Burton, Duane

ABSTRACT Background Chronic megacolon is an uncommon neurogastrointestinal disorder typically characterized by a persistent increase in colonic diameter. Methods Our aim was to identify adults with medical treatment‐refractory constipation without radiographic criteria for megacolon but with increased colonic compliance (refractory constipation with colonic hypercompliance (RCCH)), and to compare the colonic compliance in 7 identified patients with “RCCH” to colonic compliance in 10 patients with chronic megacolon by radiographic criteria (i.e., megacolon) and 40 healthy volunteers. After endoscopic placement, compliance of left or transverse colon was measured using a 10‐cm‐long infinitely compliant balloon connected to an electronically controlled rigid piston barostat. The barostat inflated the balloon from 0 to 44 mmHg in 4‐mmHg steps at 30‐s intervals to measure colonic compliance (pressure‐volume relationship). Eligibility criteria for inclusion were increased colonic compliance based on a functional assessment without meeting radiographic criteria for megacolon (i.e., RCCH). In the three groups, we compared colonic volumes at intra‐balloon pressure of 8, 16, 20, 32, and 44 mmHg, the pressure at half maximum volume, and the slope of the colonic compliance curve using ANOVA on ranks and Dunn's pairwise comparison test. Other features of colonic motility were documented. Results Colonic volumes at all pressures (8‐44 mmHg) and the pressure at half maximum volume were significantly greater in patients with megacolon and RCCH than in healthy controls ( p < 0.001 for both), but compliance was not significantly different between RCCH and megacolon. Conclusion A subset of patients with medically‐refractory chronic constipation has colonic compliance similar to that of patients with megacolon.

ABSTRACT Background Gastric emptying (GE) scintigraphy with 4‐h imaging and a radiolabeled chicken egg‐based meal (320 kcal, 30% fat) is the standard test for gastroparesis at Mayo Clinic, with an intraindividual coefficient of variation (COV intra ) of 23.8% for GE half emptying time (T 1/2 ). Alternative meals for patients with dietary restrictions, including egg allergies or vegan diets, are lacking, limiting test accessibility. The study aimed to establish a vegan, lactose‐, nut‐, and gluten‐free meal with similar caloric and fat content to the egg meal and to assess its performance in GE studies. Methods In Vitro: 99m Tc binding to egg meal over 4 h was compared to a calorically and nutritionally similar vegan alternative, JUST Egg, using a validated in vitro model simulating gastric conditions of pH, pepsin, and stirring. In Vivo: 10 healthy participants underwent randomized crossover GE scintigraphy with standard and vegan meals, spaced ≥ 3 days apart to measure GE% at 2 h, 4 h, and GE T 1/2 . Group comparisons and variance analysis included Rank Sum tests and Bland–Altman plots. Key Results In Vitro: A strong correlation ( R = 0.975, p ‐value < 0.01) between 99m Tc binding in the egg and vegan egg models was observed. Minimal variance (< 10%) was recorded at all time points. In Vivo: GE at 4 h and GE T 1/2 showed non‐statistically significant mean differences, < 2% and < 10 min respectively, between both meals. The intra‐individual variability was 18.8%. Conclusions and Inferences The vegan meal demonstrated in vitro stability, in vivo performance comparable to the egg meal, and a COV intra of 18.8%, which was lower than the 23.8% reported in repeat egg meal GE studies. Trial Registration ClinicalTrials.gov number NCT06991036 ( https://clinicaltrials.gov/study/NCT06991036?term=NCT06991036&rank=1 )

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.

Abstract Background Metabolic syndrome (MetS), which can be induced or exacerbated by the current class of antipsychotic drugs, is highly prevalent in patients with schizophrenia and presents significant challenges to lifetime disease management. Supported by initial clinical results, trace amine‐associated receptor 1 (TAAR1) agonists have emerged as potential novel treatments for schizophrenia. Notably, non‐clinical studies have also shown weight‐lowering and glucoregulatory effects of TAAR1 agonists, including the investigational agent ulotaront. However, the translatability of these findings to humans has not been adequately assessed. Given that delayed gastric emptying (GE) was identified as a potential mechanism contributing to the metabolic benefits of TAAR1 agonists in rodents, the aim of this study was to evaluate the effect of ulotaront on GE in patients with schizophrenia and concurrent MetS with prediabetes. Methods Patients with schizophrenia were randomized to receive a single oral dose of ulotaront (150 mg) and their previous antipsychotic (PA) in an open‐label, crossover, two‐sequence design (NCT05402111). Eligible participants fulfilled at least three of five MetS criteria and had prediabetes defined by elevated glycated haemoglobin (5.7‐6.4%) and/or fasting homeostatic model assessment of insulin resistance (i.e. ≥2.22). Following an overnight fast and 4 h post‐dose, participants ingested a 99m Tc‐sulphur colloid radiolabelled egg meal (320 kcal, 30% fat). GE was measured by scintigraphy over 4 h. Endpoints included GE of solids half‐time (T 1/2 ) and percentage gastric retention at 1, 2 and 4 h. Results Thirty‐one adults were randomized and 27 completed the study. Ulotaront significantly delayed GE of solids [median GE T 1/2 ulotaront at 139 min (119, 182) vs. the participant's PA of 124 min (109, 132), p = .006]. A significant increase in gastric retention was seen in the ulotaront versus the PA group at 1 h (80% vs. 75%, p = .015), 2 h (61% vs. 50%, p = .023) and 4 h (17% vs. 7%, p = .002) post‐meal. Conclusion Ulotaront delayed the GE of solids in patients with schizophrenia and concurrent MetS with prediabetes. Additional studies are needed to assess whether treatment with TAAR1 agonists is associated with weight loss and glucoregulatory improvement.

AbstractBackgroundGastrointestinal dysmotility is frequently suspected in patients with gastroparesis, functional dyspepsia, and ileus, and in the intensive care unit. Monitoring of gastric motility in clinical practice remains challenging. A novel technology was developed to meet the medical need for a widely available bedside tool to monitor gastric motility continuously. The VIPUN™ Gastric Monitoring System (GMS) comprises a nasogastric feeding tube with intragastric balloon to allow for measuring gastric contractions.AimsTo compare the performance of the VIPUN GMS versus a reference technique (manometry).MethodsIn this validation study in healthy subjects, the investigational catheter and a solid‐state manometry catheter were placed in the stomach concomitantly. Motility was recorded for 2.5 h: 2 h in a fasting state, followed by a 400‐kcal liquid meal, and monitoring of the fed state for the remaining half hour. The performance of both systems was compared by automated recognition and manual identification of the contractile activity. Data are presented as mean (standard deviation).Key ResultsThe analysis set comprised 13 healthy subjects (6 women, age: 27.5 (8.1) years, BMI: 22.2 (2.46) kg/m2). Automatically‐recognized contractility was strongly correlated between the two techniques (endpoint: contraction duration; Spearman ρ = 0.96, p < 0.001). A correlation was also observed between the number of individual contractions identified by expert gastroenterologists on both technologies independently (ρ = 0.71, p = .007) and between the contractions identified by the experts and by the GMS software (ρ = 0.87, p = 0.001). No serious or unanticipated adverse events occurred.Conclusions & InferencesThe observed strong correlations with the gold standard, manometry, validate the performance of the VIPUN GMS as a gastric monitoring system.

Objective Symptoms in gastroparesis (Gp) and functional dyspepsia (FD) overlap; using egg protein substitute to measure gastric emptying of solids (GES), ~40% of patients are reclassified from Gp to FD, and vice versa. Our aim was to assess inter-individual and intra-individual coefficients of variation (COV) in GES in symptomatic patients with Gp or FD with documented slow or normal GES, respectively. Design Scintigraphic GES (T1/2 and GE% at 2 and 4 hours) using a 320 kcal real egg meal (30% fat) was tested in the following: single measurements in 20 patients with diabetes mellitus (10 each type 1 and type 2); repeat GES to estimate COVintra measured: 3 days apart in 9 Gp, 4 weeks apart in 21 Gp and 18 with FD with normal GE assigned to placebo and in 70 patients at 94.3 weeks (median) apart. Results COVinter for GE% at 4 hours and GE T1/2 were respectively 14.2% and 23.5% in FD and 27.5% and 33% in Gp; COVintra for GE% at 4 hours and GE T1/2 up to 4 weeks apart were 23.4% and 37.9% in FD and 20.1% and 33% in Gp. GE% at 2 hours showed less consistent results. However, >85% retained original diagnosis as normal or delayed. From clinical GES to baseline research for Gp group, repeat GES (after treatment) showed the COVintra for GE% at 4 hours was 37.3% at median 94.3 weeks, with 26/70 changed diagnoses. Conclusion The 320 kcal (30% fat) GES scintigraphic test provides consistent diagnosis in >85% and should be the standard test for suspected gastric emptying disorders.

SummaryBackgroundGastroparesis is defined by delayed gastric emptying with associated symptoms in the absence of mechanical obstruction.AimTo evaluate pharmacokinetics and pharmacodynamics of felcisetrag, a highly selective 5‐HT4 receptor agonist, on total gut transit in patients with documented delayed gastric emptying of solids.MethodsSingle‐centre, placebo‐controlled study of 36 participants receiving placebo, 0.1mg, 0.3mg or 1.0mg of felcisetrag I.V. infusion, daily, for 3 days. At baseline, each participant completed a 4h, 99mTc‐egg meal (300 kcal, 30% fat) gastric emptying test. Following infusion (Day 2), gastric, small bowel and colonic transit of solids were measured over 48h (same meal plus 111In‐charcoal delivered in methacrylate‐coated capsule). Samples were collected for pharmacokinetics. The primary endpoint was gastric emptying T1/2. Statistical analysis used baseline parameters as covariates (ANCOVA).ResultsPatients (22 idiopathic, 14 diabetic gastroparesis) were randomised to felcisetrag (0.1 mg, n = 10; 0.3 mg, n = 9; 1.0 mg, n = 7) or placebo (n = 10). Compared to placebo, felcisetrag significantly accelerated gastric emptying T1/2, colonic filling at 6h, and 10% small bowel transit time (overall P < 0.01; all three doses individually Bonferroni corrected P < 0.05) for all three measurements. Ascending colon emptying (T1/2) was significantly accelerated (all doses), and colonic transit at 48 hours was accelerated with 0.1 mg and 0.3 mg felcisetrag compared to placebo. Pharmacokinetic results were dose proportional. Felcisetrag was well tolerated with no clinically significant findings from clinical laboratory, vital signs or ECG.ConclusionI.V. felcisetrag significantly accelerated gastric, small bowel and colonic transit in patients with gastroparesis, and should be further evaluated for short‐term treatment of gastric and intestinal motility disorders.ClinicalTrials.gov #NCT03281577

We show how switching from a regular diet to an HCHF increases cholesterol absorption in patients with normal weight and obesity. The decrease in cholesterol absorption from an HCHF to an LCLF, on the other hand, was only seen in normal-weight controls, underlining the importance of body weight in this regulation. In addition, changes in caloric and fat content had an immediate and direct effect on hepatic bile acid production.

INTRODUCTION: Cannabidiol (CBD), a CBR2 agonist with limited psychic effects, antagonizes CB1/CB2 receptors. Allelic variation CNR1 (gene for CBR1) rs806378 and FAAH rs324420 were associated with altered gut motility and sensation. This study aimed to compare the pharmacodynamics and clinical effects of a 4-week treatment with pharmaceutical-grade CBD vs placebo and assess the interactions of FAAH and CNR1 gene variants on the effects of CBD in patients with functional dyspepsia (FD). METHODS: We performed a randomized, double-blinded, placebo-controlled (1:1 ratio) study of CBD b.i.d. (20 mg/kg/d according to the US Food and Drug Administration escalation guidance) in FD patients with nondelayed gastric emptying (GE) at baseline. Symptoms were assessed by validated daily symptom diary (0–4 scale for upper abdominal pain, nausea, and bloating), weekly assessment of adequate relief, Leuven Postprandial Distress Scale (8 symptoms, adjectival scores rated 0–4 for severity), and quality of life (Short-Form Nepean Dyspepsia Index [average of 10 dimensions each on a 5-point scale]). After the 4-week treatment, all patients underwent measurements of GE of solids, gastric volumes, and Ensure nutrient satiation test. Statistical analysis compared 2 treatments for all endpoints and the effects of CBD in association with FAAH rs324420 and CNR1 rs806378. RESULTS: CBD and placebo effects on physiological functions and patient response outcomes were not significantly different. There were borderline CBD treatment-by-genotype interactions: rs806378 CNR1 with Leuven Postprandial Distress Scale ( P = 0.06) and GE solids ( P = 0.12). DISCUSSION: Approved doses of CBD used off-label do not relieve FD with normal baseline GE of solids or alter gastric motor functions and satiation. CBD treatment-by-gene interactions suggest potential benefits for postprandial distress with CNR1 rs806378 T allele.