Camilleri, Michael

Abstract The aims of this review are to appraise the role of the stomach in satiation, the effects of incretin and other hormone agonists on weight loss and the role of altered gastric functions in their effects on obesity or glycaemic control. In addition to the gut in its role in enzymatic digestion and hormonal responses to nutrient ingestion, gastric motor functions include accommodation, trituration and emptying [gastric emptying (GE)] of food and elicitation of postprandial satiation and satiety. The postprandially released hormones most extensively studied and utilized therapeutically are glucagon‐like peptide 1 (GLP‐1) and glucose‐dependent insulinotropic peptide (GIP). Their mechanisms of action include stimulation of pancreatic β cells to produce insulin. However, GLP‐1 reduces glucagon and slows GE, whereas GIP increases glucagon and does not alter GE. Molecular modifications of GLP‐1 (which has a T 1/2 of 3 min) led to the development of long‐acting subcutaneous or oral pharmacological agents that have been approved for the treatment of obesity, and their effects on gastric function are documented. Other medications in development target other molecular mechanisms, including glucagon and amylin. Small‐molecule GLP‐1 receptor agonists are promising for the treatment of obesity and may also slow GE. Bariatric surgery and endoscopy increase satiation by restricting gastric size; in addition Roux‐en‐Y gastric bypass and to a lesser extent sleeve gastrectomy (but not endoscopic gastroplasty) increase postprandial circulating incretins, reducing appetite. In conclusion the stomach's function is integral to the impact of the most effective pharmacological and procedural reversal of obesity related to the incretin revolution. image

AbstractIntroductionThe American Neurogastroenterology and Motility Society Gastroparesis Cardinal Symptom Index‐Daily Diary (ANMS GCSI‐DD) is a patient‐reported outcome (PRO) instrument for gastroparesis. This study evaluated the psychometric properties of the ANMS GCSI‐DD and determined a meaningful change threshold using the data from a phase 2b trial in adults with moderate‐to‐severe idiopathic or diabetic gastroparesis (DG).MethodsThe psychometric properties of ANMS GCSI‐DD were analyzed using other clinician‐ and patient‐reported outcomes from 242 patients during the 12‐week trial. Trial exit interviews were conducted in a cohort of 32 patients to capture their perspectives on meaningful change from the trial.ResultsANMS GCSI‐DD demonstrated good performance: unidimensionality scores exhibited good fit; internal consistency reliability was >0.70; test–retest reliability was above 0.90, and convergent validity showed strong correlations (0.70–0.90) with overall severity rating and moderate correlations (0.30–0.70) with other outcomes. ANMS GCSI‐DD scores discriminated among groups with varying severity of gastroparesis symptoms in known‐groups validity (p < 0.001) and were responsive to symptom improvement. Triangulation of the quantitative anchor‐based estimates of 0.9–1.4 category points as a meaningful change in the ANMS GCSI‐DD composite score, and the qualitative exit interview findings of 0.5–1.5 as meaningful change, supports a one‐point change on a five‐point scale (0–4) as the meaningful change threshold.ConclusionThe ANMS GCSI‐DD is a reliable and valid PRO instrument to employ in clinical development for patients with moderate‐to‐severe idiopathic or DG, and a one‐point score change in the ANMS GCSI‐DD composite score is recommended as a meaningful change threshold of symptom change.

INTRODUCTION: To review stool diagnostic tests in acute and chronic diarrhea. METHODS: Narrative review of published literature. RESULTS: In acute diarrhea, stool tests are indicated when there is strong pretest probability of infectious etiology or Clostridioides difficile infection suggested by > 3 unformed bowel movements per 24 hours, symptoms lasting >7 days, and circumstances that are suggestive of infection. Several commercially available rapid tests for bacterial, viral, or protozoal infections may be offered in addition to traditional methods (e.g. culture, microscopy) and provide a result within 6 hours. For C . difficile infections, a highly sensitive test such as glutamate dehydrogenase test is required; however, this does not distinguish infection from carrier state. That differentiation requires specialized nucleic acid amplification test (for toxin B) or enzyme immunoassays for toxin A or B, which are unfortunately not generally offered by microbiology laboratories. Chronic diarrhea may result from inflammatory, fatty, osmotic, or secretory causes; the commonest cause is diarrhea-predominant irritable bowel syndrome/functional diarrhea. Current recommendations in societal guidelines or clinical practice updates regarding stool tests in diarrhea-predominant irritable bowel syndrome/functional diarrhea in the absence of alarm symptoms include testing for Giardia, calprotectin, fecal immunochemical test, and bile acid diarrhea. Comprehensive stool biochemical analyses (osmolality, pH, electrolytes) differentiate osmotic from secretory diarrhea and identify laxative abuse. Specific stool diagnostic tests for bile acid diarrhea and exocrine pancreatic insufficiency can lead to specific diagnosis and treatments. Surrogate markers associated with high fecal output and rapid transit in chronic diarrhea are stool form and colonic transit. DISCUSSION: Fecal testing is still very relevant in the practice of gastroenterology and deserves introduction of advanced microbiological and biochemical tests.

Background/Objectives: Our objective was to review published studies of the intestinal barrier and permeability, the deleterious effects of dietary components (particularly fat), the impact of altered intestinal permeability in disease models and human diseases, the role of the microbiome and epigenomics in control of barrier function, and the opportunities to restore normal barrier function with dietary interventions and products of the microbiota. Methods: We conducted a literature review including the following keywords alone or in combination: intestinal barrier, permeability, microbiome, epigenomics, diet, irritable bowel syndrome, inflammatory bowel disease, probiotics. Results: Intestinal permeability is modified by a diet including fat, which increases permeability, and nutrients such as fiber, glutamine, zinc, vitamin D, polyphenols, emulsifiers, and anthocyanins, which decrease permeability. There is significant interaction of the microbiome and barrier function, including the inflammatory of luminal/bacterial antigens, and anti-inflammatory effects of commensals or probiotics and their products, including short-chain fatty acids. Epigenomic modification of barrier functions are best illustrated by effects on junction proteins or inflammation. Detailed documentation of the protective effects of diet, probiotics, prebiotics, and microbiota is provided. Conclusion: intestinal permeability is a critical factor in protection against gastrointestinal diseases and is impacted by nutrients that preserve or heal and repair the barrier and nurture anti-inflammatory effects.

AbstractBackgroundColonic transit (CT) measured by validated scintigraphy using 111In‐labeled activated charcoal particles is summarized using geometric center (GC) of isotopic distribution in four colonic regions and stool at 24 and 48 h. Diagnosis of rapid CT is currently based on GC24 ≥4.4 in females and >4.7 in males, which lack sensitivity. Our aim was to evaluate, in patients with chronic diarrhea with normal CT by GC24 and GC48, the diagnostic utility of CT change (∆GC) relative to sex‐matched normal values.MethodsWe evaluated two adult patient cohorts: 701 clinical patients (1994–2023) with chronic diarrhea and 76 research participants with irritable bowel syndrome with diarrhea (N = 63) or bile acid diarrhea (BAD, N = 13). Results of ∆GC were compared to 220 healthy controls' 95th percentiles (%ile) (≥2.0 females and ≥2.2 males). In the research cohort, we also analyzed (Spearman correlation) colonic ∆GC with ascending colon emptying T1/2 (AC T1/2), average stool frequency and consistency based on a daily diary, total fecal bile acid (BA) concentration, and % primary BA in a single stool sample.Key ResultsAmong 701 clinical patients with normal GC24, 160 (22.3%) had rapid CT based on ∆GC 95th %ile in health. Among 76 research participants, an additional 20.6% IBS‐D and 23% BAD had rapid CT ∆GC. Younger age and absence of diabetes mellitus were predictive of rapid ∆GC. ∆GC significantly correlated with AC T1/2 and with fecal BA.Conclusions & Inferences∆GC identified an additional 21%–23% patients with rapid colonic transit among patients with diarrhea and normal GC24.

Background: Following transition to digital pathology for primary diagnosis at our institution, dermatology residents have reduced exposure to light microscopy. This study compares resident competency with light microscopy versus digital pathology following practice changes. Methods: Twenty-one dermatology residents were administered a dermatopathology examination composed of 32 diagnoses evaluated using digital slides and 32 with light microscopy. Case difficulty was graded and balanced between modalities. Diagnostic accuracy was measured using the number of correct diagnoses for each modality. Participants were surveyed regarding their experience and preferences. Results: Diagnostic accuracy was higher with digital pathology than light microscopy (22/32 vs. 18/32, P < 0.001). Diagnostic accuracy with digital pathology increased with years of training, but accuracy with light microscopy did not. Residents with previous light microscopy experience achieved an average score of 19/32 on glass, as compared with 10/32 for those without experience (P = 0.039). Digital pathology was preferred over light microscopy (18/21, 85.7%). Conclusions: Trainees had better diagnostic proficiency with digital pathology and preferred this modality. Most practices at this time continue to use light microscopy. Therefore, we need to maintain proficiency in microscopy during training while concurrently preparing trainees for a digital future.