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In the original publication, the study group author names are listed under Appendix section and it should be listed in Acknowledgement section as follows.

Katia Fettucciari,1 Alessandro Fruganti,2 Andrea Marchegiani,2 Stefano Brancorsini,1 Pierfrancesco Marconi,1 Gabrio Bassotti3,4 1Department of Experimental Medicine, University of Perugia Medical School, Perugia, Italy; 2School of Biosciences and Veterinary Medicine, University of Camerino, Macerata, Italy; 3Gastroenterology, Hepatology & Digestive Endoscopy Section, Department of Medicine, University of Perugia Medical School, Perugia, Italy; 4Gastroenterology & Hepatology Unit, Santa Maria della Misericordia Hospital, Perugia, ItalyCorrespondence: Katia FettucciariDepartment of Experimental Medicine, University of Perugia Medical School, Piazza Lucio Severi 1, Edificio B IV Piano, Sant’Andrea delle Fratte, Perugia 06132, ItalyTel +39755858124Email katia.fettucciari@unipg.itAbstract: Clostridioides difficile infection (CDI) has a serious impact on the healthcare system, and most of its pathogenic effects are mainly due to the activity of toxins A and B (TcdA and TcdB, respectively). The molecular mechanisms of their cytotoxic activity are well known, especially in the colon, where the infection occurs and normally remains localized. However, the mechanisms causing toxic effects on various systemic organs (extraintestinal manifestations) with frequent lethal outcomes in some patients affected by CDI are still poorly understood. Few studies are available that demonstrate low serum levels of Tcds in both experimental animal models and patients with CDI. Until now, it has remained unclear how low levels of circulating Tcds could lead to serious toxic effects. On the basis of our previous in vitro studies, in which the proinflammatory cytokines TNF-alpha and IFN-gamma strongly potentiated the toxic activity of low doses of TcdB, we hypothesize that the presence of both TcdB in the circulation and a systemic proinflammatory cytokine storm may be responsible for the selective severe effects of TcdB in some patients. This may occur in patients with severe CDI and systemic Tcds, in whom proinflammatory cytokines such as TNF-alpha and IFN-gamma reach a significant concentration in the circulation. This hypothesis could identify therapeutic interventions based on the reduction or neutralization of the indirect toxic action of these cytokines.Keywords: Clostridioides difficile, toxin B, proinflammatory cytokines, TNF-alpha, IFN-gamma, systemic effects

Background and Aims: The Diverticular Inflammation and Complication Assessment (DICA) endoscopic classification of diverticulosis and diverticular disease (DD) is currently available. It scores severity of the disease as DICA 1, DICA 2 and DICA 3. Our aim was to assess the agreement on this classification in an international endoscopists community setting. Methods: A total of 96 doctors (82.9% endoscopists) independently scored a set of DD endoscopic videos. The percentages of overall agreement on DICA score and a free-marginal multirater kappa (κ) coefficient were reported as statistical measures of interrater agreement. Results: Overall agreement in using DICA was 91.8% with a free-marginal kappa of 88% (95% CI 80-95). The overall agreement levels were: DICA 1, 85.2%; DICA 2, 96.5%; DICA 3, 99.5%. The free marginal κ was: DICA 1 = 0.753, DICA 2 = 0.958, DICA 3 = 0.919. The agreement about the main endoscopic items was 83.4% (k 67%) for diverticular extension, 62.6% (k 65%) for number of diverticula for each district, 86.8% (k 82%) for presence of inflammation, and 98.5 (k 98%) for presence of complications. Conclusions: The overall interrater agreement in this study ranges from good to very good. DICA score is a simple and reproducible endoscopic scoring system for diverticulosis and DD.

In recent years, therapeutic agents affecting the immune system have been largely implemented in the treatment of various hematological, rheumatological and dermatological disorders. Their clinical use has offered important benefits for affected patients and has also ameliorated clinical outcome and prognosis in many cases. Nonetheless, as any treatment, the use of these drugs may be associated with side effects. One of the target organs in such cases is the gastrointestinal tract. In particular, the exacerbation or the onset of inflammatory bowel disease (IBD) in treated patients is not infrequent, although the mechanism of action of these agents may be different. In this review we will focus on the use of therapeutic agents affecting the immune system and the development or exacerbation of IBD, with a mention on the possible underlying pathogenetic mechanisms.

Background: Although diverticular disease is a common condition, its effective treatment is challenging in clinical practice. Objective: The objective of this article is to assess pharmacological management in different clinical settings of diverticular disease and factors associated with treatment using the Italian registry Registro Malattia Diverticolare (REMAD). Methods: At study enrolment, patients were categorised into subgroups: diverticulosis, symptomatic uncomplicated diverticular disease and previous diverticulitis. We registered demographic, clinical and lifestyle factors, quality of life and the use of treatments for diverticular disease in the last year. Logistic regression analysis assessed the association between clinical factors and treatment consumption. Results: A total of 500 of the 1206 individuals included had had at least one treatment for diverticular disease in the last year: 23.6% (166/702) of patients with diverticulosis, 55.9% (165/295) of patients with symptomatic diverticular disease, and 80.9% (169/209) of patients with previous diverticulitis (p < 0.001). In multivariate analysis, the following factors were significantly associated with treatment use: female gender, family history of colonic diverticula, organic digestive comorbidity and impaired physical quality of life components. Conclusion: Individuals with diverticular disease take medications based on the different clinical settings of disease. We identified different features associated with treatment use in the distinct clinical entities of diverticular disease. ClinicalTrial.gov Identifier: NCT03325829.

A limited number of sclerosing Angiomatoid Nodular Transformation (SANT) have been reported in pediatric age. We describe the first case of SANT occurring in a nine-week-old female infant that was admitted to our unit for severe abdominal distension and rectal bleeding. Enlarged spleen was detected on physical examination. Laboratory investigations revealed severe anemia and coagulation abnormalities. Abdominal ultrasound and computed tomography revealed ascites and splenomegaly with a large mass at the lower medial splenic pole. A diagnosis of intraabdominal hemorrhage was presumed and an exploratory laparotomy was performed. A complete transformation of the giant splenomegaly to bossellated masses and multiple bleeding capsular ruptures without subcapsular hematoma were found and an urgent splenectomy was performed. At histology, a SANT was diagnosed (CD34, CD31, CD8 positivity). The postoperative follow up was uneventful. SANT may also occur in infancy with a potentially lifethreatening presentation. Splenectomy may represent the only treatment in severe cases.

Non-celiac gluten sensitivity (NCGS), also referred to as non-celiac wheat sensitivity (NCWS), is a clinical syndrome characterized by both intestinal and extra-intestinal symptoms responsive to the withdrawal of gluten-containing food from the diet. The aim of this review is to summarize recent advances in research and provide a brief overview of the history of the condition for the benefit of professionals working in gastroenterology. Academic databases such as PubMed and Google Scholar were searched using key words such as ”non-celiac gluten sensitivity”, “gluten related disorders”, and the studies outlined in reference page were selected and analysed.\ud \ud Most of the analysed studiers agree that NCGS would need to be diagnosed only after exclusion of celiac disease and wheat allergy, and that a reliable serological marker is not available presently. The mechanisms causing symptoms in NCGS after gluten ingestion are largely unknown, but recent advances have begun to offer novel insights. The estimated prevalence of NCGS, at present, varies between 0.6 and 6%. There is an overlap between irritable bowel syndrome and NCGS with regard to the similarity of gastrointestinal symptoms. The histologic characteristics of NCGS are still under investigation, ranging from normal histology to slight increase in the number of T lymphocytes in the superficial epithelium of villi. Positive response to gluten free diet for a limited period (e.g., 6 weeks), followed by the reappearance of symptoms after gluten challenge appears, at this moment, to be the best approach for confirming diagnosis. The Salerno expert criteria may help to diagnose NCGS accurately in particular for research purposes but it has limited applicability in clinical practice.

Background and aim: PAC-SYM is widely adopted to asses constipation severity. However, it has been validated in a small sample, few items have been included based on expert opinion and not on empirical grounds, and its factor structure has never been replicated. We aimed at evaluating the psychometric properties of PAC-SYM in patients with chronic constipation. Methods: We enrolled 2,203 outpatients with chronic constipation in two waves. We used wave I sample to test the psychometric properties of the PAC-SYM and wave II sample to cross-validate its factor structure, to assess criterion validity, responsiveness to clinical change, and its minimal clinically important difference. Results: Only a minority of patients reported any rectal tearing (38 %). Deletion of such item leads to a 11-item version (M:PAC-SYM). The remaining items in the rectal domain were moderately correlated with the stool domain. Exploratory factor analysis and confirmatory factor analysis revealed a bifactor structure with two subscales (stool and abdominal symptoms) and a general severity factor. The M:PAC-SYM demonstrated excellent reliability, moderate correlation with SF-12 and treatment satisfaction (r = 0.28–0.45), discrimination across Rome III criteria for functional constipation and abdominal pain, and responsiveness to clinical change (β = −0.49; ω 2 = 0.25). M:PAC-SYM minimal clinically important difference was 0.24. Conclusion: Our analysis shows that the rectal domain may not represent a relevant cluster of symptoms for patients with chronic constipation. We developed a modified version of the PAC-SYM which might better represent symptom severity of most patients seeking care in gastroenterology referral centers

Inflammatory bowel disease (IBD) frequently affects young patients of childbearing age. Treatments for inflammatory bowel disease include immunosuppressive, cytotoxic and surgical therapies. Azathioprine is frequently used to treat patients with steroid dependent IBD. We report the case of a patient with ulcerative colitis, treated with azathioprine prior to conception and during the subsequent pregnancy with the subsequent successful delivery of healthy twins. Although some potential risks indeed exist, the use of AZA may not be harmful to the mother or the fetus in many instances.

The use of manometry, i.e. the recording of pressures within hollow viscera, after being successfully applied to the study of esophageal and anorectal motor dysfunctions, has also been used to investigate physiological and pathological conditions of the small bowel. By means of this technique, it has been possible to understand better the normal motor functions of the small intestine, and their relationship and variations following physiologic events, such as food ingestion. Moreover, intestinal manometry has proved useful to document motor abnormalities of the small bowel, although recognition of altered patterns specific for a determinate pathologic condition is still unavailable. However, this technique often permits the detection of abnormal gut motility in patients with abdominal symptoms such as unexplained vomiting and diarrhea, and it is sometimes also useful to address therapeutic targeting.

Background: The most frequent form of inflammatory bowel disease (IBD) in dogs is represented histologically, by lymphoplasmacytic enteritis (LPE), a histological category, often associated with other morphologic alterations including lymphangiectasia (LE). However, literature data on this latter topic are quite scarce and have mostly been obtained in single reports or in small series. Aim: We evaluated some morphologic parameters of intestinal villi and lacteals in a large cohort of dogs, and correlated them with serum albumin and cholesterol values. Patients and methods: We investigated 136 dogs (94 with LPE, and 42 with gastrointestinal problems different from IBD) and analyzed their clinical, laboratory (albumin and cholesterol values), endoscopic, and histologic variables. Results: The LPE group showed significantly impaired clinical, laboratory, endoscopic, and histologic variables compared to controls. Affected dogs showed significant correlations between canine inflammatory bowel disease activity index (CIBDAI) scores and endoscopic and histologic variables. Moreover, the grade of hematologic changes were strongly related to the intestinal histologic variables, in particular those concerning villous and lacteals morphology. Conclusion: Dogs with LPE had intestinal histologic abnormalities (height, width, height/width ratio, calculated for both villi and lacteals), whose degree correlated with the severity of hypoalbuminemia and hypocholesterolemia. Evaluation of endoscopic and histologic variables in association to the clinical findings may reveal useful insights for the pathogenesis of LPE and, hopefully, might lead to more targeted therapeutic approaches.

Ulcerative colitis is associated with several malignancies. Here we report one such association, a rare one, with papillary thyroid carcinoma, and discuss the possible risk factors of such an association.

Sintomi come la sensazione di una defecazione ostacolata, difficoltosa, che richiede uno eccessivo ponzamento, oppure la sensazione di incompletezza di ogni atto evacuativo, non sono significativamente predittivi di una patologia retto-anale; è però vero, che questi sintomi, in forme così importanti tanto da indurre la necessità di ricorrere all’evacuazione manuale o comunque assistita delle feci, in presenza di una percezione spontanea e regolare dello stimolo ad evacuare, sono fortemente suggestivi di alterazioni della dinamica retto-anale con una inefficiente espulsione del materiale giunto in ampolla. Potremmo distinguere le cause della disfunzione ano-rettale in due gruppi: · le alterazioni strutturali, anatomiche · le alterazioni della coordinazione sensitivo-motoria Nelle prime rientrano patologie quali il megaretto, il rettocele, l’intussuscezione sigmoido-rettale, l’invaginazione rettale, il prolasso mucoso interno fino al vero e proprio prolasso rettale. Tutte queste anomalie causano un ostacolo meccanico al regolare passaggio delle feci e, nello stesso tempo, questo le aggrava creando uno stretto circolo vizioso.

BACKGROUND—Intrasphincteric injection of botulinum toxin (Botx) has been proposed as treatment for oesophageal achalasia. However, the predictors of response and optimal dose remain unclear. AIMS—To compare the effect of different doses of Botx and to identify predictors of response. PATIENTS/METHODS—A total of 118 achalasic patients were randomised to receive one of three doses of Botx in a single injection: 50 U (n=40), 100 U (n=38), and 200 U (n=40). Of those who received 100 U, responsive patients were reinjected with an identical dose after 30 days. Clinical and manometric assessments were performed at baseline, 30 days after the initial injection of botulinum toxin, and at the end of follow up (mean 12 months; range 7-24 months). RESULTS—Thirty days after the initial injection, 82% of patients were considered responders without a clear dose related effect. At the end of follow up however, relapse of symptoms was evident in 19% of patients who received two injections of 100 U compared with 47% and 43% in the 50 U and 200 U groups, respectively. Using Kaplan-Meier analysis, patients in the 100×2 U group were more likely to remain in remission at any time (p

Accuracy of intraepithelial lymphocytes counts for diagnosing mild enteropathy coeliac disease in absence of villous atrophy can be limited by inappropriate controls included in the studies.To determine the diagnostic accuracy of intraepithelial lymphocytes counts utilising controls lacking HLA coeliac disease-associated alleles.Intraepithelial lymphocytes counting at villus tip and per 100 enterocytes was performed at haematoxylin and eosin (HE) and CD3-stainings in: 29 cases (21 with potential coeliac disease and 8 affected by latent coeliac disease) representing the patient population and 14 noncoeliac controls lacking HLA-DQ2/DQ8 alleles.Threshold (mean+2 s.d.) of duodenal intraepithelial lymphocytes at villus tip and per 100 enterocytes in noncoeliac controls was respectively: 3.5 and 18 at HE, 3.2 and 17 following CD3-staining. Considering the whole patient population, the sensitivity of tip intraepithelial lymphocytes in detecting mild enteropathy coeliac disease was 90% (95% CI=72.6-97.8) both at HE and CD3-stainings. The sensitivity of intraepithelial lymphocytes per 100 enterocytes was 93% (95% CI=77.2-99.2) both at HE and CD3-staining. Specificity of both intraepithelial lymphocytes counts was 100% (95% CI=76.8-100). Using a threshold of 25 intraepithelial lymphocytes per 100 enterocytes could miss 59% of cases at HE and 48% following CD3-staining.Intraepithelial lymphocytes counts are diagnostic feasible tools to detect mild enteropathy coeliac disease. Threshold of duodenal intraepithelial lymphocytes may be lower than currently accepted.

Background: eosinophilic esophagitis is an esophageal disorder characterized by esophageal and/or upper gastrointestinal tract symptoms, and by dense esophageal eosinophilia associated with a normal gastric and duodenal mucosa. Prevalently reported in children, eosinophilic esophagitis has recently been reported with increased frequency also in adults. Aims: the purpose of this study was to report our experience with eosinophilic esophagitis in Italy, since there are only very few series of such patients in our country. Patients and methods: we retrospectively reviewed the histological data of consecutive patients with a diagnosis of esophagitis or reflux disease in the period September 2004-September 2008. Eosinophils were counted where they appeared most numerous in the biopsy, with a cutoff > 15 eosinophils in more than one high-power field as diagnostic of eosinophilic esophagitis. Patients were excluded if gastric or duodenal biopsies showed a prominent eosinophilic infiltrate. Results: twenty two patients (14 adults, 8 children, age range 2-59 years) were identified according to the above criteria. The average eosinophil count was 86/ high-power field (range 31-150), associated with other pathologic features (eosinophilic microabscesses eosinophil degranulation, basal zone hyperplasia, papillary elongation). The main clinical complaints were dysphagia, food impaction, and heartburn, and endoscopic findings consisted of mucosal thickening and inelasticity, longitudinal shearing, rings, and white specks, without difference between adults and children for both clinical and endoscopic variables. Conclusions: eosinophilic esophagitis is not rare in Italy, and displays clinical, endoscopic, and pathologic features similar to those described in other countries.

Background It is unclear whether questionnaires and diary cards, which are widely used to collect data on bowel habits, provide analogous information. Aims We verified the concordance between the data provided by a daily diary and a retrospective questionnaire. Methods A 4-week diary (DIARY) concerning bowel habits was compiled by 221 subjects. They were also asked to fill out a questionnaire on their bowel habits before (BEF) and after (AFT) the diary period. Results Concerning bowel movements, no significant difference was detected in the concordance between BEF and DIARY (ρ: 0.80), AFT and DIARY (ρ: 0.84), or BEF and AFT (ρ: 0.84). The mean concordance in the other defecation-related parameters between BEF and DIARY (K: 0.62) and between DIARY and AFT (K: 0.63) were both significantly lower than that seen between BEF and AFT (K: 0.80; p Conclusion A considerable discrepancy between the two methods of assessment was found. The higher concordance between BEF and AFT than between DIARY and AFT regarding defecation-related parameters suggests that when a subject recalls events, even those from the recent past, he/she tends to generalize, reporting more or less the same data for different periods of time. These two instruments cannot be viewed as interchangeable, and their inherent differences must be taken into account when deciding which one to employ in different settings.

Background: we assessed the prevalence, the related symptoms, and the endoscopic and histologic gastric features of celiac disease (CD) in patients with Helicobacter pylori (Hp). Methods: 450 dyspeptic patients were studied. Biopsies of gastric antrum and duodenum, CD serology, and total IgA were obtained. Histological findings were scored with the Marsh-Rostami criteria. Results: 411 (91.3%) patients were Hp positive. Duodenal histology was normal in 385 (85.6%) patients, 124 (27.5%) had duodenitis and 28 (6.2%) showed duodenal abnormalities (Marsh I-IIIc). Twenty three/28 (82.1%) patients with malabsorption pattern were also Hp positive. Serological analysis: 12 of 31 (38.7%) positive patients had abnormal histology (Marsh I,-IIIc). Nine out 450 patients were IgA deficient; none of them was serologically positive for CD. Conclusion: although a high prevalence of Hp infection was found in this study, the relationship between Hp infection and CD was similar to that reported in other geographic areas.

Background: bloating is a fastidious symptom reported by many patients who also have other gastrointestinal functional disorders. Bloating is more common in women, and it is often associated with meals and improves or disappears overnight. No specific treatments are to date available for this disturbing symptom. Aims: to evaluate the effects of an oral enterovaccine (Colifagina®) on bloating and other abdominal symptoms in patients with prevalent complaints of functional bloating. Patients and methods: one hundred and forty-eight patients with functional bloating according to Rome III criteria were recruited. Questionnaires and a VAS scale on their symptoms were administered at baseline and after four weeks of therapy with Colifagina®. Results: after treatment, a significant amelioration of bloating (p < 0.0001), abdominal pain (p < 0.0001) and flatus (p < 0.0001) was observed; nausea and vomiting scores were not significantly different at the end of the treatment. Subjective wellbeing was also generally improved (p < 0.001) in treated patients. Conclusion: treatment with an enterovaccine may help improve symptoms in patients with functional bloating.

Background: obstructed defecation is one of the most common subtypes of constipation, and it is frequently responsive to biofeedback treatment. Aims: since a history of sexual and physical abuse may be present in patients with obstructed defecation, we assessed the incidence of abuse history in patients with obstructed defecation referred to a general gastroenterology practice, and whether such a history may lead to a different outcome of biofeedback training in these patients. Patients and methods: one hundred and twenty-one patients (17 men, 104 women, age 53 ± 15 years) with obstructed defecation were studied by retrospective chart review. Their history of sexual, physical and psychological abuse was obtained by a standard interview, and biofeedback training was carried out by means of a three-balloon technique. Results: a history of sexual/physical or psychological abuse was present in 12.4% patients. Biofeedback training yielded a successful improvement of obstructed defecation in 93% patients without abuse and in 100% of patients with abuse; this difference was not statistically different (p = 0.53). Conclusions: the prevalence of sexual/physical or psychological abuse in a population of patients with obstructed defecation referred to a general gastroenterology practice is relatively low; such a history seems not to affect the outcome of biofeedback training in these patients.

Many autoimmune disorders are associated to celiac disease (CD) but the association with autoimmune thyroiditis has been more frequently documented; this is in part explained by a shared immunogenetic make-up, and in part caused to time gluten-exposition, as suggested by the significant correlation observed in celiac patients between the increase occurrence of autoimmune diseases and the length of exposure to gluten. The aim of this study was to establish the prevalence of celiac disease in a group of subjects with autoimmune thyroiditis newly diagnosed on the basis of antibodies anti-peroxidase (TPO).A total of 113 untreated patients with TPO70 IU/mL were enrolled. CD was screened by measuring anti-endomysial antibodies (EMA) both IgA and IgG; an high prevalence of positive serology was resulting in this group, justified, in part, from EMA IgG investigation.In fact 31/113 patients showed IgA and/or IgG positivity and were diagnosed as celiacs with jejunal biopsy.On the basis of this paper, such as in according to current research-setting studies, the greater frequency of CD in association to autoimmune thyroid disease suggests that all subjects with TPO should be routinely screened for CD, through EMA IgA and IgG. However, the performance of this screening has never been evaluated until now, even if it could, in fact, be valid in order to increment diagnosis of CD, today still undiagnosed.

Background Available information on normal bowel habits was mainly gathered by means of telephone interviews or mailed questionnaires. Aims We undertook a prospective study to evaluate the defecatory habits in subjects perceiving themselves as normal concerning this function. Subjects and Methods A questionnaire (4-week diary with “yes–no” daily answers to six questions concerning bowel habits) was distributed to 204 subjects perceiving their defecation behaviour as normal. Results The completed questionnaire was returned by 140 subjects. No significant differences were found between sexes or age groups for any variable, even though straining at stool and feeling of incomplete and/or difficult evacuation showed a trend to increase with age. No subject had less than three bowel movements per week or more than three per day. The percentage of symptoms linked to an abnormal defecatory behaviour was well below 10%. Fifty-five percent of subjects reported at least one parameter of abnormal functioning; the most frequent was straining at stool and the rarer was the manual manoeuvres to help defecation. Conclusions In normal subjects the prevalence of symptoms considered in Rome II criteria as part of an abnormal defecatory behaviour (in more than 25% of defecations) is well below 10%, manual manoeuvres are almost never used to help defecation, and the frequency of defecations is at least three per week.