Impact of extended Elexacaftor/Tezacaftor/Ivacaftor therapy on the gut microbiome in cystic fibrosis.

BACKGROUND: There is a paucity of knowledge on the longer-term effects of CF transmembrane conductance regulator (CFTR) modulator therapies upon the gut microbiome and associated outcomes. In a pilot study, we investigated longitudinal Elexacaftor/Tezacaftor/Ivacaftor (ETI) therapy on the gut microbiota, metabolomic functioning, and clinical outcomes in people with CF (pwCF). STUDY DESIGN: Faecal samples from 20 pwCF were acquired before and then following 3, 6, and 17+ months of ETI therapy. Samples were subjected to microbiota sequencing and targeted metabolomics to profile and quantify short-chain fatty acid composition. Ten healthy matched controls were included for comparison. Clinical data, including markers of intestinal function were integrated to investigate relationships. RESULTS: Extended ETI therapy increased core microbiota diversity and composition, which translated to gradual shifts in whole microbiota composition towards that observed in healthy controls. Despite becoming more similar over time, CF microbiota and functional metabolite compositions remained significantly different to healthy controls. Antibiotic treatment for pulmonary infection significantly explained a relatively large degree of variation within the whole microbiota and rarer satellite taxa. Clinical outcomes were not significantly different following ETI. CONCLUSIONS: Whilst differences persisted, a positive trajectory towards the microbiota observed in healthy controls was found. We posit that progression was predominately impeded by pulmonary antibiotics administration. We recommend future studies use integrated omics approaches within a combination of long-term longitudinal patient studies and model experimental systems. This will deepen our understanding of the impacts of CFTR modulator therapy and respiratory antibiotic interventions upon the gut microbiome and gastrointestinal pathophysiology in CF.

The impact of heat treatment of bovine milk on gastric emptying and nutrient appearance in peripheral circulation in healthy females: a randomized controlled trial comparing pasteurized and ultra-high temperature milk.

BACKGROUND: Heat treatments of dairy, including pasteurization and ultra-high temperature (UHT) processing, alter milk macromolecular structures, and ultimately affect digestion. In vitro, animal, and human studies show faster nutrient release or circulating appearance after consuming UHT milk (UHT-M) compared with pasteurized milk (PAST-M), with a faster gastric emptying (GE) rate proposed as a possible mechanism. OBJECTIVES: To investigate the impact of milk heat treatment on GE as a mechanism of faster nutrient appearance in blood. We hypothesized that GE and circulating nutrient delivery following consumption would be faster for UHT-M than PAST-M. METHODS: In this double-blind randomized controlled cross-over trial, healthy female (n = 20; 27.3 ± 1.4 y, mean ± SD) habitual dairy consumers, consumed 500 mL of either homogenized bovine UHT-M or PAST-M (1340 compared with 1320 kJ). Gastric content volume (GCV) emptying half-time (T50) was assessed over 3 h by magnetic resonance imaging subjective digestive symptoms, plasma amino acid, lipid and B vitamin concentrations, and gastric myoelectrical activity were measured over 5 h. RESULTS: Although GCV T50 did not differ (102 ± 7 min compared with 89 ± 8 min, mean ± SEM, UHT-M and PAST-M, respectively; P = 0.051), GCV time to emptying 25% of the volume was 31% longer following UHT-M compared with PAST-M (42 ± 2 compared with 32 ± 4 min, P = 0.004). Although GCV remained larger for a longer duration following UHT-M (treatment × time interaction, P = 0.002), plasma essential amino acid AUC was greater following UHT-M than PAST-M (55,324 ± 3809 compared with 36,598 ± 5673 µmol·min·L-1, P = 0.006). Heat treatment did not impact gastric myoelectrical activity, plasma appetite hormone markers or subjective appetite scores. CONCLUSIONS: Contrary to expectations, GE was slower with UHT-M, yet, as anticipated, aminoacidemia was greater. The larger GCV following UHT-M suggests that gastric volume may poorly predict circulating nutrient appearance from complex food matrices. Dairy heat treatment may be an effective tool to modify nutrient release by impacting digestion kinetics. CLINICAL TRIAL REGISTRY: www.anzctr.org.au (ACTRN12620000172909).

Colon length in pediatric health and constipation measured using magnetic resonance imaging and three dimensional skeletonization.

Recent magnetic resonance imaging (MRI) studies showed that colonic volumes in children are different between health and functional constipation. The length of the colon has however been rarely measured and principally using unphysiological colon preparations or cadaver studies. The main objective of this study was to measure the length of the undisturbed colon in children with functional constipation (FC) and healthy controls. Here, the colon of 19 healthy controls (10-18 years old) and 16 children with FC (7-18 years old) was imaged using MRI. Different regions of the colon (ascending, transverse, descending, and sigmoid-rectum) were first segmented manually on the MRI images. Three-dimensional skeletonization image analysis methods were then used to reduce the regions of interest to a central, measurable line. Total colon length (corrected for body surface area) in healthy controls was 56±2 cm/m2 (mean±SEM). Total colon length was significantly longer in children with FC 69±3 cm/m2 compared to controls (p = 0.0037). The colon regions showing the largest differences between groups were the ascending colon (p = 0.0479) and the sigmoid-rectum (p = 0.0003). In a linear regression model, there was a positive significant correlation between total colon length and age (R = 0.45, p = 0.0064), height (R = 0.49, p = 0.0031), weight (R = 0.46, p = 0.0059) and colon volume (R = 0.4543, p = 0.0061). Our findings showed significant differences in colon lengths between healthy controls and children with constipation. A new objective diagnostic imaging endpoint such as colon length may help to improve knowledge of colon morphology and function and, in turn, understanding of colon functional pathology.

MRI tagging of colonic chyme mixing in healthy subjects: Inter-observer variability and reliability of the measurement with time.

BACKGROUND: Magnetic resonance imaging (MRI) tagging techniques have been applied to the GI tract to assess bowel contractions and content mixing. We aimed to evaluate the dependence of a tagging measurement (for assessing chyme mixing) on inter-observer variability in both the ascending colon (AC) and descending colon (DC) and to investigate the temporal variation and hence reliability of the colonic tagging technique by acquiring multiple measurements over time on healthy participants. METHODS: Two independent datasets of healthy adults were used for the retrospective inter-observer variability (Study 1: 13 datasets and Study 2: 31 datasets), and ten participants were scanned for the prospective temporal variation study following a 1 L mannitol oral preparation. All colonic tagging data were acquired on 3 T MRI scanners. The mean and the standard deviation (SD) maps were generated pixel-by-pixel using custom-written software in MATLAB. The colonic regions of interest were defined using MIPAV software. Bland-Altman plots and scatter plots were used for the inter-observer variability. The mean and SD of all repeated measures for each subject were calculated along with a one-way ANOVA to test for variations with time. RESULTS: Scatter plots and Bland-Altman plots showed a large range of data with low variation and small limits of agreements (<5% CoV). The intraclass correlation coefficient of inter-rater reliability was excellent and 0.97 or above for the AC and DC measurements for both datasets. The temporal variation study shows that there was no significant difference found between the multiple measures with time (p = 0.53, one-way repeated measures ANOVA test). CONCLUSIONS: MRI tagging technique can provide an assessment of colonic chyme mixing. The inter-observer study data showed high inter-rater agreement. The temporal variation study showed some individual variations with time suggesting multiple measurements may be needed to increase accuracy.

A comparative, randomised MRI study of the physiological and appetitive responses to gelling (alginate) and non-gelling nasogastric tube feeds in healthy men.

Inclusion in nasogastric tube feeds (NGTF) of acid-sensitive, seaweed-derived alginate, expected to form a reversible gel in the stomach, may create a more normal intragastric state and modified gastrointestinal responses. This may ameliorate NGTF-associated risk of diarrhoea, upper gastrointestinal symptoms and appetite suppression. In a randomised, crossover, comparison study, undertaken in twelve healthy males, an alginate-containing feed (F + ALG) or one that was alginate-free (F-ALG) (300 ml) was given over 1 h with a 7-14-d washout period between treatments. Baseline and for 4-h post-feed initiation, MRI measurements were made to establish small bowel water content (SBWC), gastric contents volume (GCV) and appearance, and superior mesenteric artery blood flux. Blood glucose and gut peptides were measured. Subjective appetite and upper gastrointestinal symptoms scores were obtained. Ad libitum pasta consumption 3-h post-feeding was measured. F + ALG exhibited a gastric appearance consistent with gelling surrounded by a freely mobile water halo. Significant main effects of feed were seen for SBWC (P = 0·03) and peptide YY (PYY) (P = 0·004) which were attributed to generally higher values for SBWC with F + ALG (max difference between adjusted means 72 ml at 210 min) and generally lower values for PYY with F + ALG. GCV showed a faster reduction with F + ALG, less between-participant variation and a feed-by-time interaction (P = 0·04). Feed-by-time interactions were also seen with glucagon-like-peptide 1 (GLP-1) (P = 0·02) and glucose-dependent insulinotropic polypeptide (GIP) (P = 0·002), both showing a blunted response with F + ALG. Apparent intragastric gelling with F + ALG and subsequent differences in gastrointestinal and endocrine responses have been demonstrated between an alginate-containing and alginate-free feed.

Imaging in inflammatory bowel disease: current and future perspectives.

The use of cross-sectional imaging and ultrasonography has long complemented endoscopic assessment of inflammatory bowel disease (IBD). Clinical symptoms alone are often not enough to assess disease activity, so a reliance on non-invasive techniques is essential. In this paper, we aim to examine the current use of radiological modalities in aiding the management of patients with IBD. We focus on the various sections of the gastrointestinal tract and how different modalities can aid in assessing current disease state and response to treatments. We also have a look at how newer sequences in cross-sectional imaging and ultrasonography can allow for better differentiation of disease activity (ie, fibrotic vs inflammatory) as well improve evaluation of small bowel, colonic and perianal disease. Furthermore, we examine how advanced image processing has the potential to allow radiology to be a surrogate for biomarkers. An example of this is explored when reviewing the ability of MR sequences to quantify visceral fat, which potentially plays a role in determining disease activity in Crohn's disease. Lastly, we look into the expected role for artificial intelligence to be used as an adjunct to radiology to better improve IBD evaluation.

Correction: Schütt et al. Simulating the Hydrodynamic Conditions of the Human Ascending Colon: A Digital Twin of the Dynamic Colon Model. Pharmaceutics 2022, 14, 184.

In the original publication [...].

Application of In Vivo MRI Imaging to Track a Coated Capsule and Its Disintegration in the Gastrointestinal Tract in Human Volunteers.

Oral specially coated formulations have the potential to improve treatment outcomes of a range of diseases in distal intestinal tract whilst limiting systemic drug absorption and adverse effects. Their development is challenging, partly because of limited knowledge of the physiological and pathological distal gastrointestinal factors, including colonic chyme fluid distribution and motor function. Recently, non-invasive techniques such as magnetic resonance imaging (MRI) have started to provide novel important insights. In this feasibility study, we formulated a coated capsule consisting of a hydroxypropyl methylcellulose (HPMC) shell, coated with a synthetic polymer based on polymethacrylate-based copolymer (Eudragit®) that can withstand the upper gastrointestinal tract conditions. The capsule was filled with olive oil as MRI-visible marker fluid. This allowed us to test the ability of MRI to track such a coated capsule in the gastrointestinal tract and to assess whether it is possible to image its loss of integrity by exploiting the ability of MRI to image fat and water separately and in combination. Ten healthy participants were administered capsules with varying amounts of coating and underwent MRI imaging of the gastrointestinal tract at 45 min intervals. The results indicate that it is feasible to track the capsules present in the gastrointestinal tract at different locations, as they were detected in all 10 participants. By the 360 min endpoint of the study, in nine participants the capsules were imaged in the small bowel, in eight participants in the terminal ileum, and in four in the colon. Loss of capsule integrity was observed in eight participants, occurring predominantly in distal intestinal regions. The data indicate that the described approach could be applied to assess performance of oral formulations in undisturbed distal gastrointestinal regions, without the need for ionizing radiation or contrast agents.

Simulating the Hydrodynamic Conditions of the Human Ascending Colon: A Digital Twin of the Dynamic Colon Model.

The performance of solid oral dosage forms targeting the colon is typically evaluated using standardised pharmacopeial dissolution apparatuses. However, these fail to replicate colonic hydrodynamics. This study develops a digital twin of the Dynamic Colon Model; a physiologically representative in vitro model of the human proximal colon. Magnetic resonance imaging of the Dynamic Colon Model verified that the digital twin robustly replicated flow patterns under different physiological conditions (media viscosity, volume, and peristaltic wave speed). During local contractile activity, antegrade flows of 0.06-0.78 cm s-1 and backflows of -2.16--0.21 cm s-1 were measured. Mean wall shear rates were strongly time and viscosity dependent although peaks were measured between 3.05-10.12 s-1 and 5.11-20.34 s-1 in the Dynamic Colon Model and its digital twin respectively, comparable to previous estimates of the USPII with paddle speeds of 25 and 50 rpm. It is recommended that viscosity and shear rates are considered when designing future dissolution test methodologies for colon-targeted formulations. In the USPII, paddle speeds >50 rpm may not recreate physiologically relevant shear rates. These findings demonstrate how the combination of biorelevant in vitro and in silico models can provide new insights for dissolution testing beyond established pharmacopeial methods.

Quantitative Magnetic Resonance Imaging in Perianal Crohn's Disease at 1.5 and 3.0 T: A Feasibility Study.

Perianal Crohn's Disease (pCD) is a common manifestation of Crohn's Disease. Absence of reliable disease measures makes disease monitoring unreliable. Qualitative MRI has been increasingly used for diagnosing and monitoring pCD and has shown potential for assessing response to treatment. Quantitative MRI sequences, such as diffusion-weighted imaging (DWI), dynamic contrast enhancement (DCE) and magnetisation transfer (MT), along with T2 relaxometry, offer opportunities to improve diagnostic capability. Quantitative MRI sequences (DWI, DCE, MT and T2) were used in a cohort of 25 pCD patients before and 12 weeks after biological therapy at two different field strengths (1.5 and 3 T). Disease activity was measured with the Perianal Crohn's Disease Activity index (PDAI) and serum C-reactive protein (CRP). Diseased tissue areas on MRI were defined by a radiologist. A baseline model to predict outcome at 12 weeks was developed. No differences were seen in the quantitative MR measured in the diseased tissue regions from baseline to 12 weeks; however, PDAI and CRP decreased. Baseline PDAI, CRP, T2 relaxometry and surgical history were found to have a moderate ability to predict response after 12 weeks of biological treatment. Validation in larger cohorts with MRI and clinical measures are needed in order to further develop the model.

Luminal Fluid Motion Inside an In Vitro Dissolution Model of the Human Ascending Colon Assessed Using Magnetic Resonance Imaging.

Knowledge of luminal flow inside the human colon remains elusive, despite its importance for the design of new colon-targeted drug delivery systems and physiologically relevant in silico models of dissolution mechanics within the colon. This study uses magnetic resonance imaging (MRI) techniques to visualise, measure and differentiate between different motility patterns within an anatomically representative in vitro dissolution model of the human ascending colon: the dynamic colon model (DCM). The segmented architecture and peristalsis-like contractile activity of the DCM generated flow profiles that were distinct from compendial dissolution apparatuses. MRI enabled different motility patterns to be classified by the degree of mixing-related motion using a new tagging method. Different media viscosities could also be differentiated, which is important for an understanding of colonic pathophysiology, the conditions that a colon-targeted dosage form may be subjected to and the effectiveness of treatments. The tagged MRI data showed that the DCM effectively mimicked wall motion, luminal flow patterns and the velocities of the contents of the human ascending colon. Accurate reproduction of in vivo hydrodynamics is an essential capability for a biorelevant mechanical model of the colon to make it suitable for in vitro data generation for in vitro in vivo evaluation (IVIVE) or in vitro in vivo correlation (IVIVC). This work illustrates how the DCM provides new insight into how motion of the colonic walls may control luminal hydrodynamics, driving erosion of a dosage form and subsequent drug release, compared to traditional pharmacopeial methods.

Assessing Lymphatic Uptake of Lipids Using Magnetic Resonance Imaging: A Feasibility Study in Healthy Human Volunteers with Potential Application for Tracking Lymph Node Delivery of Drugs and Formulation Excipients.

Dietary lipids and some pharmaceutical lipid excipients can facilitate the targeted delivery of drugs to the intestinal lymphatics. Here, the feasibility of magnetic resonance imaging (MRI) for imaging lipid uptake into the intestinal lymphatics was assessed, shedding light on which lymph nodes can be targeted using this approach. Three healthy male volunteers were scanned at 3.0 T at baseline, 120, 180, 240, and 300 min post high-fat meal. A sagittal multi-slice image was acquired using a diffusion-weighted whole-body imaging sequence with background suppression (DWIBS) (pre inversion TI = 260 ms). Changes in area, major, and minor axis length were compared at each time point. Apparent diffusion coefficient (ADC) was calculated (b = 0 and 600 s/mm2) across eight slices. An average of 22 nodes could be visualised across all time points. ADC increased at 120 and 180 min compared to the baseline in all three participants by an average of 9.2% and 6.8%, respectively. In two participants, mean node area and major axis lengths increased at 120 and 180 min relative to the baseline. In conclusion, the method described shows potential for repeated lymph node measurements and the tracking of lipid uptake into the lymphatics. Further studies should focus on methodology optimisation in a larger cohort.

Colonic Volume Changes in Paediatric Constipation Compared to Normal Values Measured Using MRI.

BACKGROUND: Functional constipation in children is common. Management of this condition can be challenging and is often based on symptom reports. Increased, objective knowledge of colonic volume changes in constipation compared to health could provide additional information. However, very little data on paediatric colonic volume is available except from methods that are invasive or require unphysiological colonic preparations. OBJECTIVES: (1) To measure volumes of the undisturbed colon in children with functional constipation (FC) using magnetic resonance imaging (MRI) and provide initial normal range values for healthy controls, and (2) to investigate possible correlation of colonic volume with whole gut transit time (WGTT). METHODS: Total and regional (ascending, transverse, descending, sigmoid, and rectum) colon volumes were measured from MRI images of 35 participants aged 7-18 years (16 with FC and 19 healthy controls), and corrected for body surface area. Linear regression was used to explore the relationship between total colon volume and WGTT. RESULTS: Total colonic volume was significantly higher, with a median (interquartile range) of 309 mL (243-384 mL) for the FC group than for the healthy controls of 227 mL (180-263 mL). The largest increase between patients and controls was in the sigmoid colon-rectum region. In a linear regression model, there was a positive significant correlation between total colonic volume and WGTT (R = 0.56, p = 0.0005). CONCLUSIONS: This initial study shows increased volumes of the colon in children with FC, in a physiological state, without use of any bowel preparation. Increased knowledge of colonic morphology may improve understanding of FC in this age group and help to direct treatment.

Test-retest assessment of non-contrast MRI sequences to characterise and quantify the small bowel wall in healthy participants.

OBJECTIVE: Quantitative Magnetic Resonance Imaging sequences have been investigated as objective imaging biomarkers of fibrosis and inflammation in Crohn's disease. AIM: To determine the repeatability and inter- and intra-observer agreement of these measures in the prepared small bowel wall. METHODS: Ten healthy participants were scanned at 3 T on 2 separate occasions using T1 and T2 relaxometry, IVIM-DWI and MT sequences. Test-retest repeatability was assessed using the coefficient of variation (CoV) and intra-class correlation coefficients (ICCs) were used to evaluate the intra- and inter-observer agreement RESULTS: Test-retest repeatability in the bowel wall was excellent for apparent diffusion coefficient (ADC), magnetisation transfer ratio (MTR), T1, and diffusion coefficient D (CoV 5%, 7%, 8%, and 10%, respectively), good for perfusion fraction (PF) (CoV 20%) and acceptable for T2 (CoV 21%). Inter-observer agreement was good for the T2, D and ADC (ICC = 0.89, 0.86, 0.76, respectively) and moderate for T1 (ICC = 0.55). Intra-observer agreement was similar to inter-observer agreement. DISCUSSION: This study showed variable results between the different parameters measured. Test-retest repeatability was at least acceptable for all parameters except pseudo-diffusion coefficient D*. Good inter- and intra-observer agreement was obtained for T2, ADC and D, with these parameters performing best in this technical validation study.

Postprandial changes in gastrointestinal function and transit in cystic fibrosis assessed by Magnetic Resonance Imaging.

BACKGROUND: Cystic fibrosis (CF) is a multi-system genetic disorder affecting >72,000 people worldwide. Most CF patients experience gastrointestinal symptoms and can develop complications. However, the mechanisms of CF gut disease are not well understood. We evaluated gut function and transit in CF using magnetic resonance imaging (MRI). We hypothesised oro-caecal transit time (OCTT) is longer in CF; with lower small bowel water content (SBWC). METHODS: Twelve CF patients aged 12-40 years and 12 age and sex-matched controls underwent serial MRIs over 1 day with standardised meals. The primary endpoint was OCTT, assessed by the appearance of a food bolus in the caecum. Other measures included corrected SBWC and corrected colonic volume (both area under the curve, AUC), gastric half-emptying time and gastrointestinal symptoms. RESULTS: OCTT was longer in CF (CF 330 mins [270, >360] vs. controls 210 mins [173, 315], p = 0.04), with no difference in gastric half-emptying times. Corrected SBWC was higher in CF (CF 62 L.min/m2 [36, 80] vs. controls 34 L.min/m2 [28, 41], p = 0.021); minimal postprandial decrease between T240 and T300 (CF 13 mL/m2 [-13, 57] vs. controls 102 mL/m2 [67, 108], p = 0.002) suggests impaired ileal emptying. Corrected colonic volumes were higher in CF (CF 186 L.min/m2 [167, 206] vs. controls 123 L.min/m2 [89, 146], p = 0.012). There were no differences in gastrointestinal symptoms. CONCLUSIONS: MRI provides novel insights into CF pathophysiology. Sub-clinical ileal obstruction may be more prevalent than previously thought. Gastrointestinal MRI shows promise as an investigational tool in CF.

Chronic constipation in adults: Contemporary perspectives and clinical challenges. 1: Epidemiology, diagnosis, clinical associations, pathophysiology and investigation.

BACKGROUND: Chronic constipation is a prevalent disorder that affects patients' quality of life and consumes resources in healthcare systems worldwide. In clinical practice, it is still considered a challenge as clinicians frequently are unsure as to which treatments to use and when. Over a decade ago, a Neurogastroenterology & Motility journal supplement devoted to the investigation and management of constipation was published (2009; 21 (Suppl.2)). This included seven articles, disseminating all themes covered during a preceding 2-day meeting held in London, entitled "Current perspectives in chronic constipation: a scientific and clinical symposium." In October 2018, the 3rd London Masterclass, entitled "Contemporary management of constipation" was held, again over 2 days. All faculty members were invited to author two new review articles, which represent a collective synthesis of talks presented and discussions held during this meeting. PURPOSE: This article represents the first of these reviews, addressing epidemiology, diagnosis, clinical associations, pathophysiology, and investigation. Clearly, not all aspects of the condition can be covered in adequate detail; hence, there is a focus on particular "hot topics" and themes that are of contemporary interest. The second review addresses management of chronic constipation, covering behavioral, conservative, medical, and surgical therapies.

MR Measures of Small Bowel Wall T2 Are Associated With Increased Permeability.

BACKGROUND: Increased small bowel permeability leads to bacterial translocation, associated with significant morbidity and mortality. Biomarkers are needed to evaluate these changes in vivo, stratify an individual's risk, and evaluate the efficacy of interventions. MRI is an established biomarker of small bowel inflammation. PURPOSE: To characterize changes in the small bowel with quantitative MRI measures associated with increased permeability induced by indomethacin. STUDY TYPE: Prospective single-center, double-blind, two-way crossover provocation study. SUBJECTS: A provocation cohort (22 healthy volunteers) and intrasubject reproducibility cohort (8 healthy volunteers). FIELD STRENGTH/SEQUENCE: 2D balanced turbo field echo sequences to measure small bowel wall thickness, T2 , and motility acquired at 3T. ASSESSMENT: Participants were randomized to receive indomethacin or placebo prior to assessment. After a minimum 2-week washout, measures were repeated with the alternative allocation. MR measures (wall thickness, T2 , motility) at each study visit were compared to the reference standard 2-hour lactulose/mannitol urinary excretion ratio (LMR) test performed by a lab technician. All analyses were performed blind. STATISTICAL TESTS: Normality was tested (Shapiro-Wilk's test). Paired testing (Student's t-test or Wilcoxon) determined the significance of paired differences with indomethacin provocation. Pearson's correlation coefficient compared significant measures with indomethacin provocation to LMR. Intrasubject (intraclass correlation) and interrater variability (Bland-Altman) were assessed. RESULTS: Indomethacin provocation induced a significant increase in LMR compared to placebo (P < 0.05) and a significant increase in small bowel T2 (0.12 seconds compared to placebo 0.07 seconds, P < 0.05). Small bowel wall thickness (P = 0.17) and motility (P = 0.149) showed no significant change. T2 and LMR were positively correlated (r = 0.68, P < 0.05). T2 measurements were robust to interobserver (intraclass correlation 0.89) and intrasubject variability (Bland-Altman bias of 0.005 seconds, 95% confidence interval [CI] -0.04 to +0.05 seconds, and 0.0006 seconds, 95% CI -0.05 to +0.06 seconds). DATA CONCLUSION: MR measures of small bowel wall T2 were significantly increased following indomethacin provocation and correlated with 2-hour LMR test results. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 2.

Measurement of fasted state gastric antral motility before and after a standard bioavailability and bioequivalence 240 mL drink of water: Validation of MRI method against concomitant perfused manometry in healthy participants.

OBJECTIVE: The gastrointestinal environment in which drug products need to disintegrate before the drug can dissolve and be absorbed has not been studied in detail due to limitations, especially invasiveness of existing techniques. Minimal in vivo data is available on undisturbed gastrointestinal motility to improve relevance of predictive dissolution models and in silico tools such as physiologically-based pharmacokinetic models. Recent advances in magnetic resonance imaging methods could provide novel data and insights that can be used as a reference to validate and, if necessary, optimize these models. The conventional method for measuring gastrointestinal motility is via a manometric technique involving intubation. Nevertheless, it is feasible to measure gastrointestinal motility with magnetic resonance imaging. The aim of this study was is to develop and validate a magnetic resonance imaging method using the most recent semi-automated analysis method against concomitant perfused manometry method. MATERIAL AND METHODS: Eighteen healthy fasted participants were recruited for this study. The participants were intubated with a water-perfused manometry catheter. Subsequently, stomach motility was assessed by cine-MRI acquired at intervals, of 3.5min sets, at coronal oblique planes through the abdomen and by simultaneous water perfused manometry, before and after administration of a standard bioavailability / bioequivalence 8 ounces (~240mL) drink of water. The magnetic resonance imaging motility images were analysed using Spatio-Temporal Motility analysis STMM techniques. The area under the curve of the gastric motility contractions was calculated for each set and compared between techniques. The study visit was then repeated one week later. RESULTS: Data from 15 participants was analysed. There was a good correlation between the MRI antral motility plots area under the curve and corresponding perfused manometry motility area under the curve (r = 0.860) during both antral contractions and quiescence. CONCLUSION: Non-invasive dynamic magnetic resonance imaging of gastric antral motility coupled with recently developed, semi-automated magnetic resonance imaging data processing techniques correlated well with simultaneous, 'gold standard' water perfused manometry. This will be particularly helpful for research purposes related to oral absorption where the absorption of a drug is highly depending on the underlying gastrointestinal processes such as gastric emptying, gastrointestinal motility and availability of residual fluid volumes. CLINICAL TRIAL: This trial was registered at ClinicalTrials.gov as NCT03191045.

Feasibility Study of a New Magnetic Resonance Imaging Mini-capsule Device to Measure Whole Gut Transit Time in Paediatric Constipation.

OBJECTIVE: In England, 27,500 children are referred annually to hospital with constipation. An objective measure of whole gut transit time (WGTT) could aid management. The current standard WGTT assessment, the x-ray radiopaque marker (ROM) test, gives poor definition of colonic anatomy and the radiation dose required is undesirable in children. Our objective was to develop an alternative magnetic resonance imaging (MRI) WGTT measure to the x-ray ROM test and to demonstrate its initial feasibility in paediatric constipation. METHODS: With the Nottingham Young Person's Advisory Group we developed a small (8 × 4 mm), inert polypropylene capsule shell filled with MRI-visible fat emulsion. The capsule can be imaged using MRI fat and water in-phase and out-of-phase imaging. Sixteen patients with constipation and 19 healthy participants aged 7 to 18 years old were recruited. Following a common ROM protocol, the participants swallowed 24 mini-capsules each day for 3 days and were imaged on days 4 and 7 using MRI. The number of successful studies (feasibility) and WGTT were assessed. Participants' EuroQoL Visual Analogue Scale were also collected and compared between the day before the taking the first set of mini-capsules to the day after the last MRI study day. RESULTS: The mini-capsules were imaged successfully in the colon of all participants. The WGTT was 78 ±â€Š35 hours (mean ±â€Šstandard deviation) for patients, and 36 ±â€Š16 hours, P < 0.0001 for healthy controls. Carrying out the procedures did not change the EuroQoL Visual Analogue Scale scores before and after the procedures. CONCLUSIONS: Magnetic Resonance Imaging in Paediatric Constipation was a first-in-child feasibility study of a new medical device to measure WGTT in paediatric constipation using MRI. The study showed that the new method is feasible and is well tolerated.

Dynamic Colon Model (DCM): A Cine-MRI Informed Biorelevant In Vitro Model of the Human Proximal Large Intestine Characterized by Positron Imaging Techniques.

This work used in vivo MRI images of human colon wall motion to inform a biorelevant Dynamic Colon Model (DCM) to understand the interplay of wall motion, volume, viscosity, fluid, and particle motion within the colon lumen. Hydrodynamics and particle motion within the DCM were characterized using Positron Emission Tomography (PET) and Positron Emission Particle Tracking (PEPT), respectively. In vitro PET images showed that fluid of higher viscosity follows the wall motion with poor mixing, whereas good mixing was observed for a low viscosity fluid. PEPT data showed particle displacements comparable to the in vivo data. Increasing fluid viscosity favors the net forward propulsion of the tracked particles. The use of a floating particle demonstrated shorter residence times and greater velocities on the liquid surface, suggesting a surface wave that was moving faster than the bulk liquid. The DCM can provide an understanding of flow motion and behavior of particles with different buoyancy, which in turn may improve the design of drug formulations, whereby fragments of the dosage form and/or drug particles are suspended in the proximal colon.