK, Almond Board of California, Danone, International Dried Fruit and Nut Council, Medical Research Council, National Institute for Health and care Research; royalty or license payments for Volatile organic compounds in the diagnosis and management of irritable bowel syndrome, and Wiley BDA Advances in Nutrition & Dietetics book series; personal consulting fees from Danone; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Janssen; support for attending meetings and/or travel from Yakult; participation on a Data Safety Monitoring Board or Advisory Board for the MODULATE trial (unpaid)., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Background: Key performance indicators (KPIs) are required to facilitate quality improvement for inflammatory bowel disease (IBD). Emergency admissions for IBD may represent a possible KPI., Methods: IBD emergency admissions for 2018-2019 from Hospital Episodes Statistics for England were compared per population and per IBD cases with patient-reported quality of care from the IBD Patient Survey 2019. Patient-reported accident and emergency (A&E) attendances and hospital admissions for IBD were also compared with patient-reported quality of care., Results: For 124 IBD services within England we found only a weak and not statistically significant correlation between IBD admissions per 100 000 population and patient-rated quality of care (Spearman's rho=0.171; p=0.057). Similarly, there was no significant correlation between IBD admissions per case and patient-rated quality of care (Spearman's rho=0.164; p=0.113). Patients with ≥2 A&E attendances (OR: 0.72, 95% CI: 0.57 to 0.91; p<0.001) were less likely to report quality of IBD care as good or very good compared with those without A&E attendances. Patients with ≥2 admissions were less likely to rate their care as good or very good (OR: 0.75, 95% CI: 0.65 to 0.88; p<0.0001) compared with those without hospital admissions., Conclusions: There is a clear association for individual patients with ≥2 admissions or A&E attendances with a lower perceived quality of care. In contrast we found no correlation on a per-unit basis for IBD admissions derived from Hospital Episode Statistics with patient-assessed quality of care. Further work is required to determine whether hospital admissions could be a useful KPI for IBD., Competing Interests: Competing interests: CS has received unrestricted research grants from Warner Chilcott, Janssen, Celltrion and AbbVie, has provided consultancy to Warner Chilcott, Dr Falk, AbbVie, Takeda, Fresenius Kabi, Galapagos, Ferring, RedX, Arena and Janssen, and had speaker arrangements with Warner Chilcott, Dr Falk, AbbVie, MSD, Pfizer, Bristol Myers Squibb, Celltrion and Takeda. AB’s Unit has received grants from Dr Foster (a wholly owned subsidiary of Telstra Health) and Medtronic. AB has provided consultancy to Ireland’s HSE, AZ and Lilly., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Breast cancer is still one of the main causes of cancer mortality in women worldwide, and death rates are even greater in vulnerable populations. A delay in diagnosis usually comes with advanced-stage disease, which impacts patient survival. The aim of this study was to evaluate the time for first medical consultation among women with breast cancer attending the Magdalena V. de Martínez Hospital and to determine the causes that may influence patient delay and its impact on cancer stage at diagnosis., Materials and Methods: Three hundred and six breast cancer patients were interviewed using a self-report questionnaire, and socioeconomic and demographic variables, namely, highest education level completed, employment status and breast cancer awareness, were collected. The answers were associated with patient clinical records, such as clinical staging and tumor size., Results: Forty-nine percent of the patients were diagnosed with advanced-stage disease. These women had either a deficiency in breast cancer awareness, did not visit a gynecologist after age 40 or, were unemployed, while those patients diagnosed with early-stage breast cancer had nonpalpable tumors, declared a sufficient household income or delayed less than four weeks in seeking medical attention. Moreover, the delay in the first medical visit was more than one month in 78% of the patients, being disregard the most common cause of postponement. Additionally, patient delays were associated with larger tumors and with incomplete education., Discussion: These results indicate that early detection efforts should be made to reduce the disease stage at diagnosis, which may impact on overall survival.

Progesterone receptors (PRs) are biomarkers used as prognostic and predictive factors in breast cancer, but they are still not used as therapeutic targets. We have proposed that the ratio between PR isoforms A and B (PRA and PRB) predicts antiprogestin responsiveness. The MIPRA trial confirmed the benefit of 200 mg mifepristone, administered to patients with tumors with a high PRA/PRB ratio, but dose-ranging has not been conducted. The aim of this study was to establish the plasma mifepristone levels of patients from the MIPRA trial, along with the resultant steroid profiles, and compare these with those observed in mifepristone-treated mice using therapeutic schemes able to induce the regression of experimental mammary carcinomas with high PRA/PRB ratios: 6 mg pellets implanted subcutaneously, or daily doses of 12 mg/kg body weight. The plasma levels of mifepristone and other 19 plasma steroids were measured by liquid chromatography-tandem mass spectometry. In mifepristone-treated mice, plasma levels were lower than those registered in mifepristone-treated patients (i.e. day 7 after treatment initiation, pellet-treated mice: 8.4 ± 3.9 ng/mL; mifepristone-treated patients: 300.3 ± 31.7 ng/mL (mean ± s.d.; P < 0.001)). The increase in corticoid related steroids observed in patients was not observed in mifepristone-treated mice. The increase in progesterone levels was the most significant side effect detected in mifepristone-treated mice after 14 or 21 days of treatment, probably due to an ovarian compensatory effect not observed in postmenopausal patients. We conclude that in future clinical trials using mifepristone, the possibility of lowering the standard daily dose of 200 mg should be considered.

Background and Aims: Inflammatory bowel disease colitis-associated dysplasia is managed with either enhanced surveillance and endoscopic resection or prophylactic surgery. The rate of progression to cancer after a dysplasia diagnosis remains uncertain in many cases and patients have high thresholds for accepting proctocolectomy. Individualised discussion of management options is encouraged to take place between patients and their multidisciplinary teams for best outcomes. We aimed to develop a toolkit to support a structured, multidisciplinary and shared decision-making approach to discussions about dysplasia management options between clinicians and their patients., Methods: Evidence from systematic literature reviews, mixed-methods studies conducted with key stakeholders, and decision-making expert recommendations were consolidated to draft consensus statements by the DECIDE steering group. These were then subjected to an international, multidisciplinary modified electronic Delphi process until an a priori threshold of 80% agreement was achieved to establish consensus for each statement., Results: In all, 31 members [15 gastroenterologists, 14 colorectal surgeons and two nurse specialists] from nine countries formed the Delphi panel. We present the 18 consensus statements generated after two iterative rounds of anonymous voting., Conclusions: By consolidating evidence for best practice using literature review and key stakeholder and decision-making expert consultation, we have developed international consensus recommendations to support health care professionals counselling patients on the management of high cancer risk colitis-associated dysplasia. The final toolkit includes clinician and patient decision aids to facilitate shared decision-making., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Murine intraepithelial γδ T cells include distinct tissue-protective cells selected by epithelial butyrophilin-like (BTNL) heteromers. To determine whether this biology is conserved in humans, we characterized the colonic γδ T cell compartment, identifying a diverse repertoire that includes a phenotypically distinct subset coexpressing T cell receptor Vγ4 and the epithelium-binding integrin CD103. This subset was disproportionately diminished and dysregulated in inflammatory bowel disease, whereas on-treatment CD103 + γδ T cell restoration was associated with sustained inflammatory bowel disease remission. Moreover, CD103 + Vγ4 + cell dysregulation and loss were also displayed by humans with germline BTNL3/BTNL8 hypomorphism, which we identified as a risk factor for penetrating Crohn's disease (CD). Thus, BTNL-dependent selection and/or maintenance of distinct tissue-intrinsic γδ T cells appears to be an evolutionarily conserved axis limiting the progression of a complex, multifactorial, tissue-damaging disease of increasing global incidence.

Competing Interests: Competing interests: AC reports grants from the Wellcome Trust and royalties from Elsevier all outside the submitted work. VM reports personal speaker fees from Takeda UK, and meeting and travel grants from Dr Falk Pharma (UK), Janssen-Cilag, Takeda UK, all outside the submitted work. CS reports consulting fees from Ferring, personal speaker fees from Takeda, Janssen, Abbvie, Tillotts, Norgine, Fresenius Kabi, meeting and travel grants from Tillots, Abbvie, Janssen, and advisory board fees from Galapagos, AbbVie, Arena, Janssen, Fresenius Kabi all outside the submitted work. CL reports grants from Genentech, grants and personal fees from Janssen, grants and personal fees from Takeda, grants from AbbVie, personal fees from Ferring, grants from Eli Lilly, grants from Pfizer, grants from Roche, grants from UCB Biopharma, grants from Sanofi Aventis, grants from Biogen IDEC, grants from Orion OYJ, personal fees from Dr Falk Pharma, grants from AstraZeneca, outside the submitted work. IP reports speaker fees from Olympus, Boston Scientific, and Dr Falk outside the submitted work. SD reports grants from The Helmsley Charitable Trust, Edinburgh and Lothians Health Foundation, Pathological Society of Great Britain and Northern Ireland, Lord Leonard and Lady Estelle Wolfson Foundation, consulting fees from Abbvie, personal speaker fees from Janssen and Takeda, and meeting and travel grants from Janssen, Takeda and Dr Falk, all outside the submitted work.

Objective: Despite its association with poorer outcomes, opioid use in inflammatory bowel disease (IBD) is not well characterised in the UK. We aimed to examine the extent of opioid use, the associated factors and the use of mitigation techniques such as pain-service review and opioid weaning plans among individuals with IBD., Methods: Data were collected from consecutive patients attending IBD outpatient appointments at 12 UK hospitals. A predefined questionnaire was used to collect data including patient demographics, IBD history, opioid use in the past year (>2 weeks) and opioid-use mitigation techniques. Additionally, consecutive IBD-related hospital stays leading up to July 2019 were reviewed with data collected regarding opioid use at admission, discharge and follow-up as well as details of the admission indication., Results: In 1352 outpatients, 12% had used opioids within the past 12 months. Over half of these individuals were taking opioids for non-IBD pain and less than half had undergone an attempted opioid wean.In 324 hospitalised patients, 27% were prescribed opioids at discharge from hospital. At 12 months postdischarge, 11% were using opioids. Factors associated with opioid use in both cohorts included female sex, Crohn's disease and previous surgery., Conclusions: 1 in 10 patients with IBD attending outpatient appointments were opioid exposed in the past year while a quarter of inpatients were discharged with opioids, and 11% continued to use opioids 12 months after discharge. IBD services should aim to identify patients exposed to opioids, reduce exposure where possible and facilitate access to alternative pain management approaches., Competing Interests: Competing interests: SB has had speaker arrangements with Takeda and Dr Falk, has received travel grants from Galapagos, Celltrion and Dr Falk and has provided consultancy to Galapagos. JKL has received grants from Galapagos and Takeda and speaker and consultancy fees from Abbvie, Arena, Celltrion, Ferring, Galapagos, Janssen, MSD, Pfizer and Takeda. GP has had personal fees from AbbVie, Allergan, BMS, Celltrion, Ferring, Galapagos, Janssen, Takeda, Tillotts. Travel grants from—AbbVie, Celltrion, Ferring, Janssen, Takeda, Tillotts and is a Director and Shareholder in Ampersand Health. GS has had speaker arrangements with Takeda, Abbvie, Tillotts and Galapagos. TR has received research/educational grants and/or speaker/consultation fees from Abbvie, Arena, Aslan, AstraZeneca, Boehringer-Ingelheim, BMS, Celgene, Ferring, Galapagos, Gilead, GSK, Heptares, LabGenius, Janssen, Mylan, MSD, Novartis, Pfizer, Roche, Sandoz, Takeda and UCB. CAL reports grants from Genentech, grants and personal fees from Janssen, grants and personal fees from Takeda, grants from AbbVie, personal fees from Ferring, grants from Eli Lilly, grants from Pfizer, grants from Roche, grants from UCB Biopharma, grants from Sanofi Aventis, grants from Biogen IDEC, grants from Orion OYJ, personal fees from Dr Falk Pharma, grants from AstraZeneca, outside the submitted work. NAK has served as a speaker and/or advisory board member for AbbVie, Allergan, BMS, Falk, Ferring, Galapagos, Janssen, Mylan, Pharmacosmos, Sandoz, Takeda and Tillotts. IC has speaker arrangements with Celltrion and has received a travel grant from Galapagos. RP has provided consultancy to Galapagos. CS has received unrestricted research grants from Warner Chilcott, Janssen and AbbVie, has provided consultancy to Warner Chilcott, Dr Falk, AbbVie, Takeda, Fresenius Kabi, Galapagos, Ferring, Arena and Janssen, and had speaker arrangements with Warner Chilcott, Dr Falk, AbbVie, MSD, Pfizer, Celltrion and Takeda.The preparation of this paper was funded in part by Galapagos., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Aims: Healthcare quality improvement (QI) is the systematic process to continuously improve the quality of care and outcomes for patients. The landmark Inflammatory Bowel Disease (IBD) UK National Audits provided a means to measure the variation in care, highlighting the need to define the standards of excellence in IBD care. Through a consensus approach, we aimed to establish key performance indicators (KPIs), providing reliable benchmarks for IBD care delivery in UK., Methods: KPIs that measure critical aspects of a patient journey within an IBD service were identified though stakeholder meetings. A two-stage Delphi consensus was then conducted. The first involved a multidisciplinary team of IBD clinicians and patients to refine definitions and methodology. The second stage assessed feasibility and utility of the proposed QI process by surveying gastroenterology services across UK., Results: First, the four proposed KPIs were refined and included time from primary care referral to diagnosis in secondary care, time to treatment recommendation following a diagnosis, appropriate use of steroids and advanced therapies prescreening and assessment. Second, the Delphi consensus reported >85% agreement on the feasibility of local adoption of the QI process and >75% agreement on the utility of benchmarking of the KPIs., Conclusions: Through a structured approach, we propose quantifiable KPIs for benchmarking to improve and reduce the individual variation in IBD care across the UK., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Preclinical data suggest that antiprogestins inhibit the growth of luminal breast carcinomas that express higher levels of progesterone receptor isoform A (PRA) than isoform B (PRB). Thus, we designed a presurgical window of opportunity trial to determine the therapeutic effects of mifepristone in patients with breast cancer, based on their high PRA/PRB isoform ratio (MIPRA; NCT02651844)., Patients and Methods: Twenty patients with luminal breast carcinomas with PRA/PRB > 1.5 (determined by Western blots), and PR ≥ 50%, naïve from previous treatment, were included for mifepristone treatment (200 mg/day orally; 14 days). Core needle biopsies and surgical samples were formalin fixed for IHC studies, while others were snap-frozen to perform RNA sequencing (RNA-seq), proteomics, and/or Western blot studies. Plasma mifepristone levels were determined using mass spectrometry. The primary endpoint was the comparison of Ki67 expression pretreatment and posttreatment., Results: A 49.62% decrease in Ki67 staining was observed in all surgical specimens compared with baseline (P = 0.0003). Using the prespecified response parameter (30% relative reduction), we identified 14 of 20 responders. Mifepristone induced an increase in tumor-infiltrating lymphocytes; a decrease in hormone receptor and pSer118ER expression; and an increase in calregulin, p21, p15, and activated caspase 3 expression. RNA-seq and proteomic studies identified downregulated pathways related to cell proliferation and upregulated pathways related to immune bioprocesses and extracellular matrix remodeling., Conclusions: Our results support the use of mifepristone in patients with luminal breast cancer with high PRA/PRB ratios. The combined effects of mifepristone and estrogen receptor modulators warrant clinical evaluation to improve endocrine treatment responsiveness in these patients. See related commentary by Ronchi and Brisken, p. 833., (©2022 The Authors; Published by the American Association for Cancer Research.)

Background: The combination of infliximab and immunosuppressant therapy is a standard management strategy for patients with Crohn's disease. Concerns regarding the implications of long-term combination therapy provided the rationale for a formal clinical trial of treatment de-escalation. Our aim was to compare the relapse rate and the time spent in remission over 2 years between patients continuing combination therapy and those stopping infliximab or immunosuppressant therapy., Methods: This multicentre, open-label, randomised controlled trial was performed in 64 hospitals in seven countries in Europe and Australia. Adult patients with Crohn's disease in steroid-free clinical remission for more than 6 months, on combination therapy of infliximab and immunosuppressant therapy for at least 8 months were randomly assigned (1:1:1) to either continue combination therapy (combination group), discontinue infliximab (infliximab withdrawal group), or discontinue immunosuppressant therapy (immunosuppressant withdrawal group). Randomisation was stratified according to disease duration before start of first anti-TNF treatment (≤2 or >2 years), failure of immunosuppressant therapy before start of infliximab, and presence of ulcers at baseline endoscopy. The patient number and group of each stratum were assigned by a central online randomisation website. Treatment was optimised or resumed in case of relapse in all groups. Participants, those assessing outcomes, and those analysing the data were not masked to group assignment. The coprimary endpoints were the relapse rate (superiority analysis) and time in remission over 2 years (non-inferiority analysis, non-inferiority margin 35 days). Analyses were done on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, NCT02177071, and with EU Clinical Trials Register, EUDRACT 2014-002311-41. The trial was completed in April, 2021., Findings: Between Nov 2, 2015, and April 24, 2019, 254 patients were screened. Of these, 211 were randomised and 207 were included in the final analysis (n=67 in the combination group, n=71 in the infliximab withdrawal group, and n=69 in the immunosuppressant withdrawal group). 39 patients had a relapse (eight [12%] of 67 in the combination group, 25 [35%] of 71 in the infliximab withdrawal group, six [9%] of 69 in the immunosuppressant withdrawal group). 2-year relapse rates were 14% (95% CI 4-23) in the combination group, 36% (24-47) in the infliximab withdrawal group, and 10% (2-18) in the immunosuppressant withdrawal group (hazard ratio [HR] 3·45 [95% CI 1·56-7·69], p=0·003, for infliximab withdrawal vs combination, and 4·76 [1·92-11·11], p=0·0004, for infliximab withdrawal vs immunosuppressant withdrawal). Of 28 patients who had a relapse and were retreated or optimised according to protocol, remission was achieved in 25 patients (one of two in the combination group, 22 of 23 in the infliximab withdrawal group, and two of three in the immunosuppressant withdrawal group). The mean time spent in remission over 2 years was 698 days (95% CI 668-727) in the combination group, 684 days (651-717) in the infliximab withdrawal group, and 706 days (682-730) in the immunosuppressant withdrawal group. The difference in restricted mean survival time in remission was -14 days (95% CI -56 to 27) between the infliximab withdrawal group and the combination group and -22 days (-62 to 16) between the infliximab withdrawal group and the immunosuppressant withdrawal group. The 95% CIs contained the non-inferiority threshold (-35 days). We recorded 31 serious adverse events, in 20 patients, with no difference in frequency between groups. The most frequent serious adverse events were infections (four in the combination group, two in the infliximab withdrawal group, and one in the immunosuppressant withdrawal group) and Crohn's disease exacerbation (three in the combination group, four in the infliximab withdrawal group, and one in the immunosuppressant withdrawal group). No death nor malignancy was recorded., Interpretation: In patients with Crohn's disease in sustained steroid-free remission under combination therapy with infliximab and immunosuppressant therapy, withdrawal of infliximab should only be considered after careful assessment of risks and benefits for each patient, whereas withdrawal of immunosuppressant therapy could generally represent a preferable strategy when considering treatment de-escalation., Funding: European Union's Horizon 2020., Competing Interests: Declaration of interests EL has received educational and research grants from Janssen, Pfizer, AbbVie, and Takeda, Fresenius-Kabi; speaker fees from AbbVie, Dr Falk Pharma, Ferring, Janssen, Pfizer, Celgene, Bristol Myers Squibb (BMS), Galapagos, and Takeda; advisory board fees for AbbVie, Celgene, Ferring, Janssen, BMS, Pfizer, Takeda, Gilead-Galapagos, Arena, and Elli Lilly; and consultancy fees from AbbVie. JS reports research support from European Commission Horizon 2020 programme. ND has received research grants from AbbVie, Janssen, and Takeda; speaker fees from AbbVie, Celltrion, Pfizer, Janssen, and Takeda; and advisory board fees from AbbVie, Dr Falk Pharma, and Janssen. BS has served as a consultant for AbbVie, Arena, BMS, Boehringer, CT Scout, Galapagos, Gilead, Janssen, Lilly, and PredictImmune; and has received speaker's fees from AbbVie, CED Service GmbH, Dr Falk Pharma, Ferring, Janssen, Materia Prima, Pfizer, and Lilly. GD'H reports consultancy activities for AbbVie, Agomab, Alimentiv, AstraZeneca, AM Pharma, AMT, Arena Pharmaceuticals, BMS, Boehringer Ingelheim, Celltrion, Eli Lilly, Exeliom Biosciences, Exo Biologics, Galapagos, Index Pharmaceuticals, Kaleido, Roche, Gilead, GlaxoSmithKline, Gossamerbio, Pfizer, Immunic, Johnson & Johnson, Origo, Polpharma, Procise Diagnostics, Prometheus laboratories, Prometheus Biosciences, Progenity, and Protagonist; speaker's bureau for AbbVie, Arena, Galapagos, Gilead, Pfizer, BMS, and Takeda; and fees for data monitoring board activities for Galapagos, AbbVie, Astrazeneca, and Seres Health. PB has received financial support for research from AbbVie, Amgen, Celltrion, Mylan, Pfizer and Takeda; lecture fees from AbbVie, Celltrion, Galapagos, Janssen, Lilly, Pentax, and Takeda; advisory board fees from AbbVie, Arena Pharmaceuticals, BMS, Celltrion, Dr Falk Pharma, Galapagos, Janssen, Lilly, Pentax, PSI-CRO, Roche, Takeda, and Tetrameros. LV has received fees from AbbVie, Amgen, Biogen, Mylan, Takeda, MSD, Janssen, Pfizer, Ferring, and Galapagos. PI has received honoraria for talking on behalf of AbbVie, BMS, Celgene, Celltrion, Dr Falk Pharma, Ferring, Galapagos, Gilead, MSD, Janssen, Lilly, Pfizer, Takeda, Tillotts, Sapphire Medical, Sandoz, Shire, and Warner Chilcott; and for acting in an advisory capacity to AbbVie, Arena, Boehringer-Ingelheim, BMS, Celgene, Celltrion, Connect Biopharma, Genentech, Gilead, Hospira, Janssen, Lilly, MSD, Pfizer, Pharmacosmos, Prometheus, Roche, Sandoz, Samsung Bioepis, Takeda, Topivert, VH2, Vifor Pharma, and Warner Chilcott. SV has received consulting or lecture fees for AbbVie, Amgen, Sandoz, Janssen, MSD, Pfizer, Celltrion, and Takeda. CAL has received grants from Genentech, AbbVie, Eli Lilly, Pfizer, Roche, UCB Biopharma, Sanofi Aventis, Biogen IDEC, Orion OYJ, and AstraZeneca; grants and personal fees from Janssen, Takeda, and Ferring; and personal fees from Dr Falk Pharma, outside the submitted work. FB has received grant or research support from AbbVie, Amgen, Janssen, and Takeda; honoraria from AbbVie, Dr Falk Pharma, Arena, Celgene, Mundipharma, Ferring, Vifor, Janssen, Merck Sharp & Dohme, Pfizer, Norgine, and Takeda. MN received board membership, consultancy, or lecture fees from AbbVie, Amgen, Arena, Biogen, CTMA, Celltrion, Ferring, Fresenius, Janssen, Mayoli-Spindler, MSD, Pfizer, Sandoz, and Takeda. MF received consulting or lecture fees for AbbVie, Amgen, Biogen, Gilead, Sandoz, Janssen, MSD, Pfizer, Ferring, Lilly, Tillots, Celltrion, Fresenius, Galapagos, and Takeda. CG received consulting or lecture fees from AbbVie, Amgen, Celltrion, Biogen, Fresenius, Gilead, Janssen, MSD, Mylan, Pfizer, Takeda, and Vifor. SB-H has received advisory board or consulting fees from AbbVie, Takeda, Janssen, Celltrion, Pfizer, GlaxoSmithKline, Ferring, Novartis, Roche, Gilead, NeoPharm, Predicta Med, Galmed, Medial Earlysign, and Eli Lilly, and research support from AbbVie, Takeda, Janssen, Celltrion, Pfizer, and Galmed. J-FC has received research grants from AbbVie, Pfizer, and Takeda; payment for lectures from AbbVie, Amgen, Pfizer, and Takeda; consulting fees from AbbVie, Amgen, Arena Pharmaceuticals, Boehringer Ingelheim, BMS, Celgene Corporation, Eli Lilly, Ferring Pharmaceuticals, Galmed Research, Genentech, GlaxoSmithKline, Janssen Pharmaceuticals, Kaleido Biosciences, Imedex, Immunic, Iterative Scopes, Merck, Novartis, Otsuka, PBM Capital, Pfizer, Protagonist Therapeutics, Sanofi, Takeda, TiGenix, and Vifor; and holds stock options in Intestinal Biotech Development. EH has received lecture fees from Takeda, Janssen, and BMS; and consultant or advisory board fees from AbbVie, Gilead, and Janssen. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Genomic medicine enables the identification of patients with rare or ultra-rare monogenic forms of inflammatory bowel disease (IBD) and supports clinical decision making. Patients with monogenic IBD frequently experience extremely early onset of treatment-refractory disease, with complex extraintestinal disease typical of immunodeficiency. Since more than 100 monogenic disorders can present with IBD, new genetic disorders and variants are being discovered every year, and as phenotypic expression of the gene defects is variable, adaptive genomic technologies are required. Monogenic IBD has become a key area to establish the concept of precision medicine. Clear guidance and standardised, affordable applications of genomic technologies are needed to implement exome or genome sequencing in clinical practice. This joint British Society of Gastroenterology and British Society of Paediatric Gastroenterology, Hepatology and Nutrition guideline aims to ensure that testing resources are appropriately applied to maximise the benefit to patients on a national scale, minimise health-care disparities in accessing genomic technologies, and optimise resource use. We set out the structural requirements for genomic medicine as part of a multidisciplinary team approach. Initiation of genomic diagnostics should be guided by diagnostic criteria for the individual patient, in particular the age of IBD onset and the patient's history, and potential implications for future therapies. We outline the diagnostic care pathway for paediatric and adult patients. This guideline considers how to handle clinically actionable findings in research studies and the impact of consumer-based genomics for monogenic IBD. This document was developed by multiple stakeholders, including UK paediatric and adult gastroenterology physicians, immunologists, transplant specialists, clinical geneticists, scientists, and research leads of UK genetic programmes, in partnership with patient representatives of several IBD and rare disease charities., Competing Interests: Declaration of interests All members of the panel were asked to declare a minimum of 12 months competing personal and non-personal financial or non-financial interests when joining the group and before manuscript submission. eDelphi participants could abstain from voting where they either did not have sufficient knowledge to vote on a particular statement, or where they identified themselves as having a conflict precluding voting. CAA declares directorship of Anderson Genomics Consultancy, and consultancy for Genomics and Bridge Bio. HB is a Clinical Nurse Specialist for the Chronic Granulomatous Disorder Society. KCG is a Trustee for the UK Primary Immunodeficiency Network. VG is an employee of Crohn's & Colitis UK. SHa declares consultancy for Takeda. DH declares an advisory role for The X-linked Lymphoproliferative Syndrome Research Trust. ABH has been an invited speaker for Takeda UK, Ferring, and Janssen-Cilag; is Chair of the Crohn's & Colitis UK Medical Research Awards Committee and clinical representative on the Trustee Board; is Chair of the IBD UK Benchmarking Working Group and member of the IBD UK Steering Committee. CAL declares research support or fees for development and delivery of non-promotional education (or both) from Janssen, Takeda, AbbVie, AstraZeneca, Eli Lilly, Orion, Pfizer, Roche, Sanofi Aventis, Ferring, Union Chimique Belge (UCB), Biogen, and Genentech; is Secretary of the Inflammatory Bowel Disease Section, British Society of Gastroenterology, and a member of the Steering Committee of IBD UK. MP declares speaker fees from Janssen; declares research support for the IBD BioResource from Pfizer and Gilead (and research fellow for Pfizer); and is a member of the Crohn's & Colitis UK Research Advisory Group. RKR declares honoraria from Pharmacosmos and Celltrion; declares research support from Nestle; and is a member of the European Society for Paediatric Gastroenterology Hepatology and Nutrition Porto Group Monogenic IBD Guideline. RAS declares speaker honoraria, consultancy for early phase studies, and conference fees from GlaxoSmithKline, AbbVie, and Janssen. ST declares consultancy from Biogen, Bristol-Myers Squibb, Celgene, ChemoCentryx, Cosmo, Enterome, Ferring, Giuliani, GlaxoSmithKline, Genentech, Immunocore, Immunometabolism, Janssen, Lilly, MSD, Merck, Neovacks, Novonordisk, Novartis, NPS Pharmaceuticals, Pfizer, Proximagen, Receptos, Roche, Shire, Sigmoid Pharma, Takeda, Topivert, UCB, VHsquared, Vifor, Zeria, Sensyne, Satisfai, Bioclinica, Equillium, Mestag, Sorriso, and Protagonist; declares research support from AbbVie, the International Organization for the Study of Inflammatory Bowel Diseases, Lilly, UCB, Vifor, Norman Collisson Foundation, Pfizer, UK–India Education and Research Initiative, ECCO Health Care, and the Helmsley Trust; declares honoraria from AbbVie, Amgen, Biogen, Ferring, Takeda, Lilly; and declares travel expenses covered or reimbursed from AbbVie, Lilly, Johnson & Johnson, Pfizer, Takeda, Ferring, Amgen, and Biogen. HHU declares consultancy from OMass, Mestag, and SAB Novartis; project collaboration with Celgene/Bristol-Myers Squibb, Janssen, UCB, MiroBio, and Regeneron; grant reviewing for Crohn's In Childhood Research Association; and is a member of the Porto Group of ESPGHAN. DCW declares speaker fees from Celltrion and AbbVie; and is a member of the Scientific committee of the Crohn's in Childhood Research Association charity. ELB, CB, TIC, SHe, KDJJ, JK, and AL declare no competing interests. Further details of competing interests of authors are presented in the appendix (p 1)., (Copyright © 2023 Elsevier Ltd. All rights reserved.)