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Background: Several randomized clinical trials comparing different bowel preparations (BP) have shown similar efficacy; however, there is a lack of real-world studies on this topic., Aims: This study aims to identify the most effective BP regimen in a real-world setting and any predictors of inadequate BP., Methods: A retrospective single-center study was conducted over 14 months at an academic hospital including outpatient colonoscopies in which adult patients did not teach on how to perform BP before colonoscopy. Colonoscopies with 1L-PEG, 2L-PEG and picosulphate mixtures were considered. A multivariable analysis for factors associated to poor BP was fitted., Results: Overall, 1779 patients (51 %F, 60±14) years were included. The 1L-PEG regimen provided a higher rate of BP adequacy at multivariate analysis (adjusted OR 2.30, 95 %CI 1.67-3.16,p < 0.001) and was associated with higher median Boston Bowel Preparation Scale score (p < 0.001), higher rate of right-colon cleansing (p < 0.001) and exam completion (p = 0.04). Furthermore, we identified male sex, history of constipation, active smoking, previous pelvic surgery, concomitant psychiatric/neurological or chronic kidney diseases as predictors of inadequate BP., Conclusions: This is the largest real-world study comparing 1L-PEG to other BP regimens. Our results suggest 1L-PEG provides better BP in a non-controlled setting, improving clinical practice quality and minimizing the need for repeated colonoscopies and saving healthcare resources., Competing Interests: Conflict of interest Authors declare no conflict of interests for this article., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Gastroenterologists still raise concerns about adopting a non-biopsy strategy for diagnosing celiac disease (CeD) in adults., Aim: To assess the performance of the concurrent detection of two autoantibodies targeting two independent antigens, tissue transglutaminase (tTG) and deamidated gliadin peptides (DGP)., Methods: This prospective, multicenter, binational study collected consecutive patients with a high pre-test probability for CeD. Between 2018 and 2020, adults were enrolled at four Italian and one Argentinian center. Serology was also blindly analyzed by a central laboratory (Werfen, San Diego, USA) for tTG IgA and DGP IgG by Aptiva Particle-based multi-analyte technology (PMAT) assays. CeD diagnosis required histological confirmation of Marsh 3 damage., Results: 181 adult patients with suspected CeD were enrolled (134 with histological diagnosis of CeD and 47 not histologically confirmed as CeD). Patients positive for both tTG IgA and DGP IgG (double positive) were predictive of CeD in 92.5 % of patients at >1x upper limit of normal (ULN). Double positivity for tTG IgA and DGP IgG, both at >10x ULN, had a 100 % positive predictive value for the presence of Marsh 3 histology., Conclusions: Incorporating DGP IgG alongside tTG IgA in a single-step approach can be considered a valid confirmatory strategy for definitive non-biopsy diagnosis of CeD., Competing Interests: Conflict of interest FZ served as a speaker for Werfen and a consultant for Takeda. CC served as a speaker for Werfen and Takeda. GLN was employee of Werfen at time of study. JCB was consultant for Takeda. All other authors declared no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Fecal calprotectin (FC) is a non-invasive biomarker of gut inflammation, but its role in celiac disease (CD) and non-celiac enteropathies (NCEs) is undefined., Aims: To retrospectively evaluate FC in patients with CD and NCEs as a tool for assessing disease activity and predicting long-term outcomes., Methods: Patients with uncomplicated and complicated CD, and NCEs with data on FC, evaluated at our center between June-2008 and December-2023, were enrolled. The relationship between elevated FC (>50 mg/kg) and disease activity was statistically analysed and Cox regression adjusted for age and sex was used to compare development of complications and mortality in patients with elevated and normal FC., Results: 177 patients (109F, mean age at diagnosis 39±20 years, 132 CD, 17 complicated CD, 28 NCEs) were enrolled. 55 patients had elevated FC, which was associated with lack of clinical and histological response to therapy (both p < 0.001). During a median follow-up of 103 months (IQR 54-176), 22 patients developed complications (15.4 %) and 21 died (11.9 %). Elevated FC was significantly more common in complicated CD (70.6 %) and NCEs (67.9 %) than in uncomplicated CD (18.2 %), p < 0.001. Elevated FC was independently predictive of developing complications (HR 4.8,95 %CI 1.4-17.7, p = 0.01) and mortality (HR 4.8,95 %CI 1.6-14.3, p < 0.01)., Conclusion: FC is a promising non-invasive biomarker for assessing disease severity and long-term outcomes in CD and NCEs., Competing Interests: Conflict of interest None to declare., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

We present the case of a 62-year-old man with a history of celiac disease and IgA deficiency, following a strict gluten-free diet that was admitted to our hospital for recurrent abdominal pain, fatigue and melena. Esophagogastroduodenoscopy and colonoscopy with biopsies were normal. A video-capsule endoscopy was performed and revealed a sub-stenosing, vegetating, and bleeding lesion in the first jejunal loop. He underwent laparotomic surgery with resection of the involved segment with loco-regional lymphadenectomy. The pathological report described a poorly differentiated adenocarcinoma of the jejunum, stage IIIA (pT3pN1). Analysis of next-generation sequencing (NGS) of DNA on the surgical sample revealed a likely pathogenetic variant in exon 15 of the DDR2 gene (c.2003G > A) and a TP53 non-frame-shift deletion (c.585&#95;602del). Considering the risk of recurrence, he was candidate to 6 months of adjuvant chemotherapy with platinum salt and fluoropyrimidine. Thirty-eight months after the diagnosis, the patient is still disease free and in good clinical condition. This is the first described case of SBA with DDR2 mutation. Considering the limited therapeutic options beyond surgery for SBA, molecular analyses could become promising for the search for potential targetable alterations for treatments with new available drugs., (© 2024. Japanese Society of Gastroenterology.)

Background: Data on resilience, the ability to recover from adversity, in coeliac disease (CeD) are lacking., Aim: To assess the degree of resilience in patients with CeD on a gluten-free diet (GFD), and its association with clinical features, sociodemographic factors, psychological morbidity, and quality of life (QOL)., Methods: A cross-sectional multicentre Italian study was conducted on adult CeD patients between May 2022 and April 2023. Connor-Davidson Resilience Scale (CD-RISC), the Coeliac Disease-specific Quality of Life Scale (CD-QOL), the State-Trait Anxiety Inventory scale (STAI-Y), and the Beck Depression Inventory scale (BDI) were used to evaluate resilience, QOL, anxiety, and depression, respectively. A multivariate analysis was conducted to identify factors independently associated with the degree of resilience., Results: A total of 305 patients (221 F, mean age at CeD diagnosis 36 ± 16 years) on a long-term GFD (median 8 years, IQR 3-17) were enrolled. A total of 298/305 patients (98%) had a high level of resilience (CD-RISC ≥ 35). At univariate analysis, resilience was statistically associated with male gender ( p = 0.03), age at enrolment ( p = 0.02), marital status ( p = 0.03), QOL ( p < 0.001), anxiety ( p < 0.001), and depression ( p < 0.001). On multivariate regression analysis, trait anxiety (STAI-Y2, p < 0.001) and depression (BDI, p = 0.02) were independent predictors of lower levels of resilience., Conclusions: Higher trait anxiety predicts lower levels of resilience. Targeted interventions in this subgroup of patients may be helpful for their management and follow-up.

Frailty is a multidimensional syndrome predominantly studied in the elderly, characterized by reduced resistance to stressors due to diminished physiological reserve and resilience. Advances in surgical techniques and immunosuppressive drugs have improved long-term survival rates in solid organ transplant recipients, yet the 10-year survival is satisfying. However, liver transplant recipients have a noteworthy risk of developing frailty status. After liver transplant, frailty can be favored by socioeconomic, cultural, and health-related factors, leading to increased risks of hospitalization, morbidity, and mortality. Various tools for frailty assessment exist, but none are universally validated for post-transplant patients. The integration of socioeconomic and psychological factors into frailty evaluation could improve quality of life and long-term outcomes for transplant recipients. Multidisciplinary approaches, including psychosocial support, are essential for managing frailty and enhancing the overall care of transplanted patients. This narrative review aims to comprehensively address the principal frailty risk factors associated with liver transplantation.

Introduction: To describe the clinical features and the risk of developing gastric tumors in patients with autoimmune gastritis (AIG)., Methods: This was a retrospective, longitudinal, multicenter study conducted at 8 Italian tertiary referral centers. We retrieved clinical data from all histologically proven patients with AIG. Differences between Helicobacter pylori -exposed vs H. pylori -naive and anti-parietal cell antibody (PCA)-positive vs PCA-negative patients were investigated. The rate of gastric adenocarcinoma and type 1 gastric neuroendocrine neoplasm (gNEN) was assessed. A multivariable model for factors associated with gNEN was fitted., Results: A total of 1,598 patients with AIG (median age 58 years, interquartile range 46-68; F:M ratio 2.7:1) were included. H. pylori -naive patients were more likely to have a first-degree family history of AIG (14.7% vs 8.9%; P = 0.012), type 1 diabetes mellitus (4.9% vs 2.3%; P = 0.025), and pernicious anemia (30.9% vs 21.1%; P = 0.003). PCA-positive patients had significantly more associated autoimmune diseases (59.0% vs 42.9%; P < 0.001) and were more likely to have been diagnosed by a case-finding strategy (15.3% vs 2.6%; P < 0.001). Overall, 15 cases (0.9%) of gastric adenocarcinoma and 153 cases (9.6%) of gNEN occurred, with a global rate of 0.12 (95% confidence interval [CI] 0.07-0.20) and 1.22 (95% CI 1.03-1.42) per 100 person/year, respectively. Having a vitamin B12/iron deficiency manifestation at AIG diagnosis was associated with a 16.44 (95% CI 9.94-27.20 P < 0.001) hazard ratio of gNEN., Discussion: The "pure" AIG pattern has typical features of an autoimmune disease and seems to be unrelated to H. pylori . In a tertiary referral setting, the risk of developing overt gastric adenocarcinoma is low, while patients with vitamin B12 deficiency complications at onset may benefit from a more intense endoscopic follow-up for early gNEN detection., (Copyright © 2024 by The American College of Gastroenterology.)

Background: 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., Methods: 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., Findings: 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 (1.8×upper limit of normal (ULN) (IQR 1.1-5.9) vs 12.6×ULN (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., Interpretation: 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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Grape seeds (GS), wine lees (WL), and grape pomace (GP) are common winery by-products, used as bio-fillers in this research with two distinct biopolymer matrices-poly(butylene adipate- co -terephthalate) (PBAT) and polybutylene succinate (PBS)-to create fully bio-based composite materials. Each composite included at least 30 v% bio-filler, with a sample reaching 40 v%, as we sought to determine a composition that could be economically and environmentally effective as a substitute for a pure biopolymer matrix. The compounding process employed a twin-screw extruder followed by an injection molding procedure to fabricate the specimens. An acetylation treatment assessed the specimen's efficacy in enhancing matrix-bio-filler affinity, particularly for WL and GS. The fabricated bio-composites underwent an accurate characterization, revealing no alteration in thermal properties after compounding with bio-fillers. Moreover, hygroscopic measurements indicated increased water-affinity in bio-composites compared to neat biopolymer, most significantly with GP, which exhibited a 7-fold increase. Both tensile and dynamic mechanical tests demonstrated that bio-fillers not only preserved, but significantly enhanced, the stiffness of the neat biopolymer across all samples. In this regard, the most promising results were achieved with the PBAT and acetylated GS sample, showing a 162% relative increase in Young's modulus, and the PBS and WL sample, which exhibited the highest absolute values of Young's modulus and storage modulus, even at high temperatures. These findings underscore the scientific importance of exploring the interaction between bio-fillers derived from winery by-products and three different biopolymer matrices, showcasing their potential for sustainable material development, and advancing polymer science and bio-sourced material processing. From a practical standpoint, the study highlighted the tangible benefits of using by-product bio-fillers, including cost savings, waste reduction, and environmental advantages, thus paving the way for greener and more economically viable material production practices.

Objectives: We aimed to evaluate the clinical response to cholestyramine in patients with functional chronic diarrhea and a high clinical suspicion of bile-acid diarrhea (BAD) investigated with 75-selenium homocholic acid taurine (SeHCAT) test., Methods: Adult patients attending our outpatient clinic between January and December 2021 for chronic diarrhea with suspicion of BAD were proposed SeHCAT testing and a therapeutic trial of cholestyramine 4-8 g daily. Clinical response to cholestyramine was evaluated at 1, 3, 6, and 12 months. Clinical and demographic data were analyzed according to SeHCAT test results., Results: Among the 50 patients with chronic diarrhea and clinical suspicion of BAD, 13 (26.0%) refused either SeHCAT testing or cholestyramine therapy. Finally, 37 patients (31 females, age 44 ± 14 years) agreed to undergo SeHCAT and were started on cholestyramine (median follow-up 14 months [interquartile range 6-16 months]). Initial response to cholestyramine was similar in patients with positive and negative SeHCAT test results, but improved over time in those with a positive test result. Long-term response (100% vs 65.2%, P = 0.02) and necessity of maintenance therapy for symptom control were more common in those with positive SeHCAT test result (71.4% vs 26.1%, P = 0.02). However, response to cholestyramine was also frequent in patients with a negative test result., Conclusions: The SeHCAT test accurately identifies patients with BAD who benefit from long-term cholestyramine treatment. Nevertheless, cholestyramine may be also effective in patients with chronic diarrhea but negative SeHCAT test result., (© 2024 The Author(s). Journal of Digestive Diseases published by Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Background: Few data are available on flow cytometry (FC) for monitoring intraepithelial lymphocytes (IELs) in refractory celiac disease (RCD), non-responsive celiac disease (NRCD), and non-celiac enteropathies (NCEs)., Aims: 1) To investigate the significance of monitoring IELs immunophenotype with FC in patients with NRCD, RCD and NCEs; 2) to evaluate FC concordance with immunohistochemistry (IHC) and γ-TCR clonality analysis., Methods: Patients investigated between January-2012 and February-2023 were divided into two groups: 1)confirmed RCD or NRCD being investigated for persistent symptoms and suspected complications of celiac disease (CD); 2)NCEs lacking clinical/histological response. Clinical/molecular features and outcomes were retrospectively collected and analysed according to presence/absence of aberrant IELs on FC (cut-off≥20 % CD103+sCD3-CD8-iCD3+ IELs)., Results: 52 patients (18 RCD,21 NRCD,13 NCEs; 38F, 55±13 years; median follow-up 30 months, IQR 2-58) underwent 100 FC IELs determinations. 22/52 had ≥2 FC determinations and IEL phenotype remained unchanged over time in all them (κ=1.00). Aberrant IEL phenotype in CD was associated with increased mortality (HR 4.2, 95 % CI 1.5-11.9, p < 0.01). No patients with NCEs had an aberrant IEL phenotype at FC, although 3/13 developed lymphoma and 4/13 died. Concordance of FC was fair with both IHC (κ=0.40) and γ-TCR clonality analysis (κ=0.22)., Conclusion: FC is accurate for assessing and monitoring IEL phenotype and providing important prognostic information in celiac patients. Further study is needed on its role in NCEs., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Persistent symptoms in coeliac disease (CD) can be due to not only poor gluten-free diet (GFD) adherence and complications of CD, but also functional gastrointestinal disorders such as irritable bowel syndrome (IBS). Although the role of a low fermentable oligo-, di-, and monosaccharides and polyols (FODMAP) diet is well-established in IBS, little data are available on its role in coeliac patients with persistent IBS-like symptoms despite a GFD. Methods: We systematically reviewed the literature in accordance with the PRISMA guidelines for studies evaluating the role of FODMAPs and/or a low-FODMAP diet in coeliac patients with persistent symptoms. PubMed and Embase were searched from inception to 16 January 2024 for eligible full-text papers. The study protocol was registered on Open Science Framework. Results: A total of 239 records were identified, and six papers were included. Of these, four were interventional studies comparing a low-FODMAP GFD to a regular GFD for persistent symptoms in 115 total coeliac patients (two randomized controlled trials and two open-label studies). A low-FODMAP GFD for a minimum of 4 weeks was significantly more effective than a regular GFD in reducing symptoms ( p < 0.05 in 3/4 studies). Dietary FODMAP content of a conventional GFD was significantly lower than that of non-coeliac patients on a gluten-containing diet (both p < 0.05), especially regarding high-FODMAP grain products. However, coeliac patients consumed more servings of fruits/vegetables high in FODMAP. No relationship between FODMAP intake and persistence of symptoms was reported. Conclusions: A low-FODMAP diet may be beneficial for uncomplicated celiac patients with persistent IBS-like symptoms despite strict adherence to a GFD.

Whipple's disease, an extremely rare, chronic infection caused by Tropheryma whipplei, an actinobacterium ubiquitously present in the environment, is a multisystemic condition that can affect several organs. Therefore, Whipple's disease should always be considered by physicians working across various branches of medicine, including internal medicine, rheumatology, infectious diseases, gastroenterology, haematology, and neurology. Initially, Whipple's disease is challenging to diagnose due to both its rarity and non-specific clinical features, almost indistinguishable from rheumatological conditions. A few years later, the onset of gastrointestinal symptoms increases the specificity of its clinical picture and helps in reaching the correct diagnosis. Diagnosis is typically made by finding PAS-positive macrophages in the lamina propria at duodenal biopsy. PCR for Tropheryma whipplei is nowadays also increasingly available, and represents an undeniable help in diagnosing this condition. However, it may also be misleading as false positives can occur. If not promptly recognized and treated, central nervous system involvement may develop, which can be fatal. The therapeutic gold standard has not yet been fully established, particularly in cases of recurrent disease, neurological involvement, and an immune reconstitution inflammatory syndrome that may arise following the initiation of antibiotic therapy., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Data on mortality in coeliac disease are contrasting., Aims: To systematically review the literature on all-cause and cause-specific mortality in coeliac disease compared to the general population, and evaluate differences across clinical phenotypes, geographical regions, and over time., Methods: We searched PubMed and Embase from 1 January 1970 to 31 December 2022 for eligible studies reporting on all-cause and cause-specific mortality in coeliac disease compared to the general population or controls. The protocol was registered on Open Science Framework (https://doi.org/10.17605/OSF.IO/852DN)., Results: We included 25 studies. All-cause mortality (HR 1.16, 95% CI 1.05-1.27, I 2  = 89%), mortality due to malignancies (HR 1.21, 95% CI 1.08-1.36, I 2  = 65%) and respiratory disease (HR 1.39, 95% CI 1.04-1.86, I 2  = 76%) were increased. Mortality due to non-Hodgkin lymphoma (HR 10.14, 95% CI 2.19-46.88, I 2  = 96%) was markedly increased. Mortality significantly decreased in recent decades: 1989-2004 (HR 1.61, 95% CI 1.27-2.03, I 2  = 91%), 2005-2014 (HR 1.16, 95% CI 0.99-1.36, I 2  = 89%), 2015-2022 (HR 1.19, 95% CI 1.05-1.35, I 2  = 93%). All-cause mortality was not increased in dermatitis herpetiformis (HR 0.85, 95% CI 0.73-0.99, I 2  = 40%) and undiagnosed coeliac disease (HR 1.09, 95% CI 0.95-1.25, I 2  = 0%). Mortality was increased in the UK (HR 1.23, 95% CI 1.03-1.47, I 2  = 91%) but not Scandinavia (HR 1.01, 95% CI 0.91-1.13, I 2  = 81%). Limitations include high heterogeneity and lack of data for many countries., Conclusion: Mortality in coeliac disease is increased, predominantly due to malignancies-particularly non-Hodgkin lymphoma-although differing significantly across disease phenotypes. Mortality of patients with coeliac disease has significantly decreased in recent decades. These results may influence diagnosis and management., (© 2024 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background: Although enteropathy due to angiotensin II receptor blockers (ARBs) has been known for over 10 years, clinicians' awareness of this condition is still low., Aims: To systematically review the literature about clinical phenotypes, distribution of mucosal changes throughout the gastrointestinal tract and prognosis of enteropathy due to ARBs., Methods: According to PRISMA guidelines, we searched PubMed and Embase for relevant articles up to November 6, 2023. We included full-text papers, letters, case reports and case series describing enteropathy due to ARBs. Patients were classified into subgroups based on endoscopic and histological findings of different regions of the gastrointestinal tract. The protocol was registered with Open Science Framework (https://doi.org/10.17605/OSF.IO/TK67C)., Results: We included 94 articles reporting 183 cases (101 female, mean age at diagnosis 69 ± 10 years). The clinical picture at diagnosis was characterised by severe diarrhoea (97%) and weight loss (84%, median -13 kg), leading to hospital admission in 167 (95%) patients. Olmesartan (90%) was most frequently implicated. Villous atrophy (VA) was reported in 164/183 (89%) patients. One hundred and nine had only VA, 12 had pan-gastrointestinal involvement, 23 had VA and gastric involvement and 19 had VA and colon involvement (predominantly microscopic colitis). Outcomes were reported for 178/183 (97%) patients, who all recovered clinically on ARBs withdrawal. Histological recovery occurred in all 96 patients with VA at baseline who underwent follow-up duodenal biopsy., Conclusions: Enteropathy due to ARBs is characterised by severe malabsorption often requiring hospital admission and can involve the entire gastrointestinal tract. Clinician awareness can lead to prompt diagnosis and excellent prognosis., (© 2024 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background: Whether coeliac disease in adults can be diagnosed with serology alone remains controversial. We aimed to evaluate the accuracy of serum anti-tissue transglutaminase IgA (tTG-IgA) in the diagnosis of coeliac disease., Methods: In this multicentre, prospective cohort study, adult participants (aged ≥18 years) with suspected coeliac disease without IgA deficiency who were not on a gluten-free diet and who had a local serum tTG-IgA measurement, were enrolled from Feb 27, 2018, to Dec 24, 2020, by 14 tertiary referral centres (ten from Europe, two from Asia, one from Oceania, and one from South America) to undergo local endoscopic duodenal biopsy. Local serum tTG-IgA was measured with 14 different test brands and concentration expressed as a multiple of each test's upper limit of normal (ULN), and defined as positive when greater than 1 times the ULN. The main study outcome was the reliability of serum tests for the diagnosis of coeliac disease, as defined by duodenal villous atrophy (Marsh type 3 or Corazza-Villanacci grade B). Histology was evaluated by the local pathologist, with discordant cases (positive tTG-IgA without duodenal villous atrophy or negative tTG-IgA with duodenal villous atrophy) re-evaluated by a central pathologist. The reliability of serum tests for the prediction of duodenal villous atrophy was evaluated according to sensitivity, specificity, positive predictive value, negative predictive value, and the area under the receiver operating characteristic curve (AUC) for categorical and continuous data., Findings: We enrolled 436 participants with complete local data on serum tTG-IgA and duodenal histology (296 [68%] women and 140 [32%] men; mean age 40 years [SD 15]). Positive serum tTG-IgA was detected in 363 (83%) participants and negative serum tTG-IgA in 73 (17%). Of the 363 participants with positive serum tTG-IgA, 341 had positive histology (true positives) and 22 had negative histology (false positives) after local review. Of the 73 participants with negative serum tTG-IgA, seven had positive histology (false negatives) and 66 had negative histology (true negatives) after local review. The positive predictive value was 93·9% (95% CI 89·2-98·6), the negative predictive value was 90·4% (85·5-95·3), sensitivity was 98·0% (95·3-100·0), and specificity was 75·0% (66·6-83·4). After central re-evaluation of duodenal histology in 29 discordant cases, there were 348 true positive cases, 15 false positive cases, 66 true negative cases, and seven false negative cases, resulting in a positive predictive value of 95·9% (92·0-99·8), a negative predictive value of 90·4% (85·5-95·3), a sensitivity of 98·0% (95·3-100·0), and a specificity of 81·5% (73·9-89·1). Either using the local or central definition of duodenal histology, the positive predictive value of local serum tTG-IgA increased when the serological threshold was defined at increasing multiples of the ULN (p<0·0001). The AUC for serum tTG-IgA for the prediction of duodenal villous atrophy was 0·87 (95% CI 0·81-0·92) when applying the categorical definition of serum tTG-IgA (positive [>1 × ULN] vs negative [≤1 × ULN]), and 0·93 (0·89-0·96) when applying the numerical definition of serum tTG-IgA (multiples of the ULN). Additional endoscopic findings included peptic gastritis (nine patients), autoimmune atrophic gastritis (three), reflux oesophagitis (31), gastric or duodenal ulcer (three), and Barrett's oesophagus (one). In the 1-year follow-up, a midgut ileum lymphoma was diagnosed in a woman on a gluten-free diet., Interpretation: Our data showed that biopsy could be reasonably avoided in the diagnosis of coeliac disease in adults with reliable suspicion of coeliac disease and high serum tTG-IgA., Funding: None., Competing Interests: Declaration of interests GLN is an employee of Werfen. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: Persistent villous atrophy (pVA) in coeliac disease (CD) despite a gluten-free diet (GFD) has unclear meaning. We aimed to (i) study the relationship between pVA and long-term outcomes and (ii) develop a score to identify patients at risk of pVA., Design: This is a multicentre retrospective-prospective study consisting of a study cohort (cohort 1) and an external validation cohort (cohort 2) of patients with biopsy-proven CD diagnosed between 2000 and 2021. Cohort 1 was used to (i) compare long-term outcomes between patients with and without pVA (Marsh ≥3a) at follow-up biopsy and (ii) to develop a score to evaluate the risk of pVA, which was validated in cohort 2., Results: Of 2211 patients, 694 (31%) underwent follow-up duodenal biopsy and were included in the study cohort (491F, 44±16 years). 157/694 (23%) had pVA. Risk of complications (HR 9.53, 95% CI 4.77 to 19.04, p<0.001) and mortality (HR 2.93, 95% CI 1.43 to 6.02, p<0.01) were increased in patients with pVA. A 5-point score was developed and externally validated (receiver operating characteristic area under the curve 0.78, 95% CI 0.68 to 0.89) to stratify patients by risk of pVA: low (0-1 points, 5% pVA), intermediate (2 points, 16% pVA) and high (3-5 points, 73% pVA). Predictors for pVA used in the score were age at diagnosis ≥45 years (OR 2.01, 95% CI 1.21 to 3.34, p<0.01), classical pattern of CD (OR 2.14, 95% CI 1.28 to 3.58, p<0.01), lack of clinical response to GFD (OR 2.40, 95% CI 1.43 to 4.01, p<0.001) and poor GFD adherence (OR 48.9, 95% CI 26.1 to 91.8, p<0.001)., Conclusions: Risk of complications and mortality were increased in patients with pVA. We developed a score to identify patients at risk of pVA and in need of histological reassessment and closer follow-up., Competing Interests: Competing interests: DSS is the recipient of an educational grant from Dr Schӓr. AS and DL have received honoraria from Takeda Pharmaceuticals., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Fibroblast growth factor 21 (FGF-21), previously recognized as a marker of liver damage and a potential drug target in non-alcoholic fatty liver disease (NAFLD), has unclear implications in hepatitis C virus (HCV) infections. This study aimed to investigate the relationship between FGF-21 levels and liver health in patients with HCV undergoing direct-acting antiviral (DAA) treatment. Forty-five patients were assessed for liver stiffness, blood chemistry, and other relevant metrics before and after achieving sustained viral response (SVR), defined as the absence of detectable HCV-RNA after 24 weeks of treatment. Post-treatment, all patients showed a decrease in liver stiffness and improved liver enzyme levels (AST and ALT), alongside an increase in FGF-21 levels. Interestingly, the increase in FGF-21 correlated negatively with liver stiffness but showed no correlation with hepatic steatosis. The observed elevation in FGF-21 levels at SVR following DAA therapy for chronic HCV infection can be attributed to the restoration of hepatic function, including its synthetic capabilities. Specifically, the mitigation of liver fibrosis post-HCV eradication is expected to lead to improvements in liver function, such as enhanced albumin and FGF-21 production. This improvement in synthetic function likely drives the increase in FGF-21 levels, rather than changes in liver fat content. We suggest a potential role of FGF-21 as a marker of fibrosis and hepatic cytotoxicity and as a drug target beyond NAFLD, to be confirmed by additional studies.

Objectives: Whipple's disease (WD) is a rare and potentially fatal infectious disease caused by Tropheryma whipplei. It is characterized by a long prodromal phase that mimics a rheumatological disease, often leading to immunosuppressant treatment. Immune reconstitution inflammatory syndrome (IRIS) is currently the most important complication of WD, requiring prompt recognition and treatment as it can be fatal. However, epidemiological data on IRIS are scarce. We aimed to identify the clinical and laboratory predictors of IRIS at WD diagnosis and to evaluate whether the prevalence of IRIS has changed over time., Methods: Forty-five patients with WD (mean age 52 ± 11 years; 10 females) were followed up between January 2000 and December 2021. Clinical and laboratory data at WD diagnosis were retrospectively collected and compared among patients who developed IRIS and those who did not., Results: Erythrocyte sedimentation rate (ESR; 33.4 ± 11.8 mm/h vs 67.1 ± 26.3 mm/h, P < 0.01), platelet (PLT; 234 × 10 9 /L vs 363 × 10 9 /L, P < 0.01), and body mass index (22.0 ± 2.0 kg/m 2 vs 19.8 ± 3.0 kg/m 2 , P = 0.04) differed significantly between patients who subsequently developed IRIS and those who did not. ROC analysis identified ESR ≤46 mm/h (AUROC 0.88, 95% CI 0.72-1.00) and PLT ≤ 327 × 10 9 /L (AUROC 0.85, 95% CI 0.70-1.00) as optimal cut-off values to discriminate WD patients at a high risk of developing IRIS. Prevalence of IRIS remained stable (22.2%) over time., Conclusions: Low ESR and PLT count at diagnosis help identify WD patients at high risk of developing IRIS. Instead, a greater inflammatory response suggests a lower risk of IRIS. Prevalence of IRIS did not change over two decades., (© 2023 The Authors. Journal of Digestive Diseases published by Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Background: Ongoing symptoms in treated celiac disease (CD) are frequent and are commonly thought of as being due to infractions to a gluten-free diet (GFD) or complications., Aims: To study the etiology and natural history of clinically relevant events (CREs) throughout follow-up and identify predictors thereof to guide follow-up., Methods: CREs (symptoms/signs requiring diagnostic/therapeutic interventions) occurring in celiac patients between January-2000 and May-2021 were retrospectively collected between June and September 2021 and analysed., Results: One-hundred-and-eighty-nine adult patients (133 F, age at diagnosis 36 ± 13 years, median follow-up 103 months, IQR 54-156) were enrolled. CREs were very common (88/189, 47%), but hardly due to poor GFD adherence (4%) or complications (2%). Interestingly, leading etiologies were functional gastrointestinal disorders (30%), reflux disease (18%) and micronutrient deficiencies (10%). Age at diagnosis ≥ 45 years (HR 1.68, 95%CI 1.05-2.69, p = 0.03) and classical pattern of CD (HR 1.63, 95%CI 1.04-2.54, p = 0.03) were predictors of CREs on a multivariable Cox model. At 5 years, 46% of classical patients ≥ 45 years old at diagnosis were event-free, while this was 62% for non-classical/silent ≥ 45 years, 60% for classical < 45 years, and 80% for non-classical/silent < 45 years., Conclusions: CREs occurred in almost half of CD patients during follow-up, with functional disorders being very common. New follow-up strategies for adult CD may be developed based on age and clinical pattern at diagnosis., (© 2022. The Author(s).)

Introduction: Whipple's disease is a rare systemic infection due to an impaired immunological response against T. whipplei in genetically predisposed individuals. Since we previously noted development of H. pylori related complications in some patients with Whipple's disease, our aim was to study the prevalence of H. pylori infection and H. pylori related disorders in Whipple's disease., Methods: Whipple's disease patients diagnosed from Jan-2002 to Dec-2021 and two controls per patient, matched for age, gender, ethnicity and year of H. pylori testing were enrolled., Results: 34 patients with Whipple's disease and 68 controls were enrolled. H. pylori infection (13/34 vs 8/68, p<0.01), H. pylori-related gastritis (p<0.01) and gastric atrophy (p = 0.01) were significantly more common in patients with Whipple's disease than controls. H. pylori infection and Whipple's disease were diagnosed synchronously in 6/13 patients, and during follow-up in the remaining 7. Interestingly, these last 7 patients were all on trimethoprim-sulfamethoxazole long-term therapy. Two patients developed H. pylori-related gastric malignancies during follow-up. No patients on doxycycline developed H. pylori infection., Conclusions: H. pylori infection and related disorders are common in patients with Whipple's disease and should always be excluded both at time of diagnosis and during follow-up. These findings should be taken into account when selecting antibiotics for Whipple's disease long-term prophylaxis., Competing Interests: Declaration of Competing Interest None to declare., (Copyright © 2023 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Objectives: Data are lacking on the immunogenicity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines in patients affected by coeliac disease, Whipple's disease and other noncoeliac enteropathies (NCE), characterised by primary or drug-related immunosuppression. We aimed to assess humoral response to SARS-CoV-2 vaccination in these patients compared to controls., Methods: Between December 2021 and January 2022, IgG anti-SARS-CoV-2 spike protein antibodies were measured in serum samples of coeliac disease, Whipple's disease and NCE patients attending our gastroenterology outpatient clinic for follow-up, who had received their first SARS-CoV-2 vaccination dose 3-6-9 (±1) months prior. Humoral response was compared with healthy controls (vaccinated healthcare workers undergoing serological screening), matched for gender, age, and time from first vaccine dose at sample collection., Results: A total of 120 patients [107 coeliac disease; 10 Whipple's disease; 2 common-variable immunodeficiency (CVID); 1 idiopathic villous atrophy; 77 F, 42 ± 16 years] and 240 matched controls (154 F, 43 ± 14 years) were enrolled. At 3, 6 and 9 months, humoral response in coeliac patients was not impaired compared to controls. Inadequate humoral response to vaccination was significantly more common among Whipple's disease patients than controls ( P  < 0.001). Patients on immunosuppressive therapy had markedly lower IgG anti-SARS-CoV-2 antibody titres (median 14 vs. 520 BAU/mL, P  < 0.001). As expected, patients with CVID showed no humoral response to vaccination., Conclusions: Humoral immunogenicity of SARS-CoV-2 vaccines was not reduced in coeliac disease patients compared to controls, although it was in Whipple's disease and CVID patients. Post-vaccination humoral response should be monitored in patients with Whipple's disease and chronic enteropathies on immunosuppressive therapy in order to schedule vaccine booster doses., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Using data from the 2018 round of the International Computer and Literacy Survey (ICILS), this study looks at the effect of non-cognitive skills (e.g., motivation, ambition, and conscientiousness) on digital competences as measured by the Computer and Information Literacy (CIL) test score. Non-cognitive skills may be especially important in low-stakes tests such as ICILS, where students face no consequences - positive or negative - as a result of their performance. The empirical results show that several non-self-reported measures acting as proxies for non-cognitive skills are significant determinants of CIL test scores. Furthermore, the findings point at differences in non-cognitive skills across gender, immigrant background, and socioeconomic status. This suggests that one should be cautious when inferring about inequality in digital competences along these dimensions using low-stakes test scores, and underscores the importance of controlling for non-cognitive skills., Competing Interests: None., (© 2023 The Authors. Published by Elsevier Inc.)

Background: This paper investigates how the COVID-19 school closure has affected the gender gap in grade-8 students' performance and what are the drivers behind this. By analysing four different countries (i.e., the Russian Federation, Slovenia, Uzbekistan and the United Arab Emirates), the paper represents the first study addressing the issue from a comparative perspective., Methods: The study uses data from the Responses to Educational Disruption Survey (REDS) survey, which comprises international comparable data on how students approached remote learning during the COVID-19 disruption. The extent of the gender gap is estimated by employing an ordered logit model, while the Karlson-Holm-Breen (KHB) decomposition method is used to analyse the different potential channels that could account for the gender gap during COVID-19., Results: The empirical results reveal that, during the COVID-19 school closure, girls tended to perceive changes in their learnings less favourably than boys, both in terms of improvement in self-perceived learning and self-reported improvement in grades-with odds of a more affirmative response between 20 and 25% lower for girls relative to boys. The main drivers explaining this gender gap are physical activity and psychological distress of students during the COVID-19 disruption, as well as the perceived family climate., Conclusions: The paper shows systematic gender differences in how students perceived their educational outcomes changed due to the COVID-19 disruption, providing evidence on the factors driving these differences. The findings could be employed to design policy actions aimed at increasing gender equality in education., Competing Interests: Competing interestsThe authors declare that they do not have any competing interests., (© The Author(s) 2023.)

Background: Duodenal villous atrophy is due not only to coeliac disease and its complications but also to other rare enteropathies unrelated to gluten consumption, defined as noncoeliac enteropathies. The diagnosis of noncoeliac enteropathies remains challenging, and HLA typing has been widely used to exclude coeliac disease if DQ2 and DQ8 alleles are absent. However, the frequency of the various HLA alleles in noncoeliac enteropathies is still unknown., Aims: To describe the HLA genetic profile of patients affected by noncoeliac enteropathies who have been evaluated at our centres between 2000 and 2021, and to investigate the diagnostic role of HLA typing., Methods: Genomic DNA was collected from 44 Italian and 19 British adult patients with noncoeliac enteropathies. Patient genotypes were compared with those of healthy Italian and British populations obtained from HLA bone marrow donors' banks. In addition, genotypes were also compared with those of patients with coeliac disease and complicated coeliac disease., Results: Both in the Italian and in the British group, the DQA1*0102 DQB1*0602 haplotype and related alleles occurred significantly more frequently in patients with noncoeliac enteropathies compared to coeliac disease and complicated coeliac disease., Conclusions: Together with negative HLA-DQ2 and DQ8 haplotypes, the DQA1*0102 DQB1*0602 haplotype can be used to guide the differential diagnosis between coeliac disease and noncoeliac enteropathies., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Non-coeliac gluten sensitivity (NCGS) is still a poorly defined clinical condition. This review aims to describe the clinical features of subjects with a symptomatic response to gluten intake, and to estimate the prevalence of NCGS., Evidence Acquisition: Literature search was conducted in accordance with PRISMA recommendations. The PubMed database was searched for original articles until 1 st June 2020., Evidence Synthesis: We identified 30 relevant articles, including 14 studies that investigated NCGS through a double-blind, placebo-controlled crossover trial (DBPCC), and 16 that examined the role of gluten in causing symptoms without a DBPCC. We found that regardless of the diagnostic work up, gluten-sensitive patients were predominately middle-aged females complaining of abdominal pain, bloating and diarrhea. The pooled prevalence of NCGS after DBPCC was 24% (5-34%). Subjects with irritable bowel syndrome or self-reporting gluten intolerance accounted for the vast majority of the patients who did not start a DBPCC. A symptomatic response to a gluten-free diet (GFD) occurred in between 7% and 93% of patients. No data on long-term outcomes of NCGS individuals were reported., Conclusions: Clinical features of NCGS patients did not differ among all the included studies, whereas prevalence figures are rather heterogeneous. Long-term benefit of a GFD on these patients still needs to be ascertained.

Objective: Differential diagnosis of villous atrophy (VA) without coeliac antibodies in adults includes seronegative coeliac disease (CD) and chronic enteropathies unrelated to gluten, ie. non-coeliac enteropathies (NCEs). There is currently no international consensus on the nomenclature and diagnostic criteria for these enteropathies. In this work, a Delphi process was conducted to address this diagnostic and clinical uncertainty., Design: An international task force of 13 gastroenterologists from six countries was recruited at the 16th International Coeliac Disease Symposium, Paris, 2019. Between September 2019 and July 2021, a Delphi process was conducted through mail surveys to reach a consensus on which conditions to consider in the differential diagnosis of VA with negative coeliac serology and the clinical diagnostic approaches required for these conditions. A 70% agreement threshold was adopted., Results: Chronic enteropathies characterised by VA and negative coeliac serology can be attributed to two main clinical scenarios: forms of CD presenting with negative serology, which also include seronegative CD and CD associated with IgA deficiency, and NCEs, with the latter recognising different underlying aetiologies. A consensus was reached on the diagnostic criteria for NCEs assisting clinicians in differentiating NCEs from seronegative CD. Although in adults seronegative CD is the most common aetiology in patients with VA and negative serology, discriminating between seronegative CD and NCEs is key to avoid unnecessary lifelong gluten-free diet, treat disease-specific morbidity and contrast poor long-term outcomes., Conclusion: This paper describes the Paris consensus on the definitions and diagnostic criteria for seronegative CD and chronic NCEs in adults., Competing Interests: Competing interests: JAM has received study grants from Nexpep/ImmusanT, National Institutes of Health, Immunogenics, Johnson & Johnson, Kanyos/Anakion, Takeda Pharmaceutical, Allakos, Oberkotter, and Cour; consultancy fees from Bionix, UKKO, Dren Bio, Dr. Schär USA, Immunic, Chugai Pharma; holds patents licenced to Evelo Biosciences; and receives royalties from Torax Medical. GM received consultancy fees from Calypso Biotech. DAL: Takeda Pharmaceuticals., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Coeliac disease and dermatitis herpetiformis are immune-mediated diseases triggered by the consumption of gluten in genetically predisposed individuals. These guidelines were developed to provide general practitioners, paediatricians, gastroenterologists, and other clinicians with an overview on the diagnosis, management and follow-up of coeliac patients and those with dermatitis herpetiformis., Methods: Guidelines were developed by the Italian Societies of Gastroenterology. Following a systematic literature review, the Grading of Recommendations Assessment, Development and Evaluation methodology was used to assess the certainty of the evidence. Statements and recommendations were developed by working groups consisting of gastroenterologists and a paediatrician with expertise in this field., Results: These guidelines provide a practical guidance for the diagnosis, management and follow-up of coeliac patients and dermatitis herpetiformis in children and adults, both in primary care and in specialist settings. We developed four sections on diagnosis, gluten-free diet, follow-up and risk of complications in adults, one section focused on diagnosis and follow-up in children and one on the diagnosis and management of dermatitis herpetiformis., Conclusions: These guidelines may support clinicians to improve the diagnosis and management of patients with coeliac disease., Competing Interests: Conflict of interest None declared., (Copyright © 2022. Published by Elsevier Ltd.)

Background: Modalities for the transition to adult care of celiac patients diagnosed during childhood/adolescence and their impact on long-term adherence to a gluten-free diet (GFD-A), quality of life (QOL) and maintenance of follow-up in adulthood are unknown., Aims: To evaluate whether timing of transition affects long-term GFD-A, QOL, and continuity of follow-up in adulthood and to identify predictors of long-term GFD-A., Methods: Clinical and demographic data about pediatric care and adult follow-up at our center were retrospectively collected from clinical notes of celiac patients diagnosed during childhood/adolescence and then referred to our tertiary center. QOL and adult long-term GFD-A were prospectively evaluated with validated questionnaires. These parameters were studied by means of univariate and multivariate statistical analysis., Results: 183 patients (130F, mean age at diagnosis 7.6 ± 5.8 years) were enrolled. Median age at transition to adult care was 20 years (IQR 17-25). There was no relationship between age at transition to adult care, long-term GFD-A, QOL, and continuity of follow-up. GFD-A tended to improve overall from pediatric care to adult referral (OR 2.92, 95% CI 1.13-7.87, p = 0.02) and also throughout adult follow-up (OR 9.0, 95% CI 4.2-19.7, p < 0.01). On multivariable logistic regression analysis, classical symptoms at diagnosis of celiac disease (p = 0.02) and good GFD-A at adult referral (p < 0.01) predicted good long-term GFD-A, while being lost to follow-up predicted poorer long-term GFD-A (p = 0.02)., Conclusions: Clinical characteristics can guide development of personalized strategies for implementing long-term GFD-A and ensure maintenance of regular follow-up in celiac patients diagnosed in childhood/adolescence and transitioning to adult care., (© 2021. The Author(s).)

Background & Aims: Data on factors governing long-term adherence to a gluten-free diet (GFD) in celiac disease (CD) are scarce. We aimed to determine trends and clinical predictors of long-term GFD adherence in adult CD., Methods: Initial and long-term (>3 years) GFD adherence, clinical characteristics at baseline and follow-up were collected retrospectively from celiac patients followed-up over 20 years (2000-2020). Predictors of long-term GFD adherence at diagnosis, and follow-up were evaluated by multivariate logistic regression., Results: 248 patients (37 ± 12 years, 186F, median time on a GFD 90 months) were included. Twenty-five (10.1%) had only short-term follow-up (<3 years) while 223 (89.9%) had initial and long-term dietary assessment. 187/223 (83.9%) patients were initially adherent and 36/223 (16.1%) were not. 17/36 (47.2%) patients initially not adherent become adherent, while only 4/187 (2.1%) initially adherent patients became not adherent. In the long-term, 200/223 (89.7%) were adherent and 21/223 (9.4%) patients were not. Adherence improved more frequently than worsened (OR, 39.5; 95% CI, 11.4-178.5; P < .01). Classical symptoms (diarrhea, weight loss) at diagnosis of CD predicted stricter long-term GFD adherence (OR, 3.27; 95% CI, 1.21-8.81; P = .02), while anemia (OR, 0.31; 95% CI, 0.12-0.82; P = .02) and dermatitis herpetiformis (OR, 0.23; 95% CI, 0.06-0.91; P = .04) predicted poorer long-term adherence. At follow-up, initial GFD adherence (OR, 42.70; 95% CI, 10.70-171.00; P = .04) was the major determinant of long-term GFD adherence., Conclusions: GFD adherence changes over time in <10% of patients, generally improving when it does. Major determinants of long-term GFD adherence are classical symptoms at diagnosis and initial adherence to a GFD. Patients with anemia or dermatitis herpetiformis at diagnosis require stricter dietetic input., (Copyright © 2022 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: A standard tool to assess patients' knowledge about gluten and the gluten-free diet (GFD) is lacking., Methods: We aimed to develop and validate a questionnaire to assess GFD knowledge. A 10-point questionnaire (GLU10) covering different aspects of knowledge about gluten content in food/non-food products and the gluten-free living was developed. To validate this questionnaire, it was administered to adult celiac patients already instructed on gluten and the GFD and non-celiac controls. Patients were prospectively recruited at our Gastroenterology Outpatient Clinic between August 2020 and February 2021., Results: One hundred and six patients (52 celiac patients and 54 controls) participated in the validation phase. Celiac patients scored significantly higher than controls on the GLU10 Questionnaire (median 6 points vs. 2 points, P<0.001). Higher self-reported knowledge of the GFD was related to a higher score (P<0.001). ROC curve confirmed the ability of the GLU10 Questionnaire to discriminate between subjects with good and poor GFD knowledge (AUC=0.94, 95% CI: 0.90-0.98). A score of 5 was identified as the best cut-off (sensitivity 80.8%, specificity 94.4%). On multivariable logistic regression analysis, being a celiac patient (P<0.001) and having a university degree (P=0.04) were associated to a high GLU10 Score (≥5)., Conclusions: GLU10 is the first validated questionnaire for assessing knowledge of a GFD in celiac patients and the general population.

Background: Information on the management of Helicobacter (H.) pylori infection by gastroenterologists and gastroenterology fellows are scarce. We aimed to assess practice of gastroenterologists and gastroenterology fellows and their adherence to guidelines for diagnosis and treatment of H. pylori infection in Italy., Materials and Methods: All gastroenterologists and gastroenterology fellows attending the National Congress of Digestive Diseases - FISMAD were invited to fill-in an on-line questionnaire. The questionnaire included questions on the diagnosis and treatment of H. pylori infection., Results: A total of 279 gastroenterologists and 61 gastroenterology fellows participated to the study. The 13 C-urea breath test was the most preferred method among gastroenterologists and fellows for the diagnosis of H. pylori infection (40.4% and 57.6%, respectively) and the confirmation of eradication (61.3% and 70%, respectively). Sequential therapy was the most preferred first-line treatment of H. pylori for both gastroenterologists and gastroenterology fellows (31.8% and 44%, respectively), followed by bismuth quadruple therapy (31% and 27.6%, respectively) and clarithromycin triple therapy (26.8% and 22.4%, respectively). Only 30% of gastroenterologists and 38.5% of fellows used the clarithromycin triple therapy for the recommended duration of 14 days. Bismuth quadruple therapy was the most preferred second-line therapy for both gastroenterologists and fellows. The majority of gastroenterologists and fellows would prefer an empirical therapy at third line (72.6% and 62.5%, respectively) and a susceptibility-guided therapy at fourth line (46.7% and 71.4%, respectively)., Conclusions: Practices of gastroenterologists and gastroenterology fellows are in line with guidelines' recommendations, apart for the first-line treatment of H. pylori infection. Targeted educational interventions to improve adherence to guidelines are needed., (© 2021 The Authors. Helicobacter published by John Wiley & Sons Ltd.)

The key factors playing a role in the pathogenesis of metabolic alterations observed in many patients with obesity have not been fully characterized. Their identification is crucial, and it would represent a fundamental step towards better management of this urgent public health issue. This aim could be accomplished by exploiting the potential of machine learning (ML) technology. In a single-centre study ( n = 2567), we used an ML analysis to cluster patients with metabolically healthy (MHO) or metabolically unhealthy (MUO) obesity, based on several clinical and biochemical variables. The first model provided by ML was able to predict the presence/absence of MHO with an accuracy of 66.67% and 72.15%, respectively, and included the following parameters: HOMA-IR, upper body fat/lower body fat, glycosylated haemoglobin, red blood cells, age, alanine aminotransferase, uric acid, white blood cells, insulin-like growth factor 1 (IGF-1) and gamma-glutamyl transferase. For each of these parameters, ML provided threshold values identifying either MUO or MHO. A second model including IGF-1 zSDS, a surrogate marker of IGF-1 normalized by age and sex, was even more accurate with a 71.84% and 72.3% precision, respectively. Our results demonstrated high IGF-1 levels in MHO patients, thus highlighting a possible role of IGF-1 as a novel metabolic health parameter to effectively predict the development of MUO using ML technology.

Obesity is associated with a poor COVID-19 prognosis, and it seems associated with reduced humoral response to vaccination. Public health campaigns have advocated for weight loss in subjects with obesity, hoping to eliminate this risk. However, no evidence proves that weight loss leads to a better prognosis or a stronger immune response to vaccination. We aimed to investigate the impact of rapid weight loss on the adaptive immune response in subjects with morbid obesity. Twenty-one patients followed a hypocaloric, very-low-carbohydrate diet one week before to one week after the two mRNA vaccine doses. The diet's safety and efficacy were assessed, and the adaptive humoral (anti-SARS CoV-2 S antibodies, Abs) and cell-mediated responses (IFNγ secretion on stimulation with two different SARS CoV-2 peptide mixes, IFNγ-1 and IFNγ-2) were evaluated. The patients lost ~10% of their body weight with metabolic improvement. A high baseline BMI correlated with a poor immune response (R -0.558, p = 0.013 for IFNγ-1; R -0.581, p = 0.009 for IFNγ-2; R -0.512, p = 0.018 for Abs). Furthermore, there was a correlation between weight loss and higher IFNγ-2 (R 0.471, p = 0.042), and between blood glucose reduction and higher IFNγ-1 (R 0.534, p = 0.019), maintained after weight loss and waist circumference reduction adjustment. Urate reduction correlated with higher Abs (R 0.552, p = 0.033). In conclusion, obesity is associated with a reduced adaptive response to a COVID-19 mRNA vaccine, and weight loss and metabolic improvement may reverse the effect.

This study provides comparable lower-bound estimates of inequality of opportunity for tertiary education (EIOp) for 31 countries in Europe, by using the two EU-SILC waves for which information on family background is available (2005 and 2011). The results reveal an important degree of heterogeneity, with Northern European countries showing low levels of inequality of opportunity and Mediterranean and Eastern European countries characterized by significant degrees of unfair educational inequalities. Parental education and occupation are the most relevant circumstances in the great majority of the countries considered. This study also exploits the two point-in-time observations available and analyses the relationship between some country-specific characteristics and inequality of opportunity in tertiary education. The analysis documents a negative association between EIOp and real GDP per capita, possibly indicating that higher equality of opportunity in tertiary education and economic growth are complementary objectives. Two results emerge as especially robust: in all the specifications we find a positive association between EIOp and the students/teacher ratio, and a negative one between EIOp and public spending in tertiary education. While we do not claim that such correlations should be interpreted causally, we think that they might indicate a meaningful underlying relationship between equality of opportunity in tertiary education and the availability of financial and non-financial resources., (© The Author(s) 2021.)

Objective: The differential diagnosis and management of seronegative enteropathies is challenging due to the rarity of these conditions, the overlap of clinical and histopathological features and the current lack of an international consensus on their nomenclature., Design: This is a narrative review providing pragmatic guide on the investigation and clinical management of seronegative enteropathies in adults based on the available literature and our clinical experience., Conclusions: Seronegative coeliac disease is the most frequent cause among the heterogeneous group of seronegative enteropathies and its diagnosis is confirmed by the clinical and histological response to a gluten-free diet after the exclusion of other causes of villous atrophy. Correct identification and targeted management of seronegative enteropathies is mandatory because of the variation in terms of clinical outcomes and prognosis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Seronegative coeliac disease is poorly defined., Aims: To study clinical phenotypes and long-term outcomes of seronegative coeliac disease in a multicentre cohort over 20 years., Methods: Seronegative coeliac disease was diagnosed in HLA-DQ2/DQ8-positive patients with villous atrophy (VA), negative IgA endomysial (EmA), tissue transglutaminase (tTG) and deamidated-gliadin antibodies (DGP), clinical and histological response to a gluten-free diet (GFD), and no alternative causes for VA. In patients with IgA deficiency, coeliac disease was diagnosed through VA, positive IgG EmA/tTG/DGP and clinical/histological response to a GFD (coeliac disease+IgAd). Patients with seropositive coeliac disease served as controls., Results: Of 227 patients previously diagnosed with seronegative coeliac disease, true seronegative coeliac disease was confirmed in 84, coeliac disease+IgAd in 48, and excluded in 55. Lack of follow-up duodenal biopsy precluded diagnosing seronegative coeliac disease in 40 patients. 2084 patients with seropositive coeliac disease served as controls. True seronegative coeliac disease had more severe symptoms at diagnosis and a higher risk of complications (HR 10.87, 95% CI 6.11-19.33, P < 0.001) and mortality (HR 2.18, 95% CI 1.12-4.26, P < 0.01) than seropositive coeliac disease. There were no differences between true seronegative coeliac disease and coeliac disease+IgAd. On multivariate analysis, age at diagnosis, lack of clinical response to a GFD, true seronegative coeliac disease, coeliac disease+IgAd, and classical presentation predicted complications. Age at diagnosis, complications and absence of clinical response to a GFD predicted mortality., Conclusions: Seronegative coeliac disease has a more aggressive disease phenotype than seropositive coeliac disease. These data argue against over-reliance on serology for the diagnosis of coeliac disease and support a strict clinical and histologic follow-up in seronegative coeliac disease., (© 2021 John Wiley & Sons Ltd.)

Objectives: Data on SARS-CoV-2 disease (COVID-19) in adult coeliac disease (CD) are lacking. The aim of the present study is to evaluate the epidemiology and clinical features of COVID-19 in adult coeliac patients regularly followed-up at our centre since January 2015., Methods: Data about general health status and clinical features of laboratory-confirmed COVID-19 were prospectively collected over the phone. Data about CD were retrospectively collected from clinical notes. Prevalence and incidence of COVID-19 were compared between the coeliac cohort and the figures in the general population of Lombardy, Northern Italy between 20 February to 5 June 2020 provided by the Italian National Institute of Health (Istituto Superiore di Sanità) and the Lombardy regional government., Results: Nine out of 324 patients contracted COVID-19, thus resulting in a prevalence of 2.78% [95% confidence interval (CI) 0.98-4.58] and an incidence rate of 8.15/1000 person-month (95% CI 4.24-15.66). Prevalence of COVID-19 ascertained by means of nasal swab was 1.79% (95% CI 0.22-3.35) and the incidence rate 5.26/1000 person-month (95% CI 2.19-12.63), without difference from the general population. Clinical type of CD, age, sex, duration and adherence to a gluten-free diet, and mucosal healing did not differ between coeliac patients with and without COVID-19. None of the 9 patients with COVID-19 required hospitalization., Conclusion: Patients with CD do not seem to carry an increased risk of COVID-19 compared to the general population and their disease course is mild., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Clinical elements differentiating enteropathy due to angiotensin II-receptor-blockers (ARBs-E) from coeliac disease (CD) are poorly defined. The histopathological features on duodenal and gastric biopsies in these patients still need to be investigated., Aims: To describe the clinical phenotype of ARBs-E in comparison to CD, and the histological findings of gastric and duodenal biopsies in ARBs-E., Methods: Clinical data of patients with ARBs-E and CD diagnosed between 2013 and 2020 were retrospectively reviewed. Baseline presenting symptoms and demographics were compared (Fisher's exact test and t-test). Gastric and duodenal histology in ARBs-E were revised by two independent pathologists., Results: 14 ARBs-E and 112 CD patients were enroled. Weight loss (p < 0.01), acute onset of diarrhoea (p < 0.01), hospitalization (p < 0.01), and older age at diagnosis (p < 0.01) were more common in ARBs-E. Duodenal histology in ARBs-E showed intraepithelial lymphocytosis in 71%, increased mucosal eosinophilic count in 57%, with preserved neuroendocrine, Paneth and goblet cells in all patients. Gastric histologic lesions at baseline, including lymphocytic gastritis, eosinophilic gastritis, chronic active gastritis, and metaplastic atrophic gastritis patterns were observed in 73% of patients, without Helicobacter pylori infection., Conclusions: ARBs-E showed a severe clinical phenotype, often requiring hospital admission. Gastric involvement at diagnosis is very common, and this could further support this diagnosis., Competing Interests: Declaration of Competing Interest None to declare., (Copyright © 2021. Published by Elsevier Ltd.)

Background: Duodenal dysbiosis has been suggested to possibly influence the clinical manifestations of coeliac disease (CD), both at onset and when symptoms persist despite a gluten-free diet (GFD)., Aims: To evaluate the relationship between duodenal microbiota composition and: i) clinical phenotype of untreated CD (UCD); ii) presence and type of persistent symptoms despite a satisfactory serological and histological response to a strict GFD., Methods: Duodenal microbiota was analyzed by 16S rRNA sequencing and compared with i) clinical features in 12 adult UCD patients; ii) presence/absence and type of persistent symptoms (diarrhea-predominant vs. non-diarrhea predominant) in 25 adult treated coeliac patients (TCD) on a strict GFD., Results: UCD with iron deficiency anemia (IDA) had a pro-inflammatory shift in their duodenal microbiota (reduction of Firmicutes, p = 0.03; increase of beta-Proteobacteria, p = 0.02) than those without IDA. TCD with persistent diarrhea showed a reduction of Actinobacteria (p = 0.03) and Rothia spp (p = 0.046) compared to TCD suffering from other type of persistent symptoms., Conclusion: A distinctive duodenal microbiota profile is associated with IDA in UCD, and diarrhea-predominant persistent symptoms in TCD. Clinical interventions may include reconsidering patients presenting with IDA as a specific disease subtype, and dietary rebalancing if diarrhea persists despite histological response to a GFD., Competing Interests: Declaration of Competing Interests None to declare, (Copyright © 2021 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Objective: Bile acid diarrhea is a form of chronic diarrhea caused by excessive bile reaching the colon. Conditions involving the terminal ileum and cholecystectomy are predisposing factors but an idiopathic form of bile acid diarrhea has also been described. In this study we aimed to evaluate the prevalence of bile acid diarrhea in patients consecutively evaluated for chronic diarrhea in an Outpatient Gastroenterology Clinic., Methods: Medical records of all patients admitted for chronic diarrhea (>4 weeks) between June 2018 and April 2019 were retrospectively reviewed. Bile acid diarrhea was suspected in patients with ileal disease, cholecystectomy or post-prandial diarrhea. Patients' age at diagnosis, sex, presenting symptoms, results of main test and examinations, final diagnoses and date of last follow-up visit were also collected. Exclusion of chronic diarrhea of other causes and a 6-month clinical improvement with cholestyramine treatment confirmed the diagnosis of bile acid diarrhea., Results: In total, 139 patients aged 46 ± 20 years (76 women and 63 men) were included. Diarrhea due to an organic cause was diagnosed in 16 patients. A clinical response to cholestyramine persisting for more than 6 months led to a diagnosis of bile acid diarrhea in 39 (aged 52 ± 19 years) out of the remaining 123 patients with functional forms of diarrhea. Therefore, the prevalence of bile acid diarrhea was 28.1% (95% confidence interval 19.9%-38.4%) in patients with chronic diarrhea., Conclusions: Bile acid diarrhea is a very common, yet under-recognized cause of chronic functional diarrhea. A therapeutic trial of cholestyramine is a valid diagnostic strategy., (© 2021 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Description: Our aim was to provide a consensus statement for the best approaches for diagnosis and management of patients with suspected enteropathy, but negative results from serologic tests for celiac disease (seronegative enteropathy)., Methods: We collected findings from published cohort, case-control, and cross-sectional studies of diagnosis and case series and descriptive studies of management of patients believed to have celiac disease or other enteropathies unrelated to gluten, but negative results from serologic tests. BEST PRACTICE ADVICE 1: Review histologic findings with experienced pathologists who specialize in gastroenterology. BEST PRACTICE ADVICE 2: Serologic tests are essential for an accurate diagnosis of celiac disease. For patients with suspected celiac disease but negative results from serologic tests, total IgA level should be measured; patients should also be tested for anti-tissue transglutaminase, IgA against deamidated gliadin peptide, and endomysial antibody (IgA). Patients with total IgA levels below the lower limit of detection and IgG against tissue transglutaminase or deamidated gliadin peptide, or endomysial antibody, should be considered to have celiac disease with selective IgA deficiency rather than seronegative celiac disease. BEST PRACTICE ADVICE 3: Patients' diets should be carefully reviewed and duodenal biopsies should be collected and analyzed at the time of serologic testing to determine exposure to gluten and accuracy of test results. BEST PRACTICE ADVICE 4: Thorough medication histories should be collected from patients, with attention to angiotensin II receptor blockers, such as olmesartan, along with travel histories to identify potential etiologies of villous atrophy. This will guide additional testing. BEST PRACTICE ADVICE 5: Patients should be analyzed for disease-associated variants in human leukocyte antigen genes; results must be carefully interpreted. Negative results can be used to rule out celiac disease in seronegative patients. BEST PRACTICE ADVICE 6: Patients with suspected celiac disease who are seronegative but have villous atrophy and genetic risk factors for celiac disease must undergo endoscopic evaluation after 1-3 years on a gluten-free diet to evaluate improvements in villous atrophy. A diagnosis of seronegative celiac disease can then be confirmed based on clinical and histologic markers of improvement on the gluten-free diet. BEST PRACTICE ADVICE 7: Seronegative patients with an identified cause for enteropathy should be treated accordingly; a follow-up biopsy might or might not be necessary. BEST PRACTICE ADVICE 8: Patients with persistent signs and symptoms who do not respond to a gluten-free diet, and for whom no etiology of enteropathy is ultimately identified, should be treated with budesonide., Conclusions: These best practice guidelines will aid in diagnosis and management of patients with suspected celiac disease, but negative results from serologic tests., (Copyright © 2021 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Swallowing and communication disorders are common in persons with multiple sclerosis (MS). Both disorders are extremely variable and can have a major effect on health status and quality of life. This is why it is important to provide health care professionals who are working with persons with MS with tools to signal, assess, and treat swallowing and communication disorders. This synthesis gives an update on relevant and recent literature on swallowing and communication disorders, supplemented with current practice-based evidence. Studies on swallowing and communication disorders in MS are scarce: more and higher-quality research is needed. It should be emphasized that therapists need to focus on the patient's acquisition of skills to participate in daily life. This means that each patient requires an individual approach based on their own needs., Competing Interests: Financial Disclosures: The authors declare no conflicts of interest., (© 2020 Consortium of Multiple Sclerosis Centers.)

Objectives: Exclusion of organic disorders involving the upper gastrointestinal (UGI) is a mandatory step before considering a biopsy-avoidance diagnostic strategy for adult coeliac disease. We aim to evaluate the prevalence of alarm symptoms and coincidental UGI endoscopic findings at the time of diagnosis of coeliac disease. To develop consensus criteria to identify patients with coeliac disease requiring a gastroscopy and to evaluate whether alarm symptoms prompting gastroscopy were predictive of endoscopic findings., Methods: Presenting symptoms and UGI endoscopic findings at diagnosis of coeliac disease were collected retrospectively in 278 adult patients with coeliac disease diagnosed in Pavia between January 1999 and December 2017. A panel of experts developed criteria to evaluate which clinical scenarios warrant gastroscopy, which was then applied retrospectively to patients diagnosed in Pavia., Results: At least one alarm symptom was present in 177/278 patients, 121/278 met our criteria for gastroscopy. Major UGI endoscopic findings included 3 cases of autoimmune atrophic gastritis, 19 oesophagitis and 20 Helicobacter pylori infections. No organic disorders were found. Prevalence of major endoscopic findings did not differ between patients who met our criteria and those who did not., Conclusions: Despite the high prevalence of alarm symptoms at diagnosis, coincident major UGI endoscopic findings are rare in adult coeliac disease. These results may be relevant for future developments in coeliac disease diagnosis in adults.

Objective: Causes of small-bowel villous atrophy (VA) include coeliac disease (CD), its complications and other rare non-coeliac enteropathies. However, forms of VA of unknown aetiology may also exist. We defined them as idiopathic VA (IVA). To retrospectively classify the largest cohort of IVA patients and compare their natural history with CD., Methods: Notes of 76 IVA patients attending two tertiary centres between January 2000 and March 2019 were retrospectively reviewed. CD, its complications and all the known causes of VA were excluded in all of them. Persistence of VA during follow-up and lymphoproliferative features were used to retrospectively classify IVA, as follows. Group 1: IVA with spontaneous histological recovery (50 patients). Group 2: persistent IVA without lymphoproliferative features (14 patients). Group 3: persistent IVA with lymphoproliferative features (12 patients). Survival was compared between IVA groups and 1114 coeliac patients. HLA was compared between IVA patients, coeliac patients and appropriate controls., Results: Five-year survival was 96% in IVA group 1, 100% in IVA group 2, 27% in IVA group 3 and 97% in CD. On a multivariate analysis hypoalbuminemia (P = 0.002) and age at diagnosis (P = 0.04) predicted mortality in IVA. Group 2 showed association with HLA DQB1*0301 and DQB1*06., Conclusion: IVA consists of three groups of enteropathies with distinct clinical phenotypes and prognoses. Mortality in IVA is higher than in CD and mainly due to lymphoproliferative conditions necessitating more aggressive therapies.

Background: Little is known about long-term morbidity and mortality in Whipple's disease (WD). Aim: To describe morbidity and mortality in patients with WD on a long-term follow-up. Materials & methods: Comorbidities, mortality and causes of death were retrospectively registered. Results:  A total of 35 patients with WD (9F, 54 ± 11 years) were followed-up for a median of 104 months. Nine patients developed ten complications; three patients died. A total of 31 severe comorbidities apparently unrelated to WD were found in 20 patients: preneoplastic/neoplastic disorders in seven, thromboembolic and cardiovascular events in seven, pneumonia in four, candidiasis in ten patients. Conclusion: WD is frequently complicated by potentially life-threatening infectious, neoplastic and thromboembolic disorders, thus highlighting the need for a life-long multidisciplinary follow-up.