While formalin-related specimen shrinkage is well established, this mainly relates to specimens with significant contractility, such as cutaneous specimens.
The word ‘chronic’ literally refers to disease duration. The Centers for Disease Control (CDC) define chronic diseases broadly as conditions that last 1 year or...]]>
We identified 1022 patients diagnosed with OSCC between 2013 and 2017, of which 47.2% (n=482) were females and 12.3% (n=126) were <45 years old consistent with early-onset OSCC (
Furthermore, classification of disease and biomarker discovery to personalise care have advanced in the field. This review discusses progress in biomarker discovery and personalisation of treatment in decompensated cirrhosis and ACLF.
]]>A gentleman in his early 40s with a background of schizophrenia on clozapine presented with a 2-month history of rectal bleeding, diarrhoea, weight loss, a microcytic anaemia and a quantitative faecal immunochemical test (qFIT) result >400 µg Hb/g. Colonoscopy demonstrated multiple large polypoid lesions in the rectum and in the sigmoid colon; the sigmoid was unable to be passed by the colonoscope due to narrowing of the lumen (
What is the diagnosis?
Histology reported Michaelis-Gutmann bodies, diagnostic of colonic malakoplakia (
A woman in her 70s presented to an Australian centre with right upper quadrant pain, fevers and weight loss. She was born in Greece, having lived in Australia for 50 years. Significant background included chronic lymphocytic leukaemia (CLL), treated with venetoclax and rituximab.
Her white cell count was 3.20x109/L with normal liver function tests, bilirubin of 6 µmol/L and C reactive protein of 15 mg/L.
Cross-sectional imaging with CT found intrahepatic, extrahepatic, common bile duct dilatation (CBD) to 11 mm, pancreatic duct dilatation to 6 mm (a ‘double duct’ sign) and prominent para-aortic, coeliac and porta lymph nodes (
First, a clear-cut definition on how patients should...]]>
In Gut, Wester...]]>
In this study, we first evaluated the association between smoking and Lactobacillus abundance. Although we did not observe a significant association between some smoking phenotypes (eg, Agesmk, CigDay, SmkInit and SmkIndex) and Lactobacillus, compared with former smoking,...]]>
Ultra-short coeliac disease (USCD) is defined as villous atrophy only present in the duodenal bulb (D1) with concurrent positive coeliac serology. We present the first, multicentre, international study of patients with USCD.
Patients with USCD were identified from 10 tertiary hospitals (6 from Europe, 2 from Asia, 1 from North America and 1 from Australasia) and compared with age-matched and sex-matched patients with conventional coeliac disease.
Patients with USCD (n=137, median age 27 years, IQR 21–43 years; 73% female) were younger than those with conventional coeliac disease (27 vs 38 years, respectively, p<0.001). Immunoglobulin A-tissue transglutaminase (IgA-tTG) titres at index gastroscopy were lower in patients with USCD versus conventional coeliac disease (1.8xupper limit of normal (ULN) (IQR 1.1–5.9) vs 12.6xULN (IQR 3.3–18.3), p<0.001).
Patients with USCD had the same number of symptoms overall (median 3 (IQR 2–4) vs 3 (IQR 1–4), p=0.875). Patients with USCD experienced less iron deficiency (41.8% vs 22.4%, p=0.006).
Both USCD and conventional coeliac disease had the same intraepithelial lymphocytes immunophenotype staining pattern; positive for CD3 and CD8, but not CD4.
At follow-up having commenced a gluten-free diet (GFD) (median of 1181 days IQR: 440–2160 days) both USCD and the age-matched and sex-matched controls experienced a similar reduction in IgA-tTG titres (0.5 ULN (IQR 0.2–1.4) vs 0.7 ULN (IQR 0.2–2.6), p=0.312). 95.7% of patients with USCD reported a clinical improvement in their symptoms.
Patients with USCD are younger, have a similar symptomatic burden and benefit from a GFD. This study endorses the recommendation of D1 sampling as part of the endoscopic coeliac disease diagnostic workup.
Genetic instrumental variables (IVs) for...]]>
The mechanism by which proton pump inhibitors (PPIs) alter gut microbiota remains to be elucidated. We aimed to learn whether PPI induced gut microbiota alterations by promoting oral microbial translocation.
Healthy adult volunteers were randomly assigned: PP group (n=8, 40 mg esomeprazole daily for seven days) and PM group (n=8, 40 mg esomeprazole along with chlorhexidine mouthwash after each meal for seven days). Fecal and saliva samples were analysed using 16S ribosomal RNA sequencing. Mouse models were introduced to confirm the findings in vivo, while the effect of pH on oral bacteria proliferation activity was investigated in vitro.
Taxon-based analysis indicated that PPI administration increased Streptococcus abundance in gut microbiota (P<0.001), and the increased species of Streptococcus were found to be from the oral site or oral/nasal sites, in which Streptococcus anginosus was identified as the significantly changed species (P<0.004). Microbial source tracker revealed that PPI significantly increased the contribution of oral bacteria to gut microbiota (P=0.026), and no significant difference was found in PM group (P=0.467). Compared to the baseline, there was a 42-fold increase in gut abundance of Streptococcus anginosus in PP group (P=0.002), and the times decreased to 16-fold in PM group (P=0.029). Mouse models showed that combination of PPI and Streptococcus anginosus significantly increased the gut abundance of Streptococcus anginosus compared with using PPI or Streptococcus anginosus only. Furthermore, Streptococcus anginosus cannot survive in vitro at a pH lower than 5.
PPIs altered gut microbiota by promoting oral-originated Streptococcus translocation into gut.
First, reverse causation from the diagnostic delay of neurodegenerative diseases is a big concern,
In silico prediction tools are pivotal for variant classification. AlphaMissense, a recent innovation, categorises missense variants across the human proteome into pathogenic, benign or ambiguous groups.
The correlation between cholangiocarcinoma (CCA) progression and bile is rarely studied. Here, we aimed to identify differential metabolites in benign and malignant bile ducts and elucidate the generation, function and degradation of bile metabolites.
Differential metabolites in the bile from CCA and benign biliary stenosis were identified by metabonomics. Biliary molecules able to induce mast cell (MC) degranulation were revealed by in vitro and in vivo experiments, including liquid chromatography-mass spectrometry (MS)/MS and bioluminescence resonance energy transfer assays. Histamine (HA) receptor expression in CCA was mapped using a single-cell mRNA sequence. HA receptor functions were elucidated by patient-derived xenografts (PDX) in humanised mice and orthotopic models in MC-deficient mice. Genes involved in HA-induced proliferation were screened by CRISPR/Cas9.
Bile HA was elevated in CCA and indicated poorer prognoses. Cancer-associated fibroblasts (CAFs)-derived stem cell factor (SCF) recruited MCs, and bile N,N-dimethyl-1,4-phenylenediamine (DMPD) stimulated MCs to release HA through G protein-coupled receptor subtype 2 (MRGPRX2)-Gαq signalling. Bile-induced MCs released platelet-derived growth factor subunit B (PDGF-B) and angiopoietin 1/2 (ANGPT1/2), which enhanced CCA angiogenesis and lymphangiogenesis. Histamine receptor H1 (HRH1) and HRH2 were predominantly expressed in CCA cells and CAFs, respectively. HA promoted CCA cell proliferation by activating HRH1-Gαq signalling and hastened CAFs to secrete hepatocyte growth factor by stimulating HRH2-Gαs signalling. Solute carrier family 22 member 3 (SLC22A3) inhibited HA-induced CCA proliferation by importing bile HA into cells for degradation, and SLC22A3 deletion resulted in HA accumulation.
Bile HA is released from MCs through DMPD stimulation and degraded via SLC22A3 import. Different HA receptors exhibit a distinct expression profile in CCA and produce different oncogenic effects. MCs promote CCA progression in a CCA-bile interplay pattern.
Fat deposition is modulated by environmental factors and genetic predisposition. Genome-wide association studies identified PNPLA3 p.I148M (rs738409) as a common variant that increases risk of developing liver steatosis. When and how this variant evolved in humans has not been studied to date.
Here we analyse ancient DNA to track the history of this allele throughout human history. In total, 6444 published ancient (modern humans, Neanderthal, Denisovan) and 3943 published present day genomes were used for analysis after extracting genotype calls for PNPLA3 p.I148M. To quantify changes through time, logistic and, by grouping individuals according to geography and age, linear regression analyses were performed.
We find that archaic human individuals (Neanderthal, Denisovan) exclusively carried a fixed PNPLA3 risk allele, whereas allele frequencies in modern human populations range from very low in Africa to >50% in Mesoamerica. Over the last 15 000 years, distributions of ancestral and derived alleles roughly match the present day distribution. Logistic regression analyses did not yield signals of natural selection during the last 10 000 years.
Archaic human individuals exclusively carried a fixed PNPLA3 allele associated with fatty liver, whereas allele frequencies in modern human populations are variable even in the oldest samples. Our observation might underscore the advantage of fat storage in cold climate and particularly for Neanderthal under ice age conditions. The absent signals of natural selection during modern human history does not support the thrifty gene hypothesis in case of PNPLA3 p.I148M.
Intestinal fibrosis is considered an inevitable consequence of chronic IBD, leading to stricture formation and need for surgery. During the process of fibrogenesis, extracellular matrix (ECM) components critically regulate the function of mesenchymal cells. We characterised the composition and function of ECM in fibrostenosing Crohn’s disease (CD) and control tissues.
Decellularised full-thickness intestinal tissue platforms were tested using three different protocols, and ECM composition in different tissue phenotypes was explored by proteomics and validated by quantitative PCR (qPCR) and immunohistochemistry. Primary human intestinal myofibroblasts (HIMFs) treated with milk fat globule-epidermal growth factor 8 (MFGE8) were evaluated regarding the mechanism of their antifibrotic response, and the action of MFGE8 was tested in two experimental intestinal fibrosis models.
We established and validated an optimal decellularisation protocol for intestinal IBD tissues. Matrisome analysis revealed elevated MFGE8 expression in CD strictured (CDs) tissue, which was confirmed at the mRNA and protein levels. Treatment with MFGE8 inhibited ECM production in normal control HIMF but not CDs HIMF. Next-generation sequencing uncovered functionally relevant integrin-mediated signalling pathways, and blockade of integrin αvβ5 and focal adhesion kinase rendered HIMF non-responsive to MFGE8. MFGE8 prevented and reversed experimental intestinal fibrosis in vitro and in vivo.
MFGE8 displays antifibrotic effects, and its administration may represent a future approach for prevention of IBD-induced intestinal strictures.
The primary endpoint of our study investigated whether microbial compositions can be employed as early predictors for severity of acute pancreatitis (AP). Patients with revised Atlanta classification III (RAC III) showed highly significant microbial differences compared with RAC I and RAC II. Further analysis revealed a higher abundance of species that are known producers of short-chain fatty acids (SCFA) in severe AP. Van den Berg et al mention the lack of a healthy control cohort, however, it is already known from previous studies that the microbial composition in stool samples of patients with AP is different...]]>
Colonic diverticulosis is a prevalent condition among older adults, marked by the presence of thin-walled pockets in the colon wall that can become inflamed, infected, haemorrhage or rupture. We present a case–control genetic and transcriptomic study aimed at identifying the genetic and cellular determinants underlying this condition and the relationship with other gastrointestinal disorders.
We conducted DNA and RNA sequencing on colonic tissue from 404 patients with (N=172) and without (N=232) diverticulosis. We investigated variation in the transcriptome associated with diverticulosis and further integrated this variation with single-cell RNA-seq data from the human intestine. We also integrated our expression quantitative trait loci with genome-wide association study using Mendelian randomisation (MR). Furthermore, a Polygenic Risk Score analysis gauged associations between diverticulosis severity and other gastrointestinal disorders.
We discerned 38 genes with differential expression and 17 with varied transcript usage linked to diverticulosis, indicating tissue remodelling as a primary diverticula formation mechanism. Diverticula formation was primarily linked to stromal and epithelial cells in the colon including endothelial cells, myofibroblasts, fibroblasts, goblet, tuft, enterocytes, neurons and glia. MR highlighted five genes including CCN3, CRISPLD2, ENTPD7, PHGR1 and TNFSF13, with potential causal effects on diverticulosis. Notably, ENTPD7 upregulation was confirmed in diverticulosis cases. Additionally, diverticulosis severity was positively correlated with genetic predisposition to diverticulitis.
Our results suggest that tissue remodelling is a primary mechanism for diverticula formation. Individuals with an increased genetic proclivity to diverticulitis exhibit a larger numbers of diverticula on colonoscopy.
This study aims to validate the existence of a microbiome within intraductal papillary mucinous neoplasm (IPMN) that can be differentiated from the taxonomically diverse DNA background of next-generation sequencing procedures.
We generated 16S rRNA amplicon sequencing data to analyse 338 cyst fluid samples from 190 patients and 19 negative controls, the latter collected directly from sterile syringes in the operating room. A subset of samples (n=20) and blanks (n=5) were spiked with known concentrations of bacterial cells alien to the human microbiome to infer absolute abundances of microbial traces. All cyst fluid samples were obtained intraoperatively and included IPMNs with various degrees of dysplasia as well as other cystic neoplasms. Follow-up culturing experiments were conducted to assess bacterial growth for microbiologically significant signals.
Microbiome signatures of cyst fluid samples were inseparable from those of negative controls, with no difference in taxonomic diversity, and microbial community composition. In a patient subgroup that had recently undergone invasive procedures, a bacterial signal was evident. This outlier signal was not characterised by higher taxonomic diversity but by an increased dominance index of a gut-associated microbe, leading to lower taxonomic evenness compared with the background signal.
The ‘microbiome’ of IPMNs and other pancreatic cystic neoplasms does not deviate from the background signature of negative controls, supporting the concept of a sterile environment. Outlier signals may appear in a small fraction of patients following recent invasive endoscopic procedures. No associations between microbial patterns and clinical or cyst parameters were apparent.
A 21-year-old woman presented at our hospital with recurrent fever and abdominal pain. Due to this, the patient has been hospitalised over 100 times. Initially, she was diagnosed with tuberculous peritonitis, yet showed poor response to antituberculosis medication. Besides, exploratory laparotomy at age 5 years revealed no evidence of tuberculosis. Further treatment for Crohn’s disease with infliximab for 6 months also presented no significant improvement. The symptoms persistently recurred with glucocorticoid and immunosuppressive treatment despite momentary relief. One year prior current hospitalisation, the patient endured an acute intestinal perforation, and abdominal pain recurred 3 weeks before. In her family, her elder brother died as a neonate for unknown reasons.
Large patches of brown pigmentation were examined on her back (
On the 31st day...]]>
In a survey among 260 outpatients and staff in a tertiary care endoscopy unit, we calculated transportation-related greenhouse gas emissions for each endoscopic procedure to be 11.5 kg CO2e. According to our calculation model, this represents 32.7% of scope 3 carbon emissions, highlighting the central role of patient and staff transportation. Combining two procedures into one appointment, where indicated, reduces transportation-related CO2 emissions by 13%. Notably, 37% of outpatients reported a preference for videoconferencing over in-person pre-endoscopic consultations, representing a potential 18.9% reduction in CO2 emissions from patient transportation. Recognising patient preferences for videoconferencing aligns with both patient benefits and environmental considerations.
Endoscopy units contribute significantly to the carbon footprint of healthcare. Reducing CO2 emissions from these units seems crucial for sustainability and economic reasons. The ‘Green Endoscopy Project Würzburg’
Dynamic changes in non-invasive tests, such as changes in alanine aminotransferase (ALT) and MRI proton-density-fat-fraction (MRI-PDFF), may help to detect metabolic dysfunction-associated steatohepatitis (MASH) resolution, but a combination of non-invasive tests may be more accurate than either alone. We developed a novel non-invasive score, the MASH Resolution Index, to detect the histological resolution of MASH.
This study included a derivation cohort of 95 well-characterised adult participants (67% female) with biopsy-confirmed MASH who underwent contemporaneous laboratory testing, MRI-PDFF and liver biopsy at two time points. The primary objective was to develop a non-invasive score to detect MASH resolution with no worsening of fibrosis. The most predictive logistic regression model was selected based on the highest area under the receiver operating curve (AUC), and the lowest Akaike information criterion and Bayesian information criterion. The model was then externally validated in a distinct cohort of 163 participants with MASH from a clinical trial.
The median (IQR) age and body mass index were 55 (45–62) years and 32.0 (30–37) kg/m2, respectively, in the derivation cohort. The most accurate model (MASH Resolution Index) included MRI-PDFF, ALT and aspartate aminotransferase. The index had an AUC of 0.81 (95% CI 0.69 to 0.93) for detecting MASH resolution in the derivation cohort. The score calibrated well and performed robustly in a distinct external validation cohort (AUC 0.83, 95% CI 0.76 to 0.91), and outperformed changes in ALT and MRI-PDFF.
The MASH Resolution Index may be a useful score to non-invasively identify MASH resolution.
Endoscopic neoplasia detection in inflammatory bowel disease (IBD) remains challenging. We developed and validated a novel artificial intelligence (AI) model for lesion detection and characterisation in 478 images from 30 patients with IBD, 10 of whom had a total of 25 neoplastic lesions (including 8 sessile serrated polyps); sensitivity and specificity for lesion detection were 93.5% and 80.6%, respectively. The IBD model was then further validated during a real-time endoscopic assessment of a further 30 consecutive patients with 25 neoplastic lesions found in 11/30 of them and achieved lesion detection rate, lesion per colonoscopy and neoplasia per colonoscopy of 90.4%, 4.6% and 0.96. respectively. The sensitivity and specificity of lesion characterisation were 87.5% and 80.6%, respectively.
Deep learning (DL) is a subset of AI that uses multilayered computer algorithms (also called deep artificial neural networks) to automatically learn representations of...]]>
Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), mostly characterised by HBV integrations, is prevalent worldwide. Previous HBV studies mainly focused on a few hotspot integrations. However, the oncogenic role of the other HBV integrations remains unclear. This study aimed to elucidate HBV integration-induced tumourigenesis further.
Here, we illuminated the genomic structures encompassing HBV integrations in 124 HCCs across ages using whole genome sequencing and Nanopore long reads. We classified a repertoire of integration patterns featured by complex genomic rearrangement. We also conducted a clustered regularly interspaced short palindromic repeat (CRISPR)-based gain-of-function genetic screen in mouse hepatocytes. We individually activated each candidate gene in the mouse model to uncover HBV integration-mediated oncogenic aberration that elicits tumourigenesis in mice.
These HBV-mediated rearrangements are significantly enriched in a bridge-fusion-bridge pattern and interchromosomal translocations, and frequently led to a wide range of aberrations including driver copy number variations in chr 4q, 5p (TERT), 6q, 8p, 16q, 9p (CDKN2A/B), 17p (TP53) and 13q (RB1), and particularly, ultra-early amplifications in chr8q. Integrated HBV frequently contains complex structures correlated with the translocation distance. Paired breakpoints within each integration event usually exhibit different microhomology, likely mediated by different DNA repair mechanisms. HBV-mediated rearrangements significantly correlated with young age, higher HBV DNA level and TP53 mutations but were less prevalent in the patients subjected to prior antiviral therapies. Finally, we recapitulated the TONSL and TMEM65 amplification in chr8q led by HBV integration using CRISPR/Cas9 editing and demonstrated their tumourigenic potentials.
HBV integrations extensively reshape genomic structures and promote hepatocarcinogenesis (graphical abstract), which may occur early in a patient’s life.
Submucosal endoscopy procedures including myotomy and endoresections using dissection knives can be hampered by intraprocedural bleeding, which negatively affects feasibility and procedural time. Large vessels usually require precutting coagulation with a dedicated coagulation forceps before subsequent dissection requiring frequent device exchanges between knives and coagulation forceps. Using saline immersion, vessels can be sealed with the tip of the electrosurgical knife and a special electrocautery setting. In 21 patients undergoing peroral endoscopy myotomy, there was no instrument exchange necessary as opposed to a 27% rate in a historical control group. The presealing coagulation resulted in a 21% reduction of intraprocedural bleeding that required retreatment with either dissection knife or coagulation forceps.
One of the major procedural risks of third space endoscopy techniques is represented by intraprocedural bleeding.
The analyses in our original paper suggest an elevated risk of undergoing an esophagogastroduodenoscopy (EGD) in patients treated with glucagon-like peptide-1 receptor agonists (GLP-1 RA) compared with control. As mentioned in our prior reply,
To evaluate the association between healthy lifestyle behaviours and the incidence of irritable bowel syndrome (IBS).
Population-based prospective cohort study.
The UK Biobank.
64 268 adults aged 37 to 73 years who had no IBS diagnosis at baseline were enrolled between 2006 and 2010 and followed up to 2022.
The five healthy lifestyle behaviours studied were never smoking, optimal sleep, high level of vigorous physical activity, high dietary quality and moderate alcohol intake.
The incidence of IBS.
During a mean follow-up of 12.6 years, 961 (1.5%) incident IBS cases were recorded. Among the 64 268 participants (mean age 55.9 years, 35 342 (55.0%) female, 7604 (11.8%) reported none of the five healthy lifestyle behaviours, 20 662 (32.1%) reported 1 behaviour, 21 901 (34.1%) reported 2 behaviours and 14 101 (21.9%) reported 3 to 5 behaviours at baseline. The multivariable adjusted hazard ratios associated with having 1, 2 and 3 to 5 behaviours for IBS incidence were 0.79 (95% confidence intervals 0.65 to 0.96), 0.64 (0.53 to 0.78) and 0.58 (0.46 to 0.72), respectively (P for trend <0.001). Never smoking (0.86, 0.76 to 0.98, P=0.02), high level of vigorous physical activity (0.83, 0.73 to 0.95, P=0.006) and optimal sleep (0.73, 0.60 to 0.88, P=0.001) demonstrated significant independent inverse associations with IBS incidence. No significant interactions were observed between these associations and age, sex, employment status, geographic location, gastrointestinal infection, endometriosis, family history of IBS or lifestyle behaviours.
Adhering to a higher number of healthy lifestyle behaviours is significantly associated with a lower incidence of IBS in the general population. Our findings suggest the potential of lifestyle modifications as a primary prevention strategy for IBS.
A 67-year-old man presented to the consultation in September 2022 with abdominal pain, described as a ‘stitch’ by the patient, occurring in crisis, and localised at the right hypochondrium in the last 6 months.
His medical history was marked by a cholecystectomy in 2017 and a metabolic syndrome. In addition, he reported an abdominal trauma at the age of 8 with a metal swing.
He was treated with metformin, tamsulosin, amlodipine and valsartan.
His laboratory blood tests were unremarkable.
An abdominal ultrasound was performed showing an atypical lesion of the liver segment VII. A dual-energy CT scanner and an MRI (
The radiologist suspected fatty component of the lesion, which was confirmed on a dual-energy CT (
What is your hypothesis? What would be your follow-up?
Given there was a fatty component...]]>
Inflammatory and metabolic biomarkers have been associated with hepatocellular cancer (HCC) risk in phases I and II biomarker studies. We developed and internally validated a robust metabolic biomarker panel predictive of HCC in a longitudinal phase III study.
We used data and banked serum from a prospective cohort of 2266 adult patients with cirrhosis who were followed until the development of HCC (n=126). We custom designed a FirePlex immunoassay to measure baseline serum levels of 39 biomarkers and established a set of biomarkers with the highest discriminatory ability for HCC. We performed bootstrapping to evaluate the predictive performance using C-index and time-dependent area under the receiver operating characteristic curve (AUROC). We quantified the incremental predictive value of the biomarker panel when added to previously validated clinical models.
We identified a nine-biomarker panel (P9) with a C-index of 0.67 (95% CI 0.66 to 0.67), including insulin growth factor-1, interleukin-10, transforming growth factor β1, adipsin, fetuin-A, interleukin-1 β, macrophage stimulating protein α chain, serum amyloid A and TNF-α. Adding P9 to our clinical model with 10 factors including AFP improved AUROC at 1 and 2 years by 4.8% and 2.7%, respectively. Adding P9 to aMAP score improved AUROC at 1 and 2 years by 14.2% and 7.6%, respectively. Adding AFP L-3 or DCP did not change the predictive ability of the P9 model.
We identified a panel of nine serum biomarkers that is independently associated with developing HCC in cirrhosis and that improved the predictive ability of risk stratification models containing clinical factors.
The extensive dataset of more than 127 million patients enables the detection of subtle signals, and propensity-score matching probably adapts well for measured confounders. Therefore, the main findings, increased risks of incident GERD and complications related to GERD with short-acting but not long-acting GLP-1 RAs, deserve attention. However, several factors should be considered before applying these conclusions widely.
Most significantly, the differences between short-acting and long-acting GLP-1 users may not reflect only pharmacological properties.
First, the authors did not include a control group of healthy...]]>
For this study, different cohort data sources were used for exposure and outcome to avoid sample overlap (). We used summary statistics from the medication use...]]>
In Gut, Bu et al hypothesised that exogenous metabolites from the diet might play a direct regulatory role in protein signalling and specifically in the activation of protein kinase B (AKT).
Chronic obstructive pulmonary disease (COPD) is a major cause of global illness and death, most commonly caused by cigarette smoke. The mechanisms of pathogenesis remain poorly understood, limiting the development of effective therapies. The gastrointestinal microbiome has been implicated in chronic lung diseases via the gut-lung axis, but its role is unclear.
Using an in vivo mouse model of cigarette smoke (CS)-induced COPD and faecal microbial transfer (FMT), we characterised the faecal microbiota using metagenomics, proteomics and metabolomics. Findings were correlated with airway and systemic inflammation, lung and gut histopathology and lung function. Complex carbohydrates were assessed in mice using a high resistant starch diet, and in 16 patients with COPD using a randomised, double-blind, placebo-controlled pilot study of inulin supplementation.
FMT alleviated hallmark features of COPD (inflammation, alveolar destruction, impaired lung function), gastrointestinal pathology and systemic immune changes. Protective effects were additive to smoking cessation, and transfer of CS-associated microbiota after antibiotic-induced microbiome depletion was sufficient to increase lung inflammation while suppressing colonic immunity in the absence of CS exposure. Disease features correlated with the relative abundance of Muribaculaceae, Desulfovibrionaceae and Lachnospiraceae family members. Proteomics and metabolomics identified downregulation of glucose and starch metabolism in CS-associated microbiota, and supplementation of mice or human patients with complex carbohydrates improved disease outcomes.
The gut microbiome contributes to COPD pathogenesis and can be targeted therapeutically.
A 46-year-old male patient was referred to our tertiary care hospital with multiple therapy refractory severely active ulcerative colitis (diagnosis since approximately 1 year). He was previously treated with infliximab, prednisolone, vedolizumab, filgotinib and mercaptopurine.
There was no significant medical history. Six weeks prior to admission at our ward, our patient was diagnosed with Kaposi sarcoma based on lesions on the feet and lower legs. His family history was positive for Crohn’s disease.
On admission, a sigmoidoscopy was performed, of which the images are shown below (
Additionally, an ultrasound was performed to determine the extent of the inflammation, as this could not be determined during colonoscopy. This showed that the colitis extended until the splenic flexure and that there was no inflammation of the terminal ileum.
What is the most likely diagnosis based on...]]>
As stated in the , 4907 proteins (cis-pQTLs) were used as instrumental variables...]]>
Phase II trials suggest glucagon-like peptide-1 receptor (GLP1) agonists resolve metabolic dysfunction-associated steatohepatitis but do not affect fibrosis regression. We aimed to determine the long-term causal effect of GLP1 agonists on the risk of major adverse liver outcomes (MALO) in patients with any chronic liver disease and type 2 diabetes.
We used observational data from Swedish healthcare registers 2010–2020 to emulate a target trial of GLP1 agonists in eligible patients with chronic liver disease and type 2 diabetes. We used an inverse-probability weighted marginal structural model to compare parametric estimates of 10-year MALO risk (decompensated cirrhosis, hepatocellular carcinoma, liver transplantation or MALO-related death) in initiators of GLP1 agonists with non-initiators. We randomly sampled 5% of the non-initiators to increase computational efficiency.
GLP1 agonist initiators had a 10-year risk of MALO at 13.3% (42/1026) vs 14.6% in non-initiators (1079/15 633) in intention-to-treat analysis (risk ratio (RR)=0.91, 95% CI=0.50 to 1.32). The corresponding 10-year per-protocol risk estimates were 7.4% (22/1026) and 14.4% (1079/15 633), respectively (RR=0.51, 95% CI=0.14 to 0.88). The per-protocol risk estimates at 6 years were 5.4% (21/1026) vs 9.0% (933/15 633) (RR=0.60, 95% CI=0.29 to 0.90) and at 8 years 7.2% (22/1026) vs 11.7% (1036/15 633) (RR=0.61, 95% CI=0.21 to 1.01).
In patients with chronic liver disease and type 2 diabetes who adhered to therapy over time, GLP1 agonists may result in lower risk of MALO. This suggests that GLP1 agonists are promising agents to reduce risk of chronic liver disease progression in patients with concurrent type 2 diabetes, although this needs to be corroborated in randomised trials.
Our primary objective was to validate eCura in a Western cohort that, as mentioned, showed a remarkable discriminative ability, and support that it may be applied in Western countries to stratify the risk of lymph node metastasis (LNM) after a gastric HRR. With W-eCura, we proposed a slight modification of the original system, increasing the cut-off of the submucosal invasion to 1 mm, which showed a small, although statistically significant, higher accuracy, while maintaining a very high sensitivity.
Current guidelines recommend long-term image-based surveillance for patients with low-risk intraductal papillary mucinous neoplasms (IPMNs). This simulation study aimed to examine the comparative cost-effectiveness of continued versus discontinued surveillance at different ages and define the optimal age to stop surveillance.
We constructed a Markov model with a lifetime horizon to simulate the clinical course of patients with IPMNs receiving imaging-based surveillance. We calculated incremental cost-effectiveness ratios (ICERs) for continued versus discontinued surveillance at different ages to stop surveillance, stratified by sex and IPMN types (branch-duct vs mixed-type). We determined the optimal age to stop surveillance as the lowest age at which the ICER exceeded the willingness-to-pay threshold of US$100 000 per quality-adjusted life year. To estimate model parameters, we used a clinical cohort of 3000 patients with IPMNs and a national database including 40 166 patients with pancreatic cancer receiving pancreatectomy as well as published data.
In male patients, the optimal age to stop surveillance was 76–78 years irrespective of the IPMN types, compared with 70, 73, 81, and 84 years for female patients with branch-duct IPMNs <20 mm, =20–29 mm, ≥30 mm and mixed-type IPMNs, respectively. The suggested ages became younger according to an increasing level of comorbidities. In cases with high comorbidity burden, the ICERs were above the willingness-to-pay threshold irrespective of sex and the size of branch-duct IPMNs.
The cost-effectiveness of long-term IPMN surveillance depended on sex, IPMN types, and comorbidity levels, suggesting the potential to personalise patient management from the health economic perspective.
Hyperferritinaemia is associated with liver fibrosis severity in patients with metabolic dysfunction-associated steatotic liver disease (MASLD), but the longitudinal implications have not been thoroughly investigated. We assessed the role of serum ferritin in predicting long-term outcomes or death.
We evaluated the relationship between baseline serum ferritin and longitudinal events in a multicentre cohort of 1342 patients. Four survival models considering ferritin with confounders or non-invasive scoring systems were applied with repeated five-fold cross-validation schema. Prediction performance was evaluated in terms of Harrell’s C-index and its improvement by including ferritin as a covariate.
Median follow-up time was 96 months. Liver-related events occurred in 7.7%, hepatocellular carcinoma in 1.9%, cardiovascular events in 10.9%, extrahepatic cancers in 8.3% and all-cause mortality in 5.8%. Hyperferritinaemia was associated with a 50% increased risk of liver-related events and 27% of all-cause mortality. A stepwise increase in baseline ferritin thresholds was associated with a statistical increase in C-index, ranging between 0.02 (lasso-penalised Cox regression) and 0.03 (ridge-penalised Cox regression); the risk of developing liver-related events mainly increased from threshold 215.5 µg/L (median HR=1.71 and C-index=0.71) and the risk of overall mortality from threshold 272 µg/L (median HR=1.49 and C-index=0.70). The inclusion of serum ferritin thresholds (215.5 µg/L and 272 µg/L) in predictive models increased the performance of Fibrosis-4 and Non-Alcoholic Fatty Liver Disease Fibrosis Score in the longitudinal risk assessment of liver-related events (C-indices>0.71) and overall mortality (C-indices>0.65).
This study supports the potential use of serum ferritin values for predicting the long-term prognosis of patients with MASLD.
To describe the long-term consequences of necrotising pancreatitis, including complications, the need for interventions and the quality of life.
Long-term follow-up of a prospective multicentre cohort of 373 necrotising pancreatitis patients (2005–2008) was performed. Patients were prospectively evaluated and received questionnaires. Readmissions (ie, for recurrent or chronic pancreatitis), interventions, pancreatic insufficiency and quality of life were compared between initial treatment groups: conservative, endoscopic/percutaneous drainage alone and necrosectomy. Associations of patient and disease characteristics during index admission with outcomes during follow-up were assessed.
During a median follow-up of 13.5 years (range 12–15.5 years), 97/373 patients (26%) were readmitted for recurrent pancreatitis. Endoscopic or percutaneous drainage was performed in 47/373 patients (13%), of whom 21/47 patients (45%) were initially treated conservatively. Pancreatic necrosectomy or pancreatic surgery was performed in 31/373 patients (8%), without differences between treatment groups. Endocrine insufficiency (126/373 patients; 34%) and exocrine insufficiency (90/373 patients; 38%), developed less often following conservative treatment (p<0.001 and p=0.016, respectively). Quality of life scores did not differ between groups. Pancreatic gland necrosis >50% during initial admission was associated with percutaneous/endoscopic drainage (OR 4.3 (95% CI 1.5 to 12.2)), pancreatic surgery (OR 3.2 (95% CI 1.1 to 9.5) and development of endocrine insufficiency (OR13.1 (95% CI 5.3 to 32.0) and exocrine insufficiency (OR6.1 (95% CI 2.4 to 15.5) during follow-up.
Acute necrotising pancreatitis carries a substantial disease burden during long-term follow-up in terms of recurrent disease, the necessity for interventions and development of pancreatic insufficiency, even when treated conservatively during the index admission. Extensive (>50%) pancreatic parenchymal necrosis seems to be an important predictor of interventions and complications during follow-up.
Endoscopy is among the top three contributors to CO2 emissions in hospitals, with power consumption being a key factor that can be directly addressed. Our multicentre study measured power consumption during endoscopic procedures, offering easily implementable approaches for energy conservation (
Rising greenhouse gas emissions drive climate change,
The optimal therapeutic response in cancer patients is highly dependent upon the differentiation state of their tumours. Pancreatic ductal adenocarcinoma (PDA) is a lethal cancer that harbours distinct phenotypic subtypes with preferential sensitivities to standard therapies. This study aimed to investigate intratumour heterogeneity and plasticity of cancer cell states in PDA in order to reveal cell state-specific regulators.
We analysed single-cell expression profiling of mouse PDAs, revealing intratumour heterogeneity and cell plasticity and identified pathways activated in the different cell states. We performed comparative analysis of murine and human expression states and confirmed their phenotypic diversity in specimens by immunolabeling. We assessed the function of phenotypic regulators using mouse models of PDA, organoids, cell lines and orthotopically grafted tumour models.
Our expression analysis and immunolabeling analysis show that a mucus production programme regulated by the transcription factor SPDEF is highly active in precancerous lesions and the classical subtype of PDA — the most common differentiation state. SPDEF maintains the classical differentiation and supports PDA transformation in vivo. The SPDEF tumour-promoting function is mediated by its target genes AGR2 and ERN2/IRE1β that regulate mucus production, and inactivation of the SPDEF programme impairs tumour growth and facilitates subtype interconversion from classical towards basal-like differentiation.
Our findings expand our understanding of the transcriptional programmes active in precancerous lesions and PDAs of classical differentiation, determine the regulators of mucus production as specific vulnerabilities in these cell states and reveal phenotype switching as a response mechanism to inactivation of differentiation states determinants.
Epidemiological studies highlight an association between pancreatic ductal adenocarcinoma (PDAC) and oral carriage of the anaerobic bacterium Porphyromonas gingivalis, a species highly linked to periodontal disease. We analysed the potential for P. gingivalis to promote pancreatic cancer development in an animal model and probed underlying mechanisms.
We tracked P. gingivalis bacterial translocation from the oral cavity to the pancreas following administration to mice. To dissect the role of P. gingivalis in PDAC development, we administered bacteria to a genetically engineered mouse PDAC model consisting of inducible acinar cell expression of mutant Kras (Kras+/LSL-G12D; Ptf1a-CreER, iKC mice). These mice were used to study the cooperative effects of Kras mutation and P. gingivalis on the progression of pancreatic intraepithelial neoplasia (PanIN) to PDAC. The direct effects of P. gingivalis on acinar cells and PDAC cell lines were studied in vitro.
P. gingivalis migrated from the oral cavity to the pancreas in mice and can be detected in human PanIN lesions. Repetitive P. gingivalis administration to wild-type mice induced pancreatic acinar-to-ductal metaplasia (ADM), and altered the composition of the intrapancreatic microbiome. In iKC mice, P. gingivalis accelerated PanIN to PDAC progression. In vitro, P. gingivalis infection induced acinar cell ADM markers SOX9 and CK19, and intracellular bacteria protected PDAC cells from reactive oxygen species-mediated cell death resulting from nutrient stress.
Taken together, our findings demonstrate a causal role for P. gingivalis in pancreatic cancer development in mice.
First, the authors investigated the association between on-treatment HCC risk and various baseline characteristics. However, some indicators (recently emerging biomarkers: quantified hepatitis B surface antigen (HBsAg)
Selective decontamination of the digestive tract (SDD) is a well-studied but hotly contested medical intervention of enhanced infection control. Here, we aim to characterise the changes to the microbiome and antimicrobial resistance (AMR) gene profiles in critically ill children treated with SDD-enhanced infection control compared with conventional infection control.
We conducted shotgun metagenomic microbiome and resistome analysis on serial oropharyngeal and faecal samples collected from critically ill, mechanically ventilated patients in a pilot multicentre cluster randomised trial of SDD. The microbiome and AMR profiles were compared for longitudinal and intergroup changes. Of consented patients, faecal microbiome baseline samples were obtained in 89 critically ill children. Additionally, samples collected during and after critical illness were collected in 17 children treated with SDD-enhanced infection control and 19 children who received standard care.
SDD affected the alpha and beta diversity of critically ill children to a greater degree than standard care. At cessation of treatment, the microbiome of SDD patients was dominated by Actinomycetota, specifically Bifidobacterium, at the end of mechanical ventilation. Altered gut microbiota was evident in a subset of SDD-treated children who returned late longitudinal samples compared with children receiving standard care. Clinically relevant AMR gene burden was unaffected by the administration of SDD-enhanced infection control compared with standard care. SDD did not affect the composition of the oral microbiome compared with standard treatment.
Short interventions of SDD caused a shift in the microbiome but not of the AMR gene pool in critically ill children at the end mechanical ventilation, compared with standard antimicrobial therapy.
Whether and how the PI3K-AKT pathway, a central node of metabolic homeostasis, is responsible for high-fat-induced non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) remain a mystery. Characterisation of AKT regulation in this setting will provide new strategies to combat HCC.
Metabolite library screening disclosed that palmitic acid (PA) could activate AKT. In vivo and in vitro palmitoylation assay were employed to detect AKT palmitoylation. Diverse cell and mouse models, including generation of AKT1C77S and AKT1C224S knock-in cells, Zdhhc17 and Zdhhc24 knockout mice and Akt1C224S knock-in mice were employed. Human liver tissues from patients with NASH and HCC, hydrodynamic transfection mouse model, high-fat/high-cholesterol diet (HFHCD)-induced NASH/HCC mouse model and high-fat and methionine/choline-deficient diet (HFMCD)-induced NASH mouse model were also further explored for our mechanism studies.
By screening a metabolite library, PA has been defined to activate AKT by promoting its palmitoyl modification, an essential step for growth factor-induced AKT activation. Biologically, a high-fat diet could promote AKT kinase activity, thereby promoting NASH and liver cancer. Mechanistically, palmitoyl binding anchors AKT to the cell membrane in a PIP3-independent manner, in part by preventing AKT from assembling into an inactive polymer. The palmitoyltransferases ZDHHC17/24 were characterised to palmitoylate AKT to exert oncogenic effects. Interestingly, the anti-obesity drug orlistat or specific penetrating peptides can effectively attenuate AKT palmitoylation and activation by restricting PA synthesis or repressing AKT modification, respectively, thereby antagonising liver tumorigenesis.
Our findings elucidate a novel fine-tuned regulation of AKT by PA-ZDHHC17/24-mediated palmitoylation, and highlight tumour therapeutic strategies by taking PA-restricted diets, limiting PA synthesis, or directly targeting AKT palmitoylation.
Intestinal fibrosis resulting in stricture formation and obstruction in Crohn’s disease (CD) and increased wall stiffness leading to symptoms in ulcerative colitis (UC) is among the largest unmet needs in inflammatory bowel disease (IBD). Fibrosis is caused by a multifactorial and complex process involving immune and non-immune cells, their soluble mediators and exposure to luminal contents, such as microbiota and environmental factors. To date, no antifibrotic therapy is available. Some progress has been made in creating consensus definitions and measurements to quantify stricture morphology for clinical practice and trials, but approaches to determine the degree of fibrosis within a stricture are still lacking.
We herein describe the current state of stricture pathogenesis, measuring tools and clinical trial endpoints development.
Data presented and discussed in this review derive from the past and recent literature and the authors’ own research and experience.
Significant progress has been made in better understanding the pathogenesis of fibrosis, but additional studies and preclinical developments are needed to define specific therapeutic targets.
We agree that H. pylori leads to severe complications including peptic ulcer or gastric cancer. There is unequivocal evidence that eradicating the bacterium in patients with peptic ulcer leads to a highly significant reduction in the risk of ulcer recurrence, with a number needed to treat of two or three.
OAC arises out of a metaplastic precursor in which the normal squamous lining of the oesophagus is replaced with columnar, mucin-secreting cells. This is termed Barrett’s oesophagus (BO) and is thought to form as a protective mechanism in response to gastro-oesophageal reflux disease (GORD).
The cells that make up this oesophageal metaplasia can take several forms, roughly being broken down into gastric-type (GM) and intestinal-type (IM) metaplasias and are often composed of a mixture of differentiation cell types. GM should not be confused with IM of the stomach, which largely phenocopies oesophageal IM and also carries a risk of progression to adenocarcinoma. It has been suggested that in the majority of patients,...]]>
Endoscopic mucosal resection (EMR) is the preferred treatment for non-invasive large (≥20 mm) non-pedunculated colorectal polyps (LNPCPs) but is associated with an early recurrence rate of up to 30%. We evaluated whether standardised EMR training could reduce recurrence rates in Dutch community hospitals.
In this multicentre cluster randomised trial, 59 endoscopists from 30 hospitals were randomly assigned to the intervention group (e-learning and 2-day training including hands-on session) or control group. From April 2019 to August 2021, all consecutive EMR-treated LNPCPs were included. Primary endpoint was recurrence rate after 6 months.
A total of 1412 LNPCPs were included; 699 in the intervention group and 713 in the control group (median size 30 mm vs 30 mm, 45% vs 52% size, morphology, site and access (SMSA) score IV, 64% vs 64% proximal location). Recurrence rates were lower in the intervention group compared with controls (13% vs 25%, OR 0.43; 95% CI 0.23 to 0.78; p=0.005) with similar complication rates (8% vs 9%, OR 0.93; 95% CI 0.64 to 1.36; p=0.720). Recurrences were more often unifocal in the intervention group (92% vs 76%; p=0.006). In sensitivity analysis, the benefit of the intervention on recurrence rate was only observed in the 20–40 mm LNPCPs (5% vs 20% in 20–29 mm, p=0.001; 10% vs 21% in 30–39 mm, p=0.013) but less evident in ≥40 mm LNPCPs (24% vs 31%; p=0.151). In a post hoc analysis, the training effect was maintained in the study group, while in the control group the recurrence rate remained high.
A compact standardised EMR training for LNPCPs significantly reduced recurrences in community hospitals. This strongly argues for a national dedicated training programme for endoscopists performing EMR of ≥20 mm LNPCPs. Interestingly, in sensitivity analysis, this benefit was limited for LNPCPs ≥40 mm.
NTR7477.
The Endoprem asks patients to rate the level of discomfort they experienced as well as the level of pain. According to the Collins Dictionary, however, discomfort and pain are synonyms
A 54-year-old Chinese woman presented with a 2-month history of abdominal distension, discomfort and reduced appetite. She also complained of increased stool frequency (3–5 bowel movements per day) with non-bloody loose stools, but no significant change in her weight. She had a history of total hysterectomy for uterine leiomyoma 12 years ago. Her physical examination yielded no discernible anomalies. Laboratory examinations, including haematological assessments, liver function tests and renal function tests, exhibited no evident irregularities. Moreover, stool specimens tested negative for viruses, parasites or bacteria. CT scan of the abdomen revealed no abnormalities. Consequently, she underwent a colonoscopy, which revealed multiple nodular and polypoidal protrusions (
Indeed, a perfect resection technique as evidenced by Mandarino et al is likely to reduce the need for base ablation; however, such perfect technique is not always possible be it due to polyp-related or endoscopist-related factors. Furthermore, perfect overlapping resections with wide margins would also theoretically preclude the need for snare tip soft coagulation (STSC) of the margins. However, if the theory of microscopic polyp remnants at the margins despite overlapping and wide resection holds true, then the same should be considered possible for the base. Several Randomised controlled trials (RCTs) comparing hot versus cold snare EMR have recently been presented.
We conducted a nationwide multigenerational cohort study to investigate CVD risk in family members of patients with IBD (). From the...]]>
Liver fibrosis is a prelude to a host of end-stage liver diseases. Hepatic stellate cells (HSCs), switching from a quiescent state to myofibroblasts, are the major source for excessive production of extracellular matrix proteins. In the present study, we investigated the role of Suv39h1, a lysine methyltransferase, in HSC-myofibroblast transition and the implication in liver fibrosis.
HSC-specific or myofibroblast-specific Suv39h1 deletion was achieved by crossbreeding the Suv39h1f/f mice to the Lrat-Cre mice or the Postn-CreERT2 mice. Liver fibrosis was induced by CCl4 injection or bile duct ligation.
We report that Suv39h1 expression was universally upregulated during HSC-myofibroblast transition in different cell and animal models of liver fibrosis and in human cirrhotic liver tissues. Consistently, Suv39h1 knockdown blocked HSC-myofibroblast transition in vitro. HSC-specific or myofibroblast-specific deletion of Suv39h1 ameliorated liver fibrosis in mice. More importantly, Suv39h1 inhibition by a small-molecule compound chaetocin dampened HSC-myofibroblast transition in cell culture and mitigated liver fibrosis in mice. Mechanistically, Suv39h1 bound to the promoter of heme oxygenase 1 (HMOX1) and repressed HMOX1 transcription. HMOX1 depletion blunted the effects of Suv39h1 inhibition on HSC-myofibroblast transition in vitro and liver fibrosis in vivo. Transcriptomic analysis revealed that HMOX1 might contribute to HSC-myofibroblast transition by modulating retinol homeostasis. Finally, myofibroblast-specific HMOX1 overexpression attenuated liver fibrosis in both a preventive scheme and a therapeutic scheme.
Our data demonstrate a previously unrecognised role for Suv39h1 in liver fibrosis and offer proof-of-concept of its targetability in the intervention of cirrhosis.
First, the prominent discriminative ability of both the original eCura system and W-eCura score was notable. According to our previous report,
Studies directly comparing the predictive value of both OLGA and OLGIM systems in the same cohort are scarce.
The results of Bredenoord et al
A 65-year-old woman had a positive Faecal Immunochemical Test (FIT) on a bowel cancer screening programme. Her medical history included migraines and hypercholesterolaemia. She had no allergies; she took a statin daily. She worked as a teacher, smoked five cigarettes per day and drank one glass of wine per week. At colonoscopy, there was polyposis including a 20 mm caecal polyp extending into the appendiceal orifice (
What was found in the caecum at repeat colonoscopy (
Surveillance colonoscopy revealed an everted appendix entirely occupied by polyp (
It is widely known that lactose malabsorption in adult-type hypolactasia (ATH) is caused by lactase downregulation beyond infancy.
The gain of function (GOF) CTNNB1 mutations (CTNNB1GOF) in hepatocellular carcinoma (HCC) cause significant immune escape and resistance to anti-PD-1. Here, we aimed to investigate the mechanism of CTNNB1GOF HCC-mediated immune escape and raise a new therapeutic strategy to enhance anti-PD-1 efficacy in HCC.
RNA sequencing was performed to identify the key downstream genes of CTNNB1GOF associated with immune escape. An in vitro coculture system, murine subcutaneous or orthotopic models, spontaneously tumourigenic models in conditional gene-knock-out mice and flow cytometry were used to explore the biological function of matrix metallopeptidase 9 (MMP9) in tumour progression and immune escape. Single-cell RNA sequencing and proteomics were used to gain insight into the underlying mechanisms of MMP9.
MMP9 was significantly upregulated in CTNNB1GOF HCC. MMP9 suppressed infiltration and cytotoxicity of CD8+ T cells, which was critical for CTNNB1GOF to drive the suppressive tumour immune microenvironment (TIME) and anti-PD-1 resistance. Mechanistically, CTNNB1GOF downregulated sirtuin 2 (SIRT2), resulting in promotion of β-catenin/lysine demethylase 4D (KDM4D) complex formation that fostered the transcriptional activation of MMP9. The secretion of MMP9 from HCC mediated slingshot protein phosphatase 1 (SSH1) shedding from CD8+ T cells, leading to the inhibition of C-X-C motif chemokine receptor 3 (CXCR3)-mediated intracellular of G protein-coupled receptors signalling. Additionally, MMP9 blockade remodelled the TIME and potentiated the sensitivity of anti-PD-1 therapy in HCC.
CTNNB1GOF induces a suppressive TIME by activating secretion of MMP9. Targeting MMP9 reshapes TIME and potentiates anti-PD-1 efficacy in CTNNB1GOF HCC.
A 79-year-old man was brought to the emergency department following a 2-week history of epigastric discomfort and a 4-day history of melaena and presyncope. His medical history was significant for hypertension, haemorrhagic strokes, peptic ulcer disease (PUD), previous Helicobacter pylori infection, chronic kidney disease, peripheral vascular disease and cognitive impairment. On examination, the patient was haemodynamically stable and afebrile, with tenderness elicited in his epigastrium and right upper quadrant. Laboratory results demonstrated a haemoglobin level of 93 g/L, white cell count of 9.9x109/L, urea of 28.4 mmol/L, creatinine of 109 µmol/L and estimated glomerular filtration rate of 55 mL/min/1.73 m2. His liver function tests (LFTs) were deranged with an aspartate transaminase of 374 U/L, alanine transaminase of 422 U/L, gamma-glutamyltransferase of 302 U/L, alkaline phosphatase of 507 U/L and bilirubin of 9 µmol/L.
An oesophagogastroduodenoscopy (OGD) revealed a large ulcer in the duodenal bulb and an adherent clot that was removed without any active bleeding or visible...]]>
The insights presented in this paper open discussion on the potential enhancement of EMR outcomes. Our extensive 15-year research experience at Westmead Hospital, Sydney, aligns closely with this topic.
The authors’ rationale behind base ablation is the need to treat polyp areas that might evade capture during a piecemeal resection. However, a systematic approach to LNPCP EMR may preclude its occurrence. This involves a systematic resection, starting from the lesion’s edge, ensuring a wide margin and proceeding in a...]]>
We beg to differ: previously, body mass index (BMI) has been proposed as having a moderate influence on duct diameters (r<0.3).
Regarding the influence of diabetes duration on gastroparesis prevalence, we agree on its significance. However, our methodology used propensity matching based on the presence of diabetes with neurological complications, as shown in the supplemental tables 1 and 2 in the original article,
While undiagnosed gastroparesis prior to the index date is a potential concern, our comparison of diabetes medications ensured a similar patient distribution. Additionally, by matching based on the most recent A1c levels prior to second-line diabetes medication prescription, we ensured that both cohorts were aligned in terms...]]>
Cholangiocarcinoma (CCA) is a heterogeneous malignancy with high mortality and dismal prognosis, and an urgent clinical need for new therapies. Knowledge of the CCA epigenome is largely limited to aberrant DNA methylation. Dysregulation of enhancer activities has been identified to affect carcinogenesis and leveraged for new therapies but is uninvestigated in CCA. Our aim is to identify potential therapeutic targets in different subtypes of CCA through enhancer profiling.
Integrative multiomics enhancer activity profiling of diverse CCA was performed. A panel of diverse CCA cell lines, patient-derived and cell line-derived xenografts were used to study identified enriched pathways and vulnerabilities. NanoString, multiplex immunohistochemistry staining and single-cell spatial transcriptomics were used to explore the immunogenicity of diverse CCA.
We identified three distinct groups, associated with different etiologies and unique pathways. Drug inhibitors of identified pathways reduced tumour growth in in vitro and in vivo models. The first group (ESTRO), with mostly fluke-positive CCAs, displayed activation in estrogen signalling and were sensitive to MTOR inhibitors. Another group (OXPHO), with mostly BAP1 and IDH-mutant CCAs, displayed activated oxidative phosphorylation pathways, and were sensitive to oxidative phosphorylation inhibitors. Immune-related pathways were activated in the final group (IMMUN), made up of an immunogenic CCA subtype and CCA with aristolochic acid (AA) mutational signatures. Intratumour differences in AA mutation load were correlated to intratumour variation of different immune cell populations.
Our study elucidates the mechanisms underlying enhancer dysregulation and deepens understanding of different tumourigenesis processes in distinct CCA subtypes, with potential significant therapeutics and clinical benefits.
We aim to compare the effects of proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2RAs) on the gut microbiota through longitudinal analysis.
Healthy volunteers were randomly assigned to receive either PPI (n=23) or H2RA (n=26) daily for seven consecutive days. We collected oral (saliva) and faecal samples before and after the intervention for metagenomic next-generation sequencing. We analysed intervention-induced alterations in the oral and gut microbiome including microbial abundance and growth rates, oral-to-gut transmissions, and compared differences between the PPI and H2RA groups.
Both interventions disrupted the gut microbiota, with PPIs demonstrating more pronounced effects. PPI usage led to a significantly higher extent of oral-to-gut transmission and promoted the growth of specific oral microbes in the gut. This led to a significant increase in both the number and total abundance of oral species present in the gut, including the identification of known disease-associated species like Fusobacterium nucleatum and Streptococcus anginosus. Overall, gut microbiome-based machine learning classifiers could accurately distinguish PPI from non-PPI users, achieving an area under the receiver operating characteristic curve (AUROC) of 0.924, in contrast to an AUROC of 0.509 for H2RA versus non-H2RA users.
Our study provides evidence that PPIs have a greater impact on the gut microbiome and oral-to-gut transmission than H2RAs, shedding light on the mechanism underlying the higher risk of certain diseases associated with prolonged PPI use.
ChiCTR2300072310.
Whether gastric metaplasia (GM) of the oesophagus should be considered as Barrett’s oesophagus (BO) is controversial. Given concern intestinal metaplasia (IM) may be missed due to sampling, the UK guidelines include GM as a type of BO. Here, we investigated whether the risk of misdiagnosis and the malignant potential of GM warrant its place in the UK surveillance.
We performed a thorough pathology and endoscopy review to follow clinical outcomes in a novel UK cohort of 244 patients, covering 1854 person years of follow-up. We complemented this with a comparative genomic analysis of 160 GM and IM specimens, focused on early molecular hallmarks of BO and oesophageal adenocarcinoma (OAC).
We found that 58 of 77 short-segment (<3 cm) GM (SS-GM) cases (75%) continued to be observed as GM-only across a median of 4.4 years of follow-up. We observed that disease progression in GM-only cases and GM+IM cases (cases with reported GM on some occasions, IM on others) was significantly lower than in the IM-only cases (Kaplan-Meier, p=0.03). Genomic analysis revealed that the mutation burden in GM is significantly lower than in IM (p<0.01). Moreover, GM does not bear the mutational hallmarks of OAC, with an absence of associated signatures and driver gene mutations. Finally, we established that GM found adjacent to OAC is evolutionarily distant from cancer.
SS-GM is a distinct entity from SS-IM and the malignant potential of GM is lower than IM. It is questionable whether SS-GM warrants inclusion in BO surveillance.
Endobiliary RFA uses high frequency current to generate heat, which results in coagulation and local tumour necrosis, possibly leading to delayed tumour growth. Theoretically, the potential benefit of eRFA is larger in tumours that originate from the bile duct itself rather than compressing the bile duct, such as pancreatic cancer. The safety and feasibility have been shown in multiple studies, but the efficacy has not been sufficiently studied in randomised trials yet.
Glucagon-like peptide (GLP-1) agonists, initially approved for diabetes and used off-label to treat obesity, have been shown to achieve substantial weight loss and improvement in cardiovascular health. Two...]]>
Prolonged wireless pH-monitoring off acid suppression for up to 96 hours is often recommended as the preferred testing modality for unproven GORD as it better accounts for day-to-day variability in oesophageal acid exposure and may be better tolerated than 24-hour ambulatory pH studies.
Hepatitis B virus (HBV) can integrate into the chromosomes of infected hepatocytes, contributing to the production of hepatitis B surface antigen (HBsAg) and to hepatocarcinogenesis. In this study, we aimed to explore whether transcriptionally active HBV integration events spread throughout the liver tissue in different phases of chronic HBV infection, especially in patients with HBsAg loss.
We constructed high-resolution spatial transcriptomes of liver biopsies containing 13 059 tissue spots from 18 patients with chronic HBV infection to analyse the occurrence and relative distribution of transcriptionally active viral integration events. Immunohistochemistry was performed to evaluate the expression of HBsAg and HBV core antigen. Intrahepatic covalently closed circular DNA (cccDNA) levels were quantified by real-time qPCR.
Spatial transcriptome sequencing identified the presence of 13 154 virus-host chimeric reads in 7.86% (1026 of 13 059) of liver tissue spots in all patients, including three patients with HBsAg loss. These HBV integration sites were randomly distributed on chromosomes and can localise in host genes involved in hepatocarcinogenesis, such as ALB, CLU and APOB. Patients who were receiving or had received antiviral treatment had a significantly lower percentage of viral integration-containing spots and significantly fewer chimeric reads than treatment-naïve patients. Intrahepatic cccDNA levels correlated well with viral integration events.
Transcriptionally active HBV integration occurred in chronically HBV-infected patients at different phases, including in patients with HBsAg loss. Antiviral treatment was associated with a decreased number and extent of transcriptionally active viral integrations, implying that early treatment intervention may further reduce the number of viral integration events.
An 85-year-old woman, with a high-grade fever (40°C) and abdominal pain, was referred to our hospital. Blood examination revealed an elevated white blood cell count (25.8x10/L) and elevated levels of C reactive protein (8.54 mg/dL), alanine aminotransferase (95 IU/L), aspartate transaminase (138 IU/L), alkaline phosphatase (804 IU/L), gamma-glutamyl transpeptidase (703 IU/L), and total (5.0 mg/dL) and direct (3.2 mg/dL) bilirubin. Contrast-enhanced CT (CECT) was performed (
What is the diagnosis?
CECT revealed a massive paraesophageal hernia, with prolapse of the stomach, duodenum and pancreatic head. Obstructive jaundice was accompanied by a mesenteric gastric volvulus (
In a recent study,
Recently in Gut, we described a novel m6A-XPO1-NFB pathway that is activated in patients with CD. Specifically, YTHDF1 m6A reader was found to selectively bind the 5’ UTR of XPO1 mRNA and induce its translation, increasing XPO1-mediated inflammation in intestinal cells both in vitro and in vivo.
Interestingly, novel studies have described salvianolic acid (SAC) as a selective inhibitor of YTHDF1, which can rescue Fragile X syndrome linked defects in neural progenitor cells.
While persistent T-cell receptor (TCR) signalling due to chronic tumour antigen is a major driver of exhaustion, the suppressive tumour microenvironment (TME) also contributes.
In 2013, rare heterozygous variants in CPA1 were identified in multiple cohorts of CP cases.
Similarly, we previously recruited 20 multiple affected IBD families with ≥3 first-degree members with IBD, totalling 51 patients with IBD (38 patients with CD and 13 ulcerative colitis (UC)) and 39 age-matched and gender-matched...]]>
First, medication usage as an important factor affecting CBD and PD diameters was not adequately analysed in this study. Several studies have pointed out that medications such as opioid, calcium antagonists and nitroglycerine can cause CBD or PD dilatation.
IBD-associated intestinal dysbiosis is characterised by reduced microbial diversity, increases in facultative anaerobes and a decrease in obligately anaerobic producers of short-chain fatty acids, as well as the accumulation of primary unconjugated bile acids and depletion of secondary bile acids.
Their results were in agreement with the only Western randomised controlled study conducted by Albers et al.
A previous randomised trial reported that endoscopic RFA combined with stenting significantly prolonged survival and stent patency in patients with extrahepatic CCA,...]]>
To quantify the magnitude of the possible hepatoprotective effects of FGF-21 analogues, we systematically searched three electronic databases from the inception date to 1 September 2023 to identify phase-2 randomised controlled trials (RCTs) examining the efficacy of FGF-21 analogues on the US Food and Drug Administration defined histological endpoints for conditional approval of new drugs for NASH, that is, NASH resolution without worsening of fibrosis or ≥1 stage fibrosis improvement without worsening of NASH. We also calculated the fragility...]]>
Detailed methods of the inclusion and exclusion criteria, systematic review, and statistical methods were shown in , and the registration number is CRD42023394825. Of the 489 articles identified, 476 articles were excluded (). A total of 13 RCTs were included which...]]>
However, we would like to argue that lifestyle modification as such cannot be uncoupled from the genetic background. Although the importance of genetic susceptibility in the development of IBD is widely accepted,
Although confounding may exist, our prospective cohort study design limits this possibility. For example, if an individual is not prescribed an antibiotic course for the first 10 years of follow-up, they will initially contribute at-risk time to the ‘no antibiotic exposure’ group. If, however, they are then prescribed an antibiotic course, the following 1–5 years will contribute time to the ‘antibiotic exposure group.’ At the end of these 5 years, the individual will then return and contribute additional time to the ‘no antibiotic exposure’ group until another course is prescribed. In this way, confounding is reduced, as individuals,...]]>
Expanding on Ng et al’s research, our study further investigates the associations between gut microbial taxa, metabolites and immune response to inactivated vaccines. Our findings establish a connection between maternal gut microbiota/metabolites and the efficacy of mother-to-infant antibody transfer, providing a potential protective strategy for infants against COVID-19 symptoms.
We conducted a prospective, observational investigation involving 97 vaccinated pregnant women in Guangdong, China, and profiled gut microbiota and metabolome using shotgun metagenomics and non-targeted metabolomics. All participants received two doses of inactivated SARS-CoV-2 vaccine, including CoronaVac and Sinopharm....]]>
A 33-year-old patient was referred to our tertiary care centre in poor condition. He presented a body mass index (BMI) of 12.9 kg/m2, refractory fever up to 39.5°C and abdominal pain with watery diarrhoea 15 times per day for 3 months. He reported recurrent respiratory infections since childhood, which probably caused diffuse varicose bronchiectasis with mucus plugging diagnosed at...]]>
An 18-year-old woman presented with a 4-day history of worsening abdominal pain. Physical examination revealed tenderness in the left mid abdomen, without rebound tenderness. Laboratory workups revealed neutrophilia (10 890/µL), elevated C reactive protein (38.59 mg/L) and increased faecal calprotectin (>50 µg/g). Haemoglobin, liver function, renal function and urinalysis results were within normal range. Immunological investigations, including immunoglobulin levels, antineutrophil cytoplasmic antibodies and antinuclear antibodies, were all normal. An abdominal CT scan demonstrated wall thickening of the distal duodenum and proximal jejunum (
Retrospective evidence and meta-analyses have shown conflicting results, with one of the latest suggesting similar clinical success but lower adverse events with LAMS.
However, the clinical benefits of TIPSS plus ECE, including embolisation of gastroesophageal varices and spontaneous splenorenal shunts/gastrorenal shunts, are still controversial. Indeed, previous studies yielded inconsistent results in terms of short-term or long-term clinical outcomes.
Fifteen studies () including 1408 patients with cirrhosis and variceal bleeding (1252 (88.9%) for secondary prophylaxis, 120 (8.5%) for...]]>
To investigate these links, we turned to two well-established models used previously to assess the relationship between the gut microbiota and responses to vaccination; antibiotic-treated...]]>
Using the CDC WONDER, a database with deidentified death records that included >99% of decedents in the USA, data associated with cirrhosis among adults aged 25 years and above were collected during 1 January 2012–31 December 2021. We estimated the age-standardised mortality rate (per 100 000 persons) using the direct method, referring to the 2000 US Census (standard population). To determine the impact of the pandemic on cirrhosis-related mortality (defined in ), we conducted a Prophet model to predict mortality rates in 1 March 2020–31 December 2021 based on the 1...]]>
As instrumental variables for MR analysis, independent genetic variants with genome-wide suggestive significance (p<5e-06) in each exposed dataset from public...]]>
To address this gap, we conducted a controlled acute alcohol intervention in healthy controls (n=8), individuals with ALD (n=14) and non-alcoholic fatty liver disease (NAFLD) (n=14). Ethanol (2.5 mL of 40% EtOH per kg body weight) was instilled via a nasogastric tube over 30 min by infusion pump. To sample hepatic and systemic venous blood simultaneously, we placed a catheter in a hepatic vein via a transjugular access and another catheter in the right internal jugular vein. Blood was sampled at eight time points over 3 hours (
The importance of gut resistome induction following H. pylori eradication therapies has been debated for years, and the available information is controversial; the general thought is that normal gut microbiota is restored 3–6 months after antibiotic treatment.
Therefore, we conducted a randomised controlled clinical trial as part of the GISTAR study
We would like to highlight several points relevant to the study. First, the term ‘short oesophageal myotomy’ appears to be more appropriate because the length of gastric myotomy is not intended to be modified. More importantly, ‘short’ and ‘long’ myotomy have been defined variably and...]]>
The effect of FCM on markers of bone turnover, noted by Zoller and colleagues, is of particular concern, especially the persistence of raised bone-specific alkaline phosphatase (ALP) to day 70. Patients with IBD have a higher risk of osteopenia and osteoporosis due to chronic inflammation, steroid use and nutritional deficiencies.
We previously reported 76 GC cases, positive for the antiparietal cell antibody (APCA) test; among them, 8 cases developed cancer in pure AIG stomachs without an apparent history of H. pylori infection.
These observations highlight the complexity of the regulation of gastric acid secretion and suggest that the underlying cause of hypochlorhydria is a major...]]>
To corroborate these findings, we now expanded the analysis to our cohort of 77 patients with CRC who underwent a bowel resection with anastomosis (
miRNAs are small non-coding RNAs, which regulate gene expression at the post-transcriptional level by silencing targeting mRNA(s). Intriguingly, miRNAs have been implicated in the pathogenesis of both IBD and neurodegenerative diseases (NDDs). miRNAs have emerged as important regulators of gut and blood–brain barrier (BBB) integrity.
Postinfectious IBS (PI-IBS) is a common disease in which GI symptoms begin after an episode of infective gastroenteritis. Acute gastroenteritis following infection with bacterial or viral pathogens is an important risk factor for IBS. Our previous study also confirmed that the odds of developing IBS are increased after acute GI infection.
Dr Juan Rodés, architect of the Liver Unit of the Hospital Clinic of the University of Barcelona, an internationally renowned centre for research in liver disease, died in Barcelona on 10 January 2017, aged 78 years. He was one of the most inspiring and influential leaders in the field of clinical hepatology and the physician who changed modern medical practice in Spain.
Juan graduated from the University of Barcelona School of Medicine, Barcelona, in 1962, and trained in Internal Medicine at the Hospital Clinic. The centre has had the privilege of having Dr Rodés as Head of Hepatology Professor of Medicine, Director and Chief Executive Officer, till his retirement.
Dr Rodés and five other doctors started The Liver Unit informally in 1969 in the Catalan town of Montferri, Tarragona. Prior to this, Juan had completed a 1-year fellowship in Paris with Professor Caroli. From the beginning, each member of the unit was...]]>