NIHR Nottingham Digestive Diseases Biomedical Research Unit

Abstract Introduction Classically, the common bile duct (CBD) is believed to have a variable presence of scattered smooth muscle within the muscularis mucosae. The prevalence and organisation of these fibres remain poorly defined. This study aimed to qualitatively and quantitatively assess smooth muscle in CBD resections from patients with biliary obstruction and examine correlations with peak preoperative bilirubin levels. Methods CBD specimens from 81 surgeries, between January 2019 and January 2025, were retrieved from Queen’s Medical Centre, Nottingham, and stained for desmin, smooth muscle actin (SMA), and calretinin. Qualitative analysis classified smooth muscle banding around the lumen. Quantitative analysis was conducted using QuPath, employing a semi-automated approach, with manual annotation where required. Independent reviewers resolved discrepancies >10% by consensus. Additionally, bilirubin concentrations were correlated with quantitative smooth muscle measurements. Results Smooth muscle was present in all samples. Interrupted muscle bands were observed in 74.07% of cases, focal muscle fibres in 23.46%, and concentric bands in only 2.47%. Quantitative analysis of samples demonstrated mean tissue staining of 2.54% ± 2.44 (0.26–17.30) for Desmin, 32.86% ± 12.58 (3.74–66.25) for SMA and 2.27% ± 2.25 (0.27–18.24) for Calretinin. A weak positive correlation was observed between SMA expression and peak bilirubin (ρ = 0.241, P = 0.0312); correlations with desmin and calretinin were not significant. Conclusions This study introduces a novel semi-automated method for assessing smooth muscle in the CBD. The consistent presence of smooth muscle across all specimens challenges traditional assumptions and may have implications for understanding biliary physiology, pathology, and surgical planning.

Endoscopic resection (ER) is curative for early-stage oesophageal adenocarcinoma (OAC) without high-risk features. Piecemeal endoscopic mucosal resection (pEMR) prevents assessment of lateral margins, complicating risk estimation for neoplastic recurrence. We investigated the risk factors for residual and recurrent OAC post-pEMR. We performed a longitudinal study of two independent patient cohorts: the test cohort who underwent piecemeal or en-bloc ER (n=140) and the validation cohort who underwent pEMR only (n=89). Inclusion criteria were: OAC stage T1a or low-risk T1b, no lympho-vascular invasion, and R0 resection. The primary outcome was residual OAC at first post-ER endoscopy, and secondary outcomes were residual neoplasia (high-grade dysplasia and/or OAC), recurrence of neoplasia at any post-ER endoscopy, and remission of neoplasia, dysplasia and metaplasia at most recent endoscopy. In the test cohort, the incidence of neoplastic recurrence was higher in patients treated with pEMR (n=54, 49%) versus en-bloc ER (n=7, 23%) (p=0.021). The percentage of pEMR specimens with OAC was an independent risk factor for residual OAC at the first post-pEMR endoscopy (OR for a 10% increase=1.24, CI=1.03-1.51, p=0.025). A 50% cut-off of pEMR specimens with OAC was optimal to predict residual OAC (specificity=0.68, sensitivity=0.63). Rates of residual (p=0.039) and recurrent (p=0.0052) OAC were higher when >50% of pEMR specimens were involved by OAC. In the validation cohort, recurrent OAC was also more frequent when cancer burden was >50% (p=0.013). High cancer burden on pEMR specimens correlates with the risk of residual OAC. Post-pEMR site check before endoscopic ablation is recommended if more than 50% of pEMR specimens show OAC.

BackgroundChronic pancreatitis (CP) is a debilitating condition, characterised by chronic inflammation and fibrosis of the pancreas. The population frequency of CP is poorly understood. Therefore, we used a broad pragmatic approach to estimate the frequency of CP among a patient population undergoing investigations at a UK tertiary university hospital.MethodAll adult patients who, during 2006–2014, underwent abdominal CT MRI, abdominal X-ray, endoscopic ultrasonography (EUS), faecal elastase testing, received a pancreatin prescription or a recorded primary/comorbid ICD diagnosis of CP were screened (screening cohort) for inclusion. By applying the well-recognised CT, MRI and EUS criteria to the screening cohort, patients with CP were identified (study cohort). The incidence and point prevalence of CP were calculated, and changes in incidence were modelled using Poisson regression.ResultsScreening cohort included 24 271 cases, and 1003 patients who met the diagnostic criteria for CP were included in the study cohort. The median age of diagnosis was 65 (IQR 50–76); the majority were males (n=656, 65.4%) and of European ancestry (n=884, 88.1%). The annual incidence of diagnosis increased by a mean of 4.1% per year (95% CI 0.5% to 7.8%; p=0.03) over the study period ranging from 8.5 to 13.8 per 100 000 general population. The point prevalence also increased reaching 53.6 (95% CI 48.3 to 59.4) per 100 000 population at the end of the study period.ConclusionThis study provides a clear method of pragmatically identifying patients with CP in a clinical setting. The incidence of CP diagnosis in patients undergoing investigations in hospital increased gradually in Greater Nottingham.

The human colon receives 2 L of fluid daily. Small changes in the efficacy of absorption can lead to altered stool consistency with diarrhea or constipation. Drugs and formulations can also alter colonic water, which can be assessed using the magnetic resonance imaging (MRI) longitudinal relaxation time constant, T1. We explore the use of regional T1 assessment in evaluating disorders of colonic function. Individual participant data analysis of data from 12 studies from a single center of patients with constipation, irritable bowel syndrome with diarrhea (IBS-D), and healthy volunteers (HV). T1 was quantified by measuring the signal from the tissue at different times after a pulse which inverts the magnetization. When diarrhea was induced by a macrogol laxative T1 in the ascending colon, T1AC was negatively correlated with stool bacterial content, r2 = 0.78, p < 0.001. T1AC was increased by another laxative, rhubarb. Patients with IBS-D had elevated fasting T1AC (0.78 ± 0.28 s, N = 67) compared to HV (0.62 ± 0.21 s, N = 92) while those with constipation lay within the normal range (HV 10-90th centiles 0.33-0.91 s). Fasting T1AC in IBS-D was reduced by mesalazine treatment. T1 in the descending colon was consistently lower than T1AC, with a bigger reduction in patients with constipation than HV. Pre-feeding dietary fiber (bran, nopal, and psyllium) was associated with fasting T1AC at or above the normal 90th centile. T1 is an MRI parameter which could be used to monitor effectiveness of novel agents designed to alter colonic water content and stool consistency.

The prevalence of liver disease is rising in the United Kingdom (UK), with obesity underpinning surging metabolic dysfunction-associated steatotic liver disease (MASLD). MASLD is associated with an increased cardiometabolic risk, particularly when co-existing with type 2 diabetes. Progression to metabolic dysfunction-associated steatohepatitis (MASH) with hepatic fibrosis represents a clinical milestone strongly linked to serious liver disease and mortality.Therefore, clinically meaningful and sustained weight loss (≥10%) is a primary therapeutic target for patients with MASLD. Unfortunately, this is difficult for most people who adopt traditional lifestyle approaches. However, new obesity pharmacotherapies hold promise in MASLD, given their ability to produce dramatic weight loss (10-25%) and improve cardiometabolic health. Questions remain about the ability of these agents to improve liver fibrosis and patient-reported outcomes/quality of life in patients with advanced liver disease. Led from the Midlands (UK) but with national representation, we developed a network of stakeholders (clinicians, academics, third-sector, industry, and PPIE representatives) with an interest in obesity-related liver diseases. This network was called the Midlands Liver Research Alliance (MLRA), which sought to 1) establish a PPIE stakeholder network, 2) identify research priorities, and 3) map the network infrastructure and expertise. Health inequalities within liver disease are a core priority within the MLRA. The MLRA developed a large PPIE stakeholder network in collaboration with other local liver partnerships. These networks facilitated the identification of key research priorities that led to three NIHR funding applications. Priorities centered around: 1) the importance of patient-centered outcomes in obesity-related liver disease research; 2) the potential of glucagon-like peptide 1 (GLP-1)-based obesity pharmacotherapy in alcohol use disorder; and 3) early identification and management of liver disease in primary care/community. The MLRA has created a multidisciplinary hub of research expertise in obesity-related liver disease. This foundation provides a springboard for research activities in this area.

The Rome criteria, first published in 1994 and currently in their fourth iteration, are widely considered to be the gold standard symptom-based criteria to diagnose disorders of gut-brain interaction (DGBI), formerly known as functional gastrointestinal diseases [1]. To inform the upcoming Rome V criteria, due for publication in 2026, the Rome Foundation analysed the effects of modifying symptoms (e.g., pain and discomfort) and their relative frequency on the population prevalence of irritable bowel syndrome (IBS) [2, 3]. In a three-year UK-based prospective study, Goodoory et al. [4] published the performance of two of the Rome Foundation's proposed modifications to the Rome IV IBS diagnostic criteria, the original Rome IV criteria, and the Rome III criteria, using a reference standard as a comparison (Table 1). Consistent with previous work [7], the Rome IV criteria were more specific (85.1% vs. 80%) than Rome III, but less sensitive (82.1% vs. 92.6%). Modifying the criteria by relaxing the frequency of abdominal pain to three days per month, from one day per week, led to the best performance (sensitivity 90.2%, specificity 85.1%, positive likelihood ratio 6.06, and negative likelihood ratio 0.11) (Table 1, second modification to the Rome IV criteria). These data suggest that the developers of the Rome V diagnostic criteria for IBS should prioritise pain over discomfort and consider relaxing abdominal pain from at least one day per week to three days per month. Rome IV Presence of lower abdominal pain in association with either altered stool form or stool frequency at the first outpatient clinic appointment, in a patient who exhibited no evidence of organic gastrointestinal disease (following an investigative algorithm). Rome III A similar definition to the Rome IV reference standard, but the presence of abdominal discomfort was incorporated. This paper lends support to the initiatives of the Rome Foundation [2] and offers guidance for future revisions of the diagnostic criteria for IBS, albeit to an extent. Indeed, given that the study was conducted in a tertiary referral setting enriched with patients who underwent screening for organic diseases in primary care, the specificity and sensitivity of the Rome III and IV criteria may not accurately reflect those observed in community and general gastroenterology settings, particularly in countries outside the UK. Since the Roman Empire's limited global perspective contributed to its decline, the developers of the Rome V criteria for IBS should account for different symptom patterns and their relative impact across intercontinental populations. Compared with Rome III, making abdominal pain a mandatory requirement for a Rome IV IBS diagnosis and increasing its frequency threshold appears to have led to a more significant reduction in the population prevalence of IBS in Asia—specifically Japan [9.3% vs. 2.2%] and China [7.4% vs. 2.3%] [3]—compared to North America and Europe (9.2% vs. 4.6%) [8]. Although symptoms of bloating and discomfort are arguably more relevant to persons in Asia [9], factor analysis has confirmed the global applicability of the Rome IV criteria [10], and a similar intercontinental analysis should be undertaken to ensure Rome V's survival and international relevance. Goodoory et al. [4] have provided stonemasons with an additional brick in their quest to rebuild Rome. Only time will tell how pain, discomfort or symptom frequency will shape the next Rome iteration and how such refinements may enhance patients' quality of life and support access to evidence-based treatment. Mohsin F. Butt: writing – original draft, conceptualization. Maura Corsetti: conceptualization, writing – review and editing. The authors have nothing to report. M.C. is the co-chair of the Rome V Bowel Disorders Committee. M.F.B. has no relevant conflicts of interest to disclose. This article is linked to Goodoory et al paper. To view this article, visit https://doi.org/10.1111/apt.18363. The authors have nothing to report.

Aims This single centre prospective observational study aims to measure clinical and performance outcomes using the Speedboat 10fr Inject device/SBI, and the Speedboat-assisted Endoscopic Submucosal Dissection/S-ESD modality when removing complex colorectal lesions.

Alcohol-related liver disease (ARLD) is often diagnosed at a late stage when mortality is unacceptably high. Earlier identification of ARLD may lead to reduced alcohol intake, participation in hepatocellular carcinoma surveillance and reduction in liver-related morbidity and mortality. People with alcohol use disorder (AUD) are at highest risk of ARLD. The aim of this systematic review was to understand the yield of proactive screening for ARLD amongst high-risk groups. Embase, Medline, Scopus and grey literature were searched for studies describing proactive assessment for alcohol-related liver disease in people with a history of alcohol excess or diagnosed AUD. Outcomes of interest were fibrosis and cirrhosis detection rates, clinical outcomes, portal hypertension evaluation, attendance at follow-up and cost-effectiveness. Fifteen studies were identified for inclusion from 1115 returned by the search. Four key settings for patient engagement were identified as inpatient addiction services, outpatient addiction services, general acute hospital admissions and community outreach. Of these, acute hospital admissions were the highest yield for cirrhosis at 10.8%-29.6% and community outreach the lowest was 1.2%-2.3%. Targeted fibrosis assessment of high-risk populations for ARLD is feasible to conduct and identifies a proportion of patients at risk of advanced liver disease. The highest yield is amongst inpatients admitted with AUD. Prospective work is needed to establish which are the most effective and acceptable screening methods and the impact on long-term outcomes.

BackgroundHeat treatments of dairy, including pasteurization and ultra-high temperature (UHT) processing, alter milk macromolecular structures, and ultimately affect digestion. In vitro, animal, and human studies show faster nutrient release or circulating appearance after consuming UHT milk (UHT-M) compared with pasteurized milk (PAST-M), with a faster gastric emptying (GE) rate proposed as a possible mechanism. ObjectivesTo investigate the impact of milk heat treatment on GE as a mechanism of faster nutrient appearance in blood. We hypothesized that GE and circulating nutrient delivery following consumption would be faster for UHT-M than PAST-M. MethodsIn this double-blind randomized controlled cross-over trial, healthy female (n = 20; 27.3 ± 1.4 y, mean ± SD) habitual dairy consumers, consumed 500 mL of either homogenized bovine UHT-M or PAST-M (1340 compared with 1320 kJ). Gastric content volume (GCV) emptying half-time (T50) was assessed over 3 h by magnetic resonance imaging subjective digestive symptoms, plasma amino acid, lipid and B vitamin concentrations, and gastric myoelectrical activity were measured over 5 h. ResultsAlthough GCV T50 did not differ (102 ± 7 min compared with 89 ± 8 min, mean ± SEM, UHT-M and PAST-M, respectively; P = 0.051), GCV time to emptying 25% of the volume was 31% longer following UHT-M compared with PAST-M (42 ± 2 compared with 32 ± 4 min, P = 0.004). Although GCV remained larger for a longer duration following UHT-M (treatment × time interaction, P = 0.002), plasma essential amino acid AUC was greater following UHT-M than PAST-M (55,324 ± 3809 compared with 36,598 ± 5673 μmol·min·L-1, P = 0.006). Heat treatment did not impact gastric myoelectrical activity, plasma appetite hormone markers or subjective appetite scores. ConclusionsContrary to expectations, GE was slower with UHT-M, yet, as anticipated, aminoacidemia was greater. The larger GCV following UHT-M suggests that gastric volume may poorly predict circulating nutrient appearance from complex food matrices. Dairy heat treatment may be an effective tool to modify nutrient release by impacting digestion kinetics. Clinical Trial Registrywww.anzctr.org.au (ACTRN12620000172909).