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PRSS1 and PRSS2 constitute the only functional copies of a tandemly-arranged five-trypsinogen-gene cluster (i.e., PRSS1, PRSS3P1, PRSS3P2, TRY7 and PRSS2) on chromosome 7q35. Variants in PRSS1 and PRSS2, including missense and copy number variants (CNVs), have been reported to predispose to or protect against chronic pancreatitis (CP). We wondered whether a common trypsinogen pseudogene deletion CNV (that removes two of the three trypsinogen pseudogenes, PRSS3P2 and TRY7) might be associated with CP causation/predisposition.We analyzed the common PRSS3P2 and TRY7 deletion CNV in a total of 1536 CP patients and 3506 controls from France, Germany, India and Japan by means of quantitative fluorescent multiplex polymerase chain reaction.We demonstrated that the deletion CNV variant was associated with a protective effect against CP in the French, German and Japanese cohorts whilst a trend toward the same association was noted in the Indian cohort. Meta-analysis under a dominant model yielded a pooled odds ratio (OR) of 0.68 (95% confidence interval (CI) 0.52-0.89; p = 0.005) whereas an allele-based meta-analysis yielded a pooled OR of 0.84 (95% CI 0.77-0.92; p = 0.0001). This protective effect is explicable by reference to the recent finding that the still functional PRSS3P2/TRY7 pseudogene enhancers upregulate pancreatic PRSS2 expression.The common PRSS3P2 and TRY7 deletion CNV was associated with a reduced risk for CP. This finding provides additional support for the emerging view that dysregulated PRSS2 expression represents a discrete mechanism underlying CP predisposition or protection.

For decades the rationale for treatment of gastro-oesophageal reflux disease (GORD) with acid suppressors, such as proton pump inhibitors (PPIs), was that symptoms were attributable to reflux of acidic stomach contents into the oesophagus. However, recent advances in the understanding of how brain–gut interactions can modulate the perception of visceral stimuli have complicated the concept of GORD.1 It is increasingly evident that altered perception of reflux is an important underlying cause of symptoms.2 A number of syndromes related to visceral hypersensitivity and central nervous system dysregulation are now recognised as ‘functional’ gastrointestinal (GI) disorders, potentially localised to the oesophagus,3 bowel, stomach, duodenum, anorectum, gallbladder, or multiple GI sites in the same patient. These functional syndromes are common; an internet-based health survey of almost 6000 adults in the US, Canada, and the UK found that 35% had symptoms compatible with some functional GI disorder and 7% met diagnostic criteria for a functional oesophageal disorder.4 This could potentially account for a large fraction of the adults with weekly reflux symptoms in population-based assessments (global prevalence ∼13%).5 However, it being impractical to investigate all of these patients, the recognition of altered perception as a major determinant of reflux symptoms has had little impact on management in general practice. To provide guidance for the management of uninvestigated reflux symptoms in primary care, a series of sponsored (Reckitt Benckiser Healthcare Ltd, UK) workshops were held among gastroenterologists, GI surgeons, and GPs. The objective was to translate recent research findings into clinical practice strategies. Epidemiological data suggest that the prevalence of GORD has increased considerably since the mid-1990s. However, wider public awareness of the link between reflux symptoms and oesophageal cancer6 has likely contributed to the increased presentation of symptomatic patients in primary care. Additionally, the more we understand the …

La Clasificación de Chicago v4.0 (CCv4.0) es el esquema actualizado para clasificar las alteraciones de la motilidad esofágica utilizando la métrica de la manometría de alta resolución (HRM). Para desarrollar la CCv4.0, 52 expertos internacionales diversos separados en siete subgrupos de trabajo utilizaron una metodología formalmente validada, en un periodo de dos años. Las actualizaciones claves de la CCv4.0 consisten en un protocolo de HRM más riguroso y expansivo que incorpora las posiciones en decúbito supino y sedestación, así como pruebas provocadoras; una definición refinada de la obstrucción del flujo de salida de la unión esofagogástrica (EGJOO), criterios diagnósticos más estrictos para la motilidad esofágica inefectiva, y descripción de la métrica basal de la EGJ. Adicionalmente, la CCv4.0 se propuso definir el diagnóstico de alteración de la motilidad como conclusivo o no conclusivo con base en los síntomas asociados, los hallazgos en las pruebas provocadoras, y los resultados de los exámenes de apoyo como el esofagograma con tableta de bario y/o la prueba con sonda para imagen endoluminal funcional. Estos cambios buscan minimizar la ambigüedad presente en iteraciones previas de la Clasificación de Chicago; además proveen criterios más estandarizados y rigurosos para los patrones de alteración de la peristalsis y obstrucción de la EGJ.

ObjectiveDue to an annual progression rate of Barrett’s oesophagus (BO) with low-grade dysplasia (LGD) between 9% and 13% per year endoscopic ablation therapy is preferred to surveillance. Since this recommendation is based on only one randomised trial, we aimed at checking these results by another multicentre randomised trial with a similar design.DesignA prospective randomised study was performed in 14 centres comparing radiofrequency ablation (RFA) (maximum of 4 sessions) to annual endoscopic surveillance, including patients with a confirmed diagnosis of BO with LGD. Primary outcome was the prevalence of LGD at 3 years. Secondary outcomes were the prevalence of LGD at 1 year, the complete eradication of intestinal metaplasia (CE-IM) at 3 years, the rate of neoplastic progression at 3 years and the treatment-related morbidity.Results125 patients were initially included, of whom 82 with confirmed LGD (76 men, mean age 62.3 years) were finally randomised, 40 patients in the RFA and 42 in the surveillance group. At 3 years, CE-IM rates were 35% vs 0% in the RFA and surveillance groups, respectively (pConclusionRFA modestly reduced the prevalence of LGD as well as progression risk at 3 years. The risk-benefit balance of endoscopic ablation therapy should therefore be carefully weighted against surveillance in patients with BO with confirmed LGD.Trial registration numberNCT01360541.

Background Real-life data on the efficacy of ustekinumab as first-line therapy for the treatment of luminal Crohn’s disease (CD) compared with anti-tumor necrosis factor (anti-TNF) agents are lacking. We compared the clinical response rates at 3 months in 2 cohorts of biologic-naïve patients treated by ustekinumab and anti-TNF agents. Methods Biologic-naïve patients starting either ustekinumab or an anti-TNF agent for luminal CD between 2016 and 2019 in 2 tertiary centers were retrospectively included. The primary endpoint was clinical response at 3 months, defined as a Harvey-Bradshaw Index Results We included 156 patients starting anti-TNF agents (95 adalimumab and 61 infliximab) and 50 ustekinumab. After matching, clinical response rates at 3 months were 64% and 86% in the ustekinumab and anti-TNF groups, respectively (P = .01). At 12 months, in multivariate analysis adjusted for disease duration, location, concomitant immunosuppressant and steroids, and symptoms, clinical remission was independently associated with the biological therapy received (odds ratio, 2.6 for anti-TNF agent vs ustekinumab; P = .02). With a median follow-up duration of 40 (interquartile range, 23-52) months, no difference was observed in terms of time to drug withdrawal (P = .29) or safety. Conclusions This retrospective real-world data suggest that an anti-TNF agent as a first-line biological therapy is associated with higher rates of response at 3 months than ustekinumab in patients with CD.

BEST PRACTICE ADVICE 1: A diagnosis of functional heartburn should be considered when retrosternal burning pain or discomfort persists despite maximal (double-dose) proton pump inhibitor (PPI) therapy taken appropriately before meals during a 3-month period. BEST PRACTICE ADVICE 2: A diagnosis of functional heartburn requires upper endoscopy with esophageal biopsies to rule out anatomic and mucosal abnormalities, esophageal high-resolution manometry to rule out major motor disorders, and pH monitoring off PPI therapy (or pH-impedance monitoring on therapy in patients with proven gastroesophageal reflux disease [GERD]), to document physiologic levels of esophageal acid exposure in the distal esophagus with absence of reflux-symptom association (ie, negative symptom index and symptom association probability). BEST PRACTICE ADVICE 3: Overlap of functional heartburn with proven GERD is diagnosed according to Rome IV criteria when heartburn persists despite maximal PPI therapy in patients with history of proven GERD (ie, positive pH study, erosive esophagitis, Barrett's esophagus, or esophageal ulcer), and pH impedance testing on PPI therapy demonstrates physiologic acid exposure without reflux-symptom association (ie, negative symptom index and symptom association probability). BEST PRACTICE ADVICE 4: PPIs have no therapeutic value in functional heartburn, the exception being proven GERD that overlaps with functional heartburn. BEST PRACTICE ADVICE 5: Neuromodulators, including tricyclic antidepressants, selective serotonin reuptake inhibitors, tegaserod, and histamine-2 receptor antagonists have benefit as either primary therapy in functional heartburn or as add-on therapy in functional heartburn that overlaps with proven GERD. BEST PRACTICE ADVICE 6: Based on available evidence, acupuncture and hypnotherapy may have benefit as monotherapy in functional heartburn, or as adjunctive therapy combined with other therapeutic modalities. BEST PRACTICE ADVICE 7: Based on available evidence, anti-reflux surgery and endoscopic GERD treatment modalities have no therapeutic benefit in functional heartburn and should not be recommended.

Background/Aims Peroral endoscopy myotomy (POEM) is effective to treat achalasia. We aim to determine POEM effect on esophageal function and search for predictive factors of response to POEM and co-occurrence of gastroesophageal reflux disease (GERD). Methods A total of 64 untreated achalasia patients who underwent high-resolution manometry (HRM) before and 3 months after POEM were retrospectively included. Response to treatment was defined as an Eckardt score < 3. Reflux symptoms and patient’s satisfaction were evaluated. Data were compared using paired t test, Chi-square test or log rank test. Results The 2-year success rate in response to POEM was 90%. All responders reported being satisfied while only 33% of non-responders did (P < 0.001) and 64% of patients with reflux symptoms were satisfied versus 96% of those without (P = 0.009). On HRM, the integrated relaxation pressure and the contractile pattern changed significantly after POEM but were not predictive of response. Between pre and post POEM HRM, a decrease in maximal esophageal pressurization during rapid drink challenge (RDC) was associated with a better response rate than an increase of pressurization (91% vs 50%, P = 0.004). As evidenced by pH monitoring performed after POEM, GERD was pathological or borderline in 50% of patients (18/36) while only 19% (11/59) reported clinically significant reflux symptoms. On post POEM HRM, maximal esophageal pressurization during RDC was lower in patients with pathological or borderline GERD compared to those without (P = 0.054). Conclusions Esophageal HRM parameters changed significantly after POEM. Maximal esophageal pressurization during RDC may be useful to predict outcome. (J Neurogastroenterol Motil 2020;26:204-214)

Per-oral endoscopic myotomy (POEM) is effective in achalasia. The objective of this study was to evaluate the short-term clinical efficacy of POEM in non-achalasia esophageal motility disorders (NAEMD). Patients with NAEMD diagnosed by high-resolution manometry were included in a retrospective multicentric study. For each individual case, two controls paired on gender and age were matched: one with type I/II achalasia and one with type III achalasia. The clinical response, defined by an Eckardt score ≤ 3, was assessed at 3 and 6 months. Ninety patients (mean age 66 years, 57 men) were included, 30 patients with NAEMD (13 jackhammer esophagus, 6 spastic esophageal disorders, 4 nutcracker esophagus, and 7 esophagogastric junction obstruction), 30 patients with type I–II achalasia, and 30 patients with type III achalasia. The 3-month response rates were 80% (24/30), 90% (27/30), and 100% (30/30) in NAEMD, type I–II achalasia and type III achalasia, respectively (p

Home parenteral nutrition (HPN) is the recommended treatment in patients with chronic intestinal failure (CIF). HPN is associated with a worsening of patients' quality of life and has a dramatic impact on personal and familial daily life. Little is known about the informal caregiver burden of patients receiving HPN.To assess informal caregiver burden and the factors associated with moderate-to-severe caregiver burden in patients treated with HPN.Informal caregivers of consecutive patients treated with HPN in a French nutrition referral center were invited to participate in a survey between January 2021 and June 2021. They had to fill out an anonymous standardized self-questionnaire evaluating burden by the Zarit Burden Interview (ZBI) and depression and anxiety symptoms by the Hospital Anxiety and Depression Scale (HADS) score since HPN introduction.Among the 87 HPN patients having informal caregivers, 53 (61%) completed the questionnaire. Thirty (57%) informal caregivers were women. The caregiver's median age was 62 years (IQR, 21.0). Twelve (22%) expressed moderate to severe burden (ZBI score, 41-88). In a multivariate analysis, the caregiver's male gender (odds ratio [OR], 16.45; 95% CI, 2.30-238.75; P = 0.014) and the number of simultaneous infusions per day1 (OR, 9.92; 95% CI, 1.35-121.60; P = 0.0038) were associated with a moderate to severe burden. Twenty caregivers reported anxious and depressive symptoms with an elevated HADS score.In this prospective survey, a minority of informal caregivers of patients with CIF being treated with HPN expressed moderate to severe burden. The caregiver's male gender was associated with a higher burden in patients with CIF.

BACKGROUND AND AIMS: There is a need to evaluate the benefit-risk ratio of current therapies in inflammatory bowel disease (IBD) patients to provide the best quality of care. The primary objective of I-CARE (IBD Cancer and serious infections in Europe) was to assess prospectively safety concerns in IBD, with specific focus on the risk of cancer/lymphoma and serious infections in patients treated with anti-tumor necrosis factor and other biologic monotherapy as well as in combination with immunomodulators.METHODS: I-CARE was designed as a European prospective longitudinal observational multicenter cohort study to include patients with a diagnosis of Crohn's disease, ulcerative colitis, or IBD unclassified established at least 3 months prior to enrollment.RESULTS: A total of 10,206 patients were enrolled between March 2016 and April 2019, including 6169 (60.4%) patients with Crohn's disease, 3853 (37.8%) with ulcerative colitis, and 184 (1.8%) with a diagnosis of IBD unclassified. Thirty-two percent of patients were receiving azathioprine/thiopurines, 4.6% 6-mercaptopurine, and 3.2% methotrexate at study entry. At inclusion, 47.3% of patients were treated with an anti-tumor necrosis factor agent, 8.8% with vedolizumab, and 3.4% with ustekinumab. Roughly one-quarter of patients (26.8%) underwent prior IBD-related surgery. Sixty-six percent of patients had been previously treated with systemic steroids. Three percent of patients had a medical history of cancer prior to inclusion and 1.1% had a history of colonic, esophageal, or uterine cervix high-grade dysplasia.CONCLUSIONS: I-CARE is an ongoing investigator-initiated observational European prospective cohort study that will provide unique information on the long-term benefits and risks of biological therapies in IBD patients. (EudraCT, Number: 2014-004728-23; ClinicalTrials.gov, Number: NCT02377258).

Gastroesophageal reflux disease (GERD) is one of the most frequent gastrointestinal disorders. Proton pump inhibitors (PPIs) are effective in healing lesions and improving symptoms in most cases, although up to 40% of GERD patients do not respond adequately to PPI therapy. Refractory GERD (rGERD) is one of the most challenging problems, given its impact on the quality of life and consumption of health care resources. The definition of rGERD is a controversial topic as it has not been unequivocally established. Indeed, some patients unresponsive to PPIs who experience symptoms potentially related to GERD may not have GERD; in this case the definition could be replaced with “reflux-like PPI-refractory symptoms.” Patients with persistent reflux-like symptoms should undergo a diagnostic workup aimed at finding objective evidence of GERD through endoscopic and pH-impedance investigations. The management strategies regarding rGERD, apart from a careful check of patient's compliance with PPIs, a possible change in the timing of their administration and the choice of a PPI with a different metabolic pathway, include other pharmacologic treatments. These include histamine-2 receptor antagonists (H2RAs), alginates, antacids and mucosal protective agents, potassium competitive acid blockers (PCABs), prokinetics, gamma aminobutyric acid-B (GABA-B) receptor agonists and metabotropic glutamate receptor-5 (mGluR5) antagonists, and pain modulators. If there is no benefit from medical therapy, but there is objective evidence of GERD, invasive antireflux options should be evaluated after having carefully explained the risks and benefits to the patient. The most widely performed invasive antireflux option remains laparoscopic antireflux surgery (LARS), even if other, less invasive, interventions have been suggested in the last few decades, including endoscopic transoral incisionless fundoplication (TIF), magnetic sphincter augmentation (LINX) or radiofrequency therapy (Stretta). Due to the different mechanisms underlying rGERD, the most effective strategy can vary, and it should be tailored to each patient. The aim of this paper is to review the different management options available to successfully deal with rGERD.

Summary Background Quadruple therapy using a single capsule formulation of bismuth, metronidazole and tetracycline (BMT; Pylera®), associated with omeprazole for the eradication of Helicobacter pylori, represents the reintroduction of bismuth in France after 40 years. Objective To describe the real-life patterns of use of BMT following a request from the French health authorities. Methods Patients with a first BMT dispensing (index date, ID), with one year of data before and after ID, were identified in the French nationwide claims database 1/97 sample. Misuse of BMT was defined as dispensing >1 pack of BMT at ID or absence of a diagnostic test in the preceding year. Results In total, 540 patients were included. Prescribers were gastroenterologists (n = 243; 45%) and general practitioners (n = 160; 30%). A proton pump inhibitor was co-dispensed to 504 patients (96%). Ten patients (2%) had contraindications to BMT. Fifty-nine patients (11%) met the misuse criteria: ten (2%) were dispensed > 1 pack of BMT and 49 (9%) had not had a diagnostic test for H. pylori in the previous year. During follow-up, 27 patients (5%) required retreatment (treatment failure). Conclusion In this real-life study, most patients were dispensed only one pack of BMT, consistent with recommendations. Misuse related principally to the absence of prior diagnostic test for H. pylori.

Summary Background While all resources have been mobilized to fight COVID-19, this study aimed to analyze the consequences of lockdown and pandemic stress in participants with and without Irritable Bowel Syndrome (IBS). Methodology An online survey was proposed to people with or without IBS during the exponential phase of the pandemic in France. The questionnaire included questions about socio-demographic data, conditions of confinement , activities carried out, IBS characteristics, measurement of stress level, consequences on sleep, fatigue, anxiety and depression, and quality of life (both perceived non-specific and specific for IBS). Results/Discussion From March 31 to April 15, 2020, 304 participants, 232 with IBS and 72 without were included in the survey (mean age: 46.8 ± 16.8 years, female gender: 75.3%). Age, level of education, financial resources, living space per person and activities performed during confinement were identical in both groups. Stress linked to fear of COVID-19, lockdown and financial worries was at the same level in both groups, but the psychological consequences and deterioration of quality of life (QOL) were both higher in IBS participants. In a univariate analysis , teleworking, solitary confinement, and low household resources had a variable impact on the scores of depression, anxiety, fatigue and non-specific perceived QOL, but in a multivariate analysis , the only factor explaining a deterioration of non-specific QOL was the fact of suffering from IBS. Conclusion/Perspectives Stress linked to the COVID-19 pandemic and confinement is high and equivalent in both IBS and non-IBS participants, with higher psychological and QOL consequences in IBS patients who have altered coping capacities.

Esophageal hypomotility disorders manifest with abnormal esophageal body contraction vigor, breaks in peristaltic integrity, or failure of peristalsis in the context of normal lower esophageal sphincter relaxation on esophageal high-resolution manometry (HRM). The Chicago Classification version 4.0 recognizes two hypomotility disorders, ineffective esophageal motility (IEM) and absent contractility, while fragmented peristalsis has been incorporated into the IEM definition. Updated criteria for ineffective swallows consist of weak esophageal body contraction vigor measured using distal contractile integral (DCI, 100-450 mmHg·cm·s), transition zone defects >5 cm measured using a 20 mmHg isobaric contour, or failure of peristalsis (DCI < 100 mmHg·cm·s). More than 70% ineffective swallows and/or ≥50% failed swallows are required for a conclusive diagnosis of IEM. When the diagnosis is inconclusive (50%-70% ineffective swallows), supplementary evidence from multiple rapid swallows (absence of contraction reserve), barium radiography (abnormal bolus clearance), or HRM with impedance (abnormal bolus clearance) could support a diagnosis of IEM. Absent contractility requires 100% failed peristalsis, consistent with previous versions of the classification. Consideration needs to be given for the possibility of achalasia in absent contractility with dysphagia despite normal IRP, and alternate complementary tests (including timed upright barium esophagram and functional lumen imaging probe) are recommended to confirm or refute the presence of achalasia. Future research to quantify esophageal bolus retention on stationary HRM with impedance and to understand contraction vigor thresholds that predict bolus clearance will provide further refinement to diagnostic criteria for esophageal hypomotility disorders in future iterations of the Chicago Classification.

AIM Low anterior resection syndrome (LARS) following sphincter-preserving surgery for rectal cancer has a high prevalence, with an impact on long-term bowel dysfunction and quality of life. We designed the bowel rehabilitation programme (BOREAL) as a proactive strategy to assess and treat patients with LARS. The BOREAL programme consists of a stepwise approach of escalating treatments: medical management (steps 0-1), pelvic floor physiotherapy, biofeedback and transanal irrigation (step 2), sacral nerve neuromodulation (step 3), percutaneous endoscopic caecostomy and anterograde enema (step 4) and definitive colostomy (step 5). METHODS A pilot study was undertaken to assess the feasibility of collecting LARS data routinely with the parallel implementation of the BOREAL programme. All patients who underwent total mesorectal excision for rectal cancer between February 2017 and March 2019 were included. LARS was assessed using the LARS score and the Wexner Faecal Incontinence score at 30 days and 3, 6, 9 and 12 months postoperatively. A good functional result was considered to be a combined LARS score

Sleep is involved in the regulation of inflammation, healing, and digestion. The pathophysiology of Crohn’s disease (CD) is unclear, and the role of sleep disturbances has recently been suggested. The present study investigated a putative association between sleep disturbances and CD activity. We conducted a prospective observational monocenter translational study, recruiting major CD patients from 2013 to 2015. Disease activity was assessed by the Harvey-Bradshaw index and the CD activity index. Objective sleep quantity and quality were measured by wrist actigraphy over a period of 7 days. The primary objective was to look for an association between wrist actigraphy parameters and CD activity. Thirty-four CD patients, including 14 with active disease and 20 in remission, were included. Sleep efficiency measured by wrist actigraphy was lower in patients with active CD compared to patients in remission. Wake after sleep onset time best predicted CD activity with an AUROC of 0.83. Patients with active CD were more frequently characterized as “poor sleepers” and frequently suffered from excessive daytime sleepiness. Sleep efficiency is lower in patients with active CD than in those in remission. Further studies aimed at better characterizing CD patients’ sleep are warranted.

BACKGROUND The low FODMAPs (fermentable oligo-, di-, monosaccharides, and polyols) diet improves lower gastrointestinal symptoms. Patients suffering from proton pump inhibitor (PPI) refractory gastroesophageal reflux disease (GERD) have limited treatment options. We investigated the efficacy of a low FODMAPs diet in patients with PPI refractory GERD. METHODS This multicenter, randomized, open-label study compared the efficacy of a 4-week low FODMAPs diet and usual dietary advice (ie, low-fat diet and head of bed elevation) in patients with symptomatic PPI refractory GERD, defined by a Reflux Disease Questionnaire (RDQ) score >3 and abnormal pH-impedance monitoring on PPIs. The primary endpoint was the percentage of responders (RDQ ≤3) at the end of the diet. RESULTS Thirty-one patients (55% women, median age 45 years) were included, 16 randomized in the low FODMAPs diet group and 15 in the usual dietary advice group. Adherence to the assigned diet was good, with a significant difference in the FODMAPs intake per day between the low FODMAPs diet (2.5 g) and the usual dietary advice group (13 g) (p

BACKGROUND: Gastroparesis is a condition characterized by epigastric symptoms and delayed gastric emptying (GE) rate in the absence of any mechanical obstruction. The condition is challenging in clinical practice by the lack of guidance concerning diagnosis and management of gastroparesis. METHODS: A Delphi consensus was undertaken by 40 experts from 19 European countries who conducted a literature summary and voting process on 89 statements. Quality of evidence was evaluated using grading of recommendations assessment, development, and evaluation criteria. Consensus (defined as ≥80% agreement) was reached for 25 statements. RESULTS: The European consensus defined gastroparesis as the presence of symptoms associated with delayed GE in the absence of mechanical obstruction. Nausea and vomiting were identified as cardinal symptoms, with often coexisting postprandial distress syndrome symptoms of dyspepsia. The true epidemiology of gastroparesis is not known in detail, but diabetes, gastric surgery, certain neurological and connective tissue diseases, and the use of certain drugs recognized as risk factors. While the panel agreed that severely impaired gastric motor function is present in these patients, there was no consensus on underlying pathophysiology. The panel agreed that an upper endoscopy and a GE test are required for diagnosis. Only dietary therapy, dopamine-2 antagonists and 5-HT4 receptor agonists were considered appropriate therapies, in addition to nutritional support in case of severe weight loss. No consensus was reached on the use of proton pump inhibitors, other classes of antiemetics or prokinetics, neuromodulators, complimentary, psychological, or more invasive therapies. Finally, there was consensus that gastroparesis adversely impacts on quality of life and healthcare costs and that the long-term prognosis of gastroparesis depends on the cause. CONCLUSIONS AND INFERENCES: A multinational group of European experts summarized the current state of consensus on definition, symptom characteristics, pathophysiology, diagnosis, and management of gastroparesis. ispartof: UNITED EUROPEAN GASTROENTEROLOGY JOURNAL vol:9 issue:3 pages:287-306 ispartof: location:England status: published

BACKGROUND High-resolution impedance manometry (HRIM) evaluates esophageal peristalsis and bolus transit. We used esophageal impedance integral (EII), the ratio between bolus presence before and after an expected peristaltic wave, to evaluate predictors of bolus transit. METHODS From HRIM studies performed on 61 healthy volunteers (median age 27 years, 48%F), standard metrics were extracted from each of 10 supine water swallows: distal contractile integral (DCI, mmHg cm s), integrated relaxation pressure (IRP, mmHg), and breaks in peristaltic integrity (cm, using 20 mmHg isobaric contour). Pressure and impedance coordinates for each swallow were exported into a dedicated, python-based program for EII calculation (EII ratio ≥ 0.3 = abnormal bolus clearance). Univariate and multivariate analyses were performed to assess predictors of abnormal bolus clearance. KEY RESULTS Of 591 swallows, 80.9% were intact, 10.5% were weak, and 8.6% failed. Visual analysis overestimated abnormal bolus clearance compared to EII ratio (p ≤ 0.01). Bolus clearance was complete (median EII ratio 0.0, IQR 0-0.12) in 82.0% of intact swallows in contrast to 53.3% of weak swallows (EII ratio 0.29, IQR 0.0-0.57), and 19.6% of failed swallows (EII ratio 0.5, IQR 0.34-0.73, p

Aim: Little is known about the pathophysiology of low anterior resection syndrome (LARS), and evidence concerning the management of patients diagnosed with this condition is scarce. The aim of the LARS Expert Advisory Panel was to develop practical guidance for healthcare professionals dealing with LARS. Method: The ‘Management guidelines for low anterior resection syndrome’ (MANUEL) project was promoted by a team of eight experts in the assessment and management of patients with LARS. After a face-to-face meeting, a strategy was agreed to create a comprehensive, practical guide covering all aspects that were felt to be clinically relevant. Eight themes were decided upon and working groups established. Each working group generated a draft; these were collated by another collaborator into a manuscript, after a conference call. This was circulated among the collaborators, and it was revised following the comments received. A lay patient revised the manuscript, and contributed to a section containing a patient's perspective. The manuscript was again circulated and finalized. A final teleconference was held at the end of the project. Results: The guidance covers all aspects of LARS management, from pathophysiology, to assessment and management. Given the lack of sound evidence and the often poor quality of the studies, most of the recommendations and conclusions are based on the opinions of the experts. Conclusions: The MANUEL project provides an up-to-date practical summary of the available evidence concerning LARS, with useful directions for healthcare professional and patients suffering from this debilitating condition.

Background Esophagogastric junction contractile integral (EGJ-CI) and EGJ morphology are high-resolution manometry (HRM) metrics that assess EGJ barrier function. Normative data standardized across world regions and HRM manufacturers are limited. Methods Our aim was to determine normative EGJ metrics in a large international cohort of healthy volunteers undergoing HRM (Medtronic, Laborie, and Diversatek software) acquired from 16 countries in four world regions. EGJ-CI was calculated by the same two investigators using a distal contractile integral-like measurement across the EGJ for three respiratory cycles and corrected for respiration (mm Hg cm), using manufacturer-specific software tools. EGJ morphology was designated according to Chicago Classification v3.0. Median EGJ-CI values were calculated across age, genders, HRM systems, and regions. Results Of 484 studies (28.0 years, 56.2% F, 60.7% Medtronic studies, 26.0% Laborie, and 13.2% Diversatek), EGJ morphology was type 1 in 97.1%. Median EGJ-CI was similar between Medtronic (37.0 mm Hg cm, IQR 23.6-53.7 mm Hg cm) and Diversatek (34.9 mm Hg cm, IQR 22.1-56.1 mm Hg cm, P = 0.87), but was significantly higher using Laborie equipment (56.5 mm Hg cm, IQR 35.0-75.3 mm Hg cm, P < 0.001). 5(th) percentile EGJ-CI values ranged from 6.9 to 12.1 mm Hg cm. EGJ-CI values were consistent across world regions, but different between manufacturers even within the same world region (P = 0.3) but higher in women (P < 0.001). Conclusions EGJ morphology is predominantly type 1 in healthy adults. EGJ-CI varies widely in health, with significant gender influence, but is consistent within each HRM system. Manufacturer-specific normative values should be utilized for clinical HRM interpretation.

Background and Aims Acid exposure time (AET) and reflux episode thresholds from the Lyon Consensus may not apply for pH impedance studies performed while on proton pump inhibitor (PPI) therapy. We aimed to determine metrics from “on PPI” pH impedance studies predicting need for escalation of therapy. Methods De-identified pH impedance studies performed while on twice-daily PPI (Diversatek, Boulder, CO) in healthy volunteers (n = 66, median age 37.5 years, 43.9% female), and patients with proven gastroesophageal reflux disease (GERD) (European heartburn-predominant cohort: n = 43, median age 57.0 years, 55.8% female; North American regurgitation-predominant cohort: n = 42, median age 41.6 years, 42.9% female) were analyzed. Median values and interquartile ranges for pH impedance metrics in healthy volunteers were compared with proven GERD patients with and without 50% symptom improvement on validated measures. Receiver operating characteristic (ROC) analyses identified optimal thresholds predicting symptom response. Results Both conventional and novel reflux metrics were similar between PPI responders and nonresponders (P ≥ .1 for each) despite differences from healthy volunteers. Combinations of metrics associated with conclusively abnormal reflux burden (AET >4%, >80 reflux episodes) were seen in 32.6% and 40.5% of heartburn and regurgitation-predominant patients, respectively, 57.1% and 82.4% of whom reported nonresponse; and 85% with these metrics improved with invasive GERD management. On ROC analysis, AET threshold of 0.5% modestly predicted nonresponse (sensitivity, 0.62; specificity, 0.51; P = .22), and 40 reflux episodes had better performance characteristics (sensitivity, 0.80; specificity, 0.51; P = .002); 79% with these metrics improved with invasive GERD management. Conclusion Combinations of abnormal “on PPI” pH impedance metrics are associated with PPI nonresponse in proven GERD patients, and can be targeted for treatment escalation, including surgery, particularly in regurgitation-predominant GERD.

Objective Limitations of existing impedance-pH thresholds include small sample size of normative studies, inclusion of artefactual pH drops and incorrect identification of impedance reflux events. We aimed to obtain new impedance-pH thresholds from expert consensus analysis of tracings from a large number of healthy subjects. Design Of 541 studies performed worldwide using two different systems (Diversatek, USA, and Laborie, Netherlands), 150 tracings with oesophageal diagnoses, behavioural disorders and study-related artefacts were excluded. The remainder studies were subject to two reviewer consensus analysis, in-person or through video conference, consisting of editing meals and pH drops, identification of impedance reflux and postreflux swallow-induced peristaltic wave (PSPW) using strict pre-established criteria and measurement of distal mean nocturnal baseline impedance (MNBI). Results Consensus analysis was performed in 391 tracings (age 32.7 years, range 18-71, 54.2% female). Normative thresholds were significantly different between Diversatek and Laborie (total acid exposure time: 2.8% and 5%; reflux episodes: 55 and 78; MNBI at 3 cm: 1400 and 1500 ohms, at 5 cm: 1400 and 1800 ohms). Males had higher acid exposure, more reflux episodes and lower MNBI. Significant regional differences were identified, including higher PSPW scores in Western countries, and higher MNBI in Asia using Diversatek, and higher acid exposure in the Netherlands, higher MNBI in Asia and South Africa, and lower MNBI in Turkey using Laborie. Conclusion Normal impedance-pH monitoring thresholds have regional and system-related differences. Clinical interpretation needs to use normal thresholds valid for the system used and world region, following careful editing of the tracings., Queen Mary University of London, UK [DDCH1A3R], The study was conducted with financial support from Research Grant DDCH1A3R, Queen Mary University of London, UK.

International audience; BACKGROUND/AIMS: Few data on the evolution of endoscopic findings are available in patients with acute severe ulcerative colitis (ASUC). The aim of this study was to describe this evolution in a prospective cohort. METHODS: Patients admitted for a steroid-refractory ASUC and included in a randomized trial comparing infliximab and cyclosporine were eligible if they achieved steroid-free clinical remission at day 98. Flexible sigmoidoscopies were performed at baseline, days 7, 42 and 98. Ulcerative colitis endoscopic index of severity (UCEIS) and its sub-scores - vascular pattern, bleeding and ulceration/erosion - were post-hoc calculated. Global endoscopic remission was defined by a UCEIS of 0, and partial endoscopic remission by any UCEIS sub-score of 0. RESULTS: Among the 55 patients analyzed (29 infliximab and 26 cyclosporine), 49 (83%) had UCEIS >= 6 at baseline at baseline. Partial endoscopic remission rates were higher for bleeding than for vascular pattern and for ulcerations/erosions at day 7 (20% vs. 4% and 5% (n = 55); p

Chicago Classification v4.0 (CCv4.0) is the updated classification scheme for esophageal motility disorders using metrics from high-resolution manometry (HRM). Fifty-two diverse international experts separated into seven working subgroups utilized formal validated methodologies over two-years to develop CCv4.0. Key updates in CCv.4.0 consist of a more rigorous and expansive HRM protocol that incorporates supine and upright test positions as well as provocative testing, a refined definition of esophagogastric junction (EGJ) outflow obstruction (EGJOO), more stringent diagnostic criteria for ineffective esophageal motility and description of baseline EGJ metrics. Further, the CCv4.0 sought to define motility disorder diagnoses as conclusive and inconclusive based on associated symptoms, and findings on provocative testing as well as supportive testing with barium esophagram with tablet and/or functional lumen imaging probe. These changes attempt to minimize ambiguity in prior iterations of Chicago Classification and provide more standardized and rigorous criteria for patterns of disorders of peristalsis and obstruction at the EGJ. © 2020 John Wiley & Sons Ltd, National Institute of Diabetes and Digestive and Kidney Diseases, NIDDK: P01 DK092217, National Institute of Diabetes and Digestive and Kidney Diseases, Grant/Award Number: P01 DK092217

Up to 40% of patients with symptoms suspicious of gastroesophageal reflux disease (GERD) do not respond completely to proton pump inhibitor (PPI) therapy. The term “refractory GERD” has been used loosely in the literature. A distinction should be made between refractory symptoms (ie, symptoms may or may not be GERD-related), refractory GERD symptoms (ie, persisting symptoms in patients with proven GERD, regardless of relationship to ongoing reflux), and refractory GERD (ie, objective evidence of GERD despite adequate medical management). The present ESNM/ANMS consensus paper proposes use the term “refractory GERD symptoms” only in patients with persisting symptoms and previously proven GERD by either endoscopy or esophageal pH monitoring. Even in this context, symptoms may or may not be reflux related. Objective evaluation, including endoscopy and esophageal physiologic testing, is requisite to provide insights into mechanisms of symptom generation and evidence of true refractory GERD. Some patients may have true ongoing refractory acid or weakly acidic reflux despite PPIs, while others have no evidence of ongoing reflux, and yet others have functional esophageal disorders (overlapping with proven GERD confirmed off therapy). In this context, attention should also be paid to supragastric belching and rumination syndrome, which may be important contributors to refractory symptoms.

When esophageal acid exposure time (AET) is physiologic, ROME IV stratifies functional esophageal disorders into functional heartburn (FH, with negative reflux-symptom association) and reflux hypersensitivity (RH, with positive reflux-symptom association), and hypothesizes that FH/RH could overlap with proven gastroesophageal reflux disease (GERD). We compared conventional FH/RH diagnosed off antisecretory therapy with overlap FH/RH coexisting with proven GERD.Adult patients with heartburn underwent pH-impedance testing on therapy (proven GERD) and off therapy (unproven GERD) and completed validated questionnaires defining symptoms (Reflux Diagnostic Questionnaire, RDQ), affective state (Hospital Anxiety and Depression Scale, HADS; Visceral Sensitivity Index, VSI), and functional diagnoses (irritable bowel syndrome, IBS; functional dyspepsia, FD on ROME diagnostic questionnaire). AET (pathologic:6%, physiologic4%) and mean nocturnal baseline impedance (MNBI) were calculated. Clinical, psychological, and functional profiles were compared between FH and RH and to a comparison cohort of non-erosive reflux disease (NERD, AET 6%).Study patients included 19 with RH (10 with overlap RH), 60 with FH (31 with overlap FH), and 26 patients with NERD. Clinical, psychological, and functional profiles of conventional FH/RH were similar to overlap FH/RH. Compared with NERD, combined FH and RH cohorts had higher anxiety scores, and lower proportions with IBS. Compared with FH with low MNBI, FH defined using both normal AET and normal MNBI had higher depression scores (p = 0.008), and trended toward higher anxiety scores (p = 0.059).Conventional and overlap FH and RH have similar clinical, psychological and functional profiles, thereby proving ROME IV hypotheses.

Medico-economic data of patients suffering from chronic nausea and vomiting are lacking. In these patients, gastric electrical stimulation (GES) is an effective, but costly treatment. The aim of this study was to assess the efficacy, safety and medico-economic impact of Enterra therapy in patients with chronic medically refractory nausea and vomiting.Data were collected prospectively from patients with medically refractory nausea and/or vomiting, implanted with an Enterra device and followed for two years. Gastrointestinal quality of life index (GIQLI) score, vomiting frequency, nutritional status and safety were evaluated. Direct and indirect expenditure data were prospectively collected in diaries.Complete clinical data were available for142 patients (60 diabetic, 82 non-diabetic) and medico-economic data were available for 96 patients (36 diabetic, 60 non-diabetic), 24 months after implantation. GIQLI score increased by 12.1 ± 25.0 points (p.001), with a more significant improvement in non-diabetic than in diabetic patients (+15.8 ± 25.0 points, p.001 versus 7.3 ± 24.5 points, p = .027, respectively). The proportion of patients vomiting less than once per month increased by 25.5% (p.001). Hospitalisations, time off work and transport were the main sources of costs. Enterra therapy decreased mean overall healthcare costs from 8873 US$ to 5525 US$ /patient/year (p = .001), representing a saving of 3348 US$ per patient and per year. Savings were greater for diabetic patients (4096 US$ /patient/year) than for non-diabetic patients (2900 US$ /patient/year).Enterra therapy is an effective, safe and cost-effective option for patients with refractory nausea and vomiting.gov Identifier: NCT00903799.

Background Oesophageal radiofrequency reduces use of proton pump inhibitors (PPIs) in patients with gastro-oesophageal reflux disease responding to PPIs. Aim To determine the efficacy of oesophageal radiofrequency in patients with PPI-refractory heartburn. Methods A randomised, double-blind, sham-controlled multicentre study was designed to assess the efficacy of oesophageal radiofrequency in PPI non-responding patients with heartburn. Patients had moderate-to-severe heartburn defined by at least 3 occurrences a week, and not improved by continuous PPI treatment. The primary endpoint was clinical success at week 24, defined by intake of less than 7 PPI doses over the 2 preceding weeks and adequate symptom control determined by the patient. Results Sixty two patients were randomised, 29 to the oesophageal radiofrequency group and 33 to the sham group. Intention-to-treat analysis showed that 1/29 (3.4%) and 5/33 (15.1%) achieved the primary endpoint in the oesophageal radiofrequency and sham groups, respectively (NS). There was no significant difference between oesophageal radiofrequency and sham regarding the number of days without heartburn, days with PPI consumption in the last 2 weeks, and patients not taking PPIs. No pH-impedance parameter was associated with clinical response. The occurrence of adverse events was similar in both groups. Conclusion This sham-controlled, randomised study did not demonstrate any efficacy of oesophageal radiofrequency for the treatment of PPI-refractory heartburn regarding symptom relief or consumption of PPIs. ClinicalTrials.gov NCT01682265.

BACKGROUND The definition and relevance of ineffective esophageal motility (IEM) remains debated. Our aim was to determine motility patterns and symptoms associated with IEM defined as impaired bolus clearance. METHODS To define altered bolus clearance, normal range of swallows with complete bolus transit (CBT) on high-resolution impedance manometry (HRIM) was determined in 44 asymptomatic controls. The results were then applied to a cohort of 81 patients with esophageal symptoms to determine the motility patterns which best predicted altered bolus clearance. Subsequently, in a cohort of 281 consecutive patients the identified motility patterns were compared with patients' customary symptoms. KEY RESULTS In asymptomatic controls, the normal range of swallows with CBT was 50%-100%. In patients, altered bolus transit (

There have been conflicting results from trials of gastric electrical stimulation (GES) for treatment of refractory vomiting, associated or not with gastroparesis. We performed a large, multicenter, randomized, double-blind trial with crossover to study the efficacy of GES in patients with refractory vomiting, with or without gastroparesis.For 4 months, we assessed symptoms in 172 patients (66% women; mean age ± standard deviation, 45 ± 12 years; 133 with gastroparesis) with chronic (12 months) of refractory vomiting (idiopathic, associated with a type 1 or 2 diabetes, or postsurgical). A GES device was implanted and left unactivated until patients were randomly assigned, in a double-blind manner, to groups that received 4 months of stimulation parameters (14 Hz, 5 mA, pulses of 330 μs) or no stimulation (control); 149 patients then crossed over to the other group for 4 months. Patients were examined at the end of each 4-month period (at 5 and 9 months after implantation). Primary endpoints were vomiting score, ranging from 0 (daily vomiting) to 4 (no vomiting), and the quality of life, assessed by the Gastrointestinal Quality of Life Index scoring system. Secondary endpoints were changes in other digestive symptoms, nutritional status, gastric emptying, and control of diabetes.During both phases of the crossover study, vomiting scores were higher in the group with the device on (median score, 2) than the control group (median score, 1; P.001), in diabetic and nondiabetic patients. Vomiting scores increased significantly when the device was ON in patients with delayed (P.01) or normal gastric emptying (P = .05). Gastric emptying was not accelerated during the ON period compared with the OFF period. Having the GES turned on was not associated with increased quality of life.In a randomized crossover study, we found that GES reduced the frequency of refractory vomiting in patients with and without diabetes, although it did not accelerate gastric emptying or increase of quality of life. Clinicaltrials.gov, Number: NCT00903799.

In case reports or small studies, percutaneous endoscopic caecostomy (PEC) has been proposed as an alternative to the Malone intervention to perform antegrade colonic enemas. Our goal was to assess the feasibility, efficacy, and tolerance of PEC in a large group of patients with refractory colorectal functional disorders. From September 2006 to April 2014, all patients undergoing PEC for constipation, fecal incontinence, and incontinence after rectal resection in two expert centers were studied. The PEC procedure consisted in anchoring the caecum to the abdominal wall (caecopexy) and placing a specifically designed tube in the colonic lumen to perform antegrade enemas. The quality of life (GIQLI), constipation (Kess), and incontinence (Cleveland) scores were assessed before PEC and at 3, 6, 12, and 24 months. A total of 69 patients were included. GIQLI scores were significantly improved in constipation group (n = 43), incontinence group (n = 19), and rectal resection group (n = 10). In the constipation group, Kess score decreased from 25.9 before PEC to 20.6 at 2 years (p = 0.01). In the incontinence and post-rectal resection groups, Cleveland scores decreased from 14.3 before PEC to 2.7 at 6 months (p = 0.01) and to 10.4 at 2 years (p = 0.04). Overall, PEC was considered successful by patients in 58%, 74%, and 90% of cases, in constipation, incontinence, and rectal resection groups, respectively. Chronic pain (52%) at the catheter site was the most frequent complication. Percutaneous endoscopic caecostomy for antegrade colonic enemas improves significantly the quality of life of patients with colorectal disorder refractory to medical treatment.

Globus is a non-painful sensation of a tightness or a lump/foreign body in the throat that is not associated with dysphagia and may actually improve during meals. While several otorhinolaryngologic, thyroid, and esophageal disorders have been linked to globus, cause-and-effect relationships are difficult to establish. Consequently, though part of the evaluation, objective otorhinolaryngologic and esophageal testing is often negative. The presence of alarm symptoms, particularly pain, weight loss, dysphagia, or odynophagia is indications for objective testing. A diagnosis of idiopathic globus requires exclusion of pharyngeal, laryngeal, and esophageal disorders with laryngoscopy, endoscopy, high-resolution manometry, barium radiography, and/or ambulatory reflux monitoring. A trial of acid-suppressive therapy may be reasonable in the absence of alarm symptoms, especially if concurrent reflux symptoms are identified. Ablation of heterotopic gastric mucosa in the proximal esophagus has been reported to improve globus symptoms. Beyond these specific approaches, further management of idiopathic globus consists of reassurance, neuromodulators, and complementary approaches. Globus has a benign course with no long-term consequences, and the overall prognosis is good as the magnitude of symptoms may decline over time.

International audience; BACKGROUND:According to infliximab (IFX) license in Crohn's disease (CD), infusion doses are based on patient's body-weight. Dose banding providing standardized doses (SD) has been implemented in parenteral chemotherapy in order to optimize aseptic unit capacity and reduce drug expenditure, duration of hospital stay and costs without decreasing efficacy.MATERIAL AND METHOD:The first part was a single-center retrospective analysis of consecutive CD patients receiving IFX maintenance therapy to determine standardized doses covering more than 50% of infusions. The second part was a prospective cohort study assessing the impact of SD compared to body-weight doses (BWD) on admission duration and costs.RESULTS:Six IFX SD covering more than 90% of infusion doses were implemented for dose banding. According to the Monte-Carlo simulation, there was no significant difference between IFX SD and BWD maintenance regimens. When assessed prospectively in 116 patients (75 patients treated with SD and 41 with BWD) corresponding to 128 infusions, hospitalization duration was shortened by 70 min per patient (p