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.

Background/AimsThe Chicago Classification for diagnosis of esophageal motility disorders by high-resolution manometry (HRM) is based on single water swallows (SWS). Emerging data suggest that a Rapid Drink Challenge (RDC) increases sensitivity for motility disorders. This study establishes normal values and diagnostic thresholds for RDC in clinical practice.MethodsTwo cohort studies were performed in patients with dysphagia or reflux symptoms (development and validation sets). Healthy subjects and patient controls provided reference values. Ten SWS and two 200-mL RDC were performed. Primary diagnosis for SWS was established by the Chicago Classification. Abnormal RDC was defined by impaired esophagogastric junction (EGJ) function (elevated integrated relaxation pressure during RDC [IRP-RDC]); incomplete inhibition of contractility during and ineffective contraction after RDC. Diagnostic thresholds identified in the development set were prospectively tested in the validation set.ResultsNormal values were determined in healthy (n=95; age 37.812) and patient controls (n=44; age 46.4 +/- 15). Development and validation sets included 178 (54 +/- 17years) and 226 (53 +/- 16years) patients, respectively. Integrated relaxation pressure during RDC was higher for SWS than RDC in all groups (overall P<.001), except achalasia. Rapid Drink Challenge suppressed contractility, except in achalasia type III, spasm, and hypercontractile motility disorders (P<.001). An effective after-contraction was present more often in health than disease (P<.001). Optimal diagnostic thresholds identified in the development set (IRP-RDC 12mmHg achalasia, IRP-RDC 8mmHg all cause EGJ dysfunction), were confirmed in the validation set (both, sensitivity similar to 85%, specificity >95%).ConclusionsRapid Drink Challenge contributes clinically relevant information to routine HRM studies, especially in patients with EGJ dysfunction.

Background The use of high-resolution manometry (HRM) to diagnose oesophageal motility disorders is based on ten single water swallows (SWS); however, this approach might not be representative of oesophageal function during the ingestion of normal food. We tested whether inclusion of a standardised solid test meal (STM) to HRM studies increases test sensitivity for major motility disorders. Additionally, we assessed the frequency and cause of patient symptoms during STM. Methods Consecutive patients who were referred for investigation of oesophageal symptoms were recruited at Nottingham University Hospitals (Nottingham, UK) in the development study and at University Hospital Zürich (Zürich, Switzerland) in the validation study. HRM was done in the upright, seated position with a solid-state assembly. During HRM, patients ingested ten SWS, followed by a standardised 200 g STM. Diagnosis of oesophageal motility disorders was based on the Chicago Classification validated for SWS (CCv3) and with STM (CC-S), respectively. These studies are registered with ClinicalTrials.gov, numbers NCT02407938 and NCT02397616. Findings The development cohort included 750 patients of whom 360 (48%) had dysphagia and 390 (52%) had reflux or other symptoms. The validation cohort consisted of 221 patients, including 98 (44%) with dysphagia and 123 (56%) with reflux symptoms. More patients were diagnosed with a major motility disorder by use of an STM than with SWS in the development set (321 [43%] patients diagnosed via STM vs 163 [22%] via SWS; p<0·0001) and validation set (73 [33%] vs 49 [22%]; p=0·014). The increase was most evident in patients with dysphagia (241 [67%] of 360 patients on STM vs 125 [35%] patients on SWS in the development set, p<0·0001), but was also present in those referred with reflux symptoms (64 [19%] of 329 patients vs 32 [10%] patients in the development set, p=0·00060). Reproduction of symptoms was reported by nine (1%) of 750 patients during SWS and 461 (61%) during STM (p<0·0001). 265 (83%) of 321 patients with major motility disorders and 107 (70%) of 152 patients with minor motility disorders reported symptoms during the STM (p=0·0038), compared with 89 (32%) of 277 patients with normal motility as defined with CC-S (p<0·0001). Interpretation The diagnostic sensitivity of HRM for major motility disorders is increased with use of the STM compared with SWS, especially in patients with dysphagia. Observations made during STM can establish motility disorders as the cause of oesophageal symptoms. Funding None.

The rate and extent of drug dissolution and absorption from solid oral dosage forms is highly dependent on the volume of liquid in the gastrointestinal tract (GIT). However, little is known about the time course of GIT liquid volumes after drinking a glass of water (8 oz), particularly in the colon, which is a targeted site for both locally and systemically acting drug products. Previous magnetic resonance imaging (MRI) studies offered novel insights on GIT liquid distribution in fasted humans in the stomach and small intestine, and showed that freely mobile liquid in the intestine collects in fairly distinct regions or "pockets". Based on this previous pilot data, we hypothesized that (1) it is possible to quantify the time course of the volume and number of liquid pockets in the undisturbed colon of fasted healthy humans following ingestion of 240 mL, using noninvasive MRI methods; (2) the amount of freely mobile water in the fasted human colon is of the order of only a few milliliters. Twelve healthy volunteers fasted overnight and underwent fasted abdominal MRI scans before drinking 240 mL (∼8 fluid ounces) of water. After ingesting the water they were scanned at frequent intervals for 2 h. The images were processed to quantify freely mobile water in the total and regional colon: ascending, transverse, and descending. The fasted colon contained (mean ± SEM) 11 ± 5 pockets of resting liquid with a total volume of 2 ± 1 mL (average). The colonic fluid peaked at 7 ± 4 mL 30 min after the water drink. This peak fluid was distributed in 17 ± 7 separate liquid pockets in the colon. The regional analysis showed that pockets of free fluid were found primarily in the ascending colon. The interindividual variability was very high; the subjects showed a range of number of colonic fluid pockets from 0 to 89 and total colonic freely mobile fluid volume from 0 to 49 mL. This is the first study measuring the time course of the number, regional location, and volume of pockets of freely mobile liquid in the undisturbed colon of fasted humans after ingestion of a glass of water. Novel insights into the colonic fluid environment will be particularly relevant to improve our understanding and design of the in vivo performance of controlled release formulations targeted to the colon. The in vivo quantitative information presented here can be input into physiologically based mechanistic models of dissolution and absorption, and can be used in the design and set up of novel in vitro performance tools predictive of the in vivo environment.

G A A b st ra ct s study was to determine if EWBP in patients with nutcracker esophagus was different when compared to normal subjects. Furthermore, we examined esophageal mucosa biopsy specimens for evidence of HIF 1a, a marker of hypoxia in normal subject and patients. Methods: studies were performed in 12 normal healthy subjects (mean age = 51, 11 males) and 12 patients (mean age = 52, 9 males) with angina-like with a negative cardiac work up and manometric diagnosis of nutcracker esophagus. A laser Doppler probe was anchored to the esophageal wall, 5cm above the LES, as described previously. A HRM catheter was placed via the nose into the esophagus. Recordings were performed for one hour in the fasting and 2 hours following a meal. Esophageal mucosa biopsy, (5cm above LES) was obtained on a separate day during sedated endoscopy. Biopsy specimens were immunostained for marker of tissue hypoxia (immunostaining for hypoxia -inducible factor HIF 1a) by fluorescent labeling and imaged by confocal microscopy. Results: Mean esophageal wall perfusion (EWP) was lower in patients compared to normal subjects, in both fasting and post-prandial state. Frequency distribution of the esophageal wall perfusion values revealed a curve shifted to the left as compared to normal subjects (figure 1). Mucosa biopsy specimens revealed dramatically increased immuno-staining for hypoxia-inducible factor (HIF 1a) (Figure 2) and other markers of hypoxia related injury in patients as compared to normal subjects. Conclusions: we propose that low EWBP; or ischemia of the esophageal wall is a possible cause of esophageal pain and hypoxia related injury to the esophageal mucosa.

BACKGROUND:Intragastric creaming and droplet size of fat emulsions may affect intragastric behavior and gastrointestinal and satiety responses. OBJECTIVES:We tested the hypotheses that gastrointestinal physiologic responses and satiety will be increased by an increase in intragastric stability and by a decrease in fat droplet size of a fat emulsion. METHODS:This was a double-blind, randomized crossover study in 11 healthy persons [8 men and 3 women, aged 24 ± 1 y; body mass index (in kg/m(2)): 24.4 ± 0.9] who consumed meals containing 300-g 20% oil and water emulsion (2220 kJ) with 1) larger, 6-μm mean droplet size (Coarse treatment) expected to cream in the stomach; 2) larger, 6-μm mean droplet size with 0.5% locust bean gum (LBG; Coarse+LBG treatment) to prevent creaming; or 3) smaller, 0.4-μm mean droplet size with LBG (Fine+LBG treatment). The participants were imaged hourly by using MRI and food intake was assessed by using a meal that participants consumed ad libitum. RESULTS:The Coarse+LBG treatment (preventing creaming in the stomach) slowed gastric emptying, resulting in 12% higher gastric volume over time (P < 0.001), increased small bowel water content (SBWC) by 11% (P < 0.01), slowed appearance of the (13)C label in the breath by 17% (P < 0.01), and reduced food intake by 9% (P < 0.05) compared with the Coarse treatment. The Fine+LBG treatment (smaller droplet size) slowed gastric emptying, resulting in 18% higher gastric volume (P < 0.001), increased SBWC content by 15% (P < 0.01), and significantly reduced food intake by 11% (P < 0.05, equivalent to an average of 411 kJ less energy consumed) compared with the Coarse+LBG treatment. These high-fat meals stimulated substantial increases in SBWC, which increased to a peak at 4 h at 568 mL (range: 150-854 mL; P < 0.01) for the Fine+LBG treatment. CONCLUSION:Manipulating intragastric stability and fat emulsion droplet size can influence human gastrointestinal physiology and food intake.

BACKGROUND & AIMS: Management of patients with dysphagia, regurgitation, and related symptoms after antireflux surgery is challenging. This prospective, case-control study tested the hypothesis that compared with standard high-resolution manometry (HRM) with single water swallows (SWS), adding multiple water swallows (MWS) and a solid test meal increases diagnostic yield and clinical impact of physiological investigations.METHODS: Fifty-seven symptomatic and 12 asymptomatic patients underwent HRM with SWS, MWS, and a solid test meal. Dysphagia and reflux were assessed by validated questionnaires. Diagnostic yield of standard and full HRM studies with 24-hour pH-impedance monitoring was compared. Pneumatic dilatation was performed for outlet obstruction on HRM studies. Clinical outcome was assessed by questionnaires and an analogue scale with "satisfactory" defined as at least 40% symptom improvement requiring no further treatment.RESULTS: Postoperative esophagogastric junction pressure was similar in all groups. Abnormal esophagogastric junction morphology (double high pressure band) was more common in symptomatic than in control patients (13 of 57 vs 0 of 12, P = .004). Diagnostic yield of HRM was 11 (19%), 11 (19%), and 33 of 57 (58%), with SWS, MWS, and solids, respectively (P < .001); it was greatest for solids in patients with dysphagia (19 of 27, 70%). Outlet obstruction was present in 4 (7%), 11 (19%), and 15 of 57 patients (26%) with SWS, MWS, and solids, respectively (P < .009). No asymptomatic control had clinically relevant dysfunction on solid swallows. Dilatation was performed in 12 of 15 patients with outlet obstruction during the test meal. Symptom response was satisfactory, good, or excellent in 7 of 12 (58%) with no serious complications.CONCLUSIONS: The addition of MWS and a solid test meal increases the diagnostic yield of HRM studies in patients with symptoms after fundoplication and identifies additional patients with outlet obstruction who benefit from endoscopic dilatation.

Introduction Dilatation of the Oesophago-Gastric Junction (OGJ) provides effective symptom relief in 58–95% of patients with achalasia, similar to that achieved by Heller’s myotomy. Dilatation is also used in patients with persistent (>6 months) dysphagia after fundoplication surgery; there is insufficient safety and outcome data of this procedure. Our aim is to compare patient outcome of endoscopic dilatation for both these conditions. Methods We present 18 month experience of referrals to the dysphagia service 2012–2013. All patients underwent a diagnostic gastroscopy with biopsies, excluding inflammation or neoplasia. Patients with achalasia or clinically relevant outlet obstruction post-fundoplication diagnosed by elevated integrated relaxation pressure (>25 mmHg) on high resolution manometry were selected. Dilatation was performed by 30–35mm Rigiflex II Balloon or Savary-Gillard Bougies (max 18mm) under fluoroscopic guidance. Primary outcome was symptom response at 3–6 months post-procedure by clinic or telephone follow-up. Overall symptom response was documented on an analogue scale from 0% >100% (inadequate <40%, satisfactory 40–60%, good 60–80% and excellent >80%). Results 46/71 referrals had either achalasia or dysphagia post fundoplication. 30 (41%) had achalasia, 6 had prior Heller’s myotomy and 7 had prior Botulinum toxin. 16 (22%) patients had OGJ obstruction after fundoplication. 29/30 patients with achalasia underwent pneumatic dilatation, one bougie dilatation. Overall symptom response was inadequate in 5 (16% referred for surgery), satisfactory in 3 (11%) and good-excellent in 22 (73%).14/16 patients with post fundoplication dysphagia had pneumatic balloon dilatation, 2 had bougie dilatation. Overall symptom response was inadequate in 7 (44% referred for surgery), satisfactory in 4 (25%) and good-excellent in 5 (31%). Complications from the both groups include chest pain (n = 2), chest infection (n = 1), reflux symptoms (n = 4 in each group) and minor bleeding. All resolved with conservative treatment. More than half of achalasia and post-fundoplication patients reported “at least satisfactory” outcome 3–6 months after dilatation (84% vs. 56%; p < 0.07 Fisher Exact Test). A good-excellent symptom response was reported more often by achalasia patients (p = 0.010). Conclusion Endoscopic dilatation is safe and effective treatment for patients with dysphagia related to achalasia and also OGJ obstruction post-fundoplication. A good-excellent response was reported less frequently by the post-fundoplication patients; however more than half had at least “satisfactory” symptom relief and, therefore, a trial of endoscopic dilatation can be considered a viable alternative to re-operation. Disclosure of Interest None Declared.

High-resolution esophageal manometry (HRM) is a recent development used in the evaluation of esophageal function. Our aim was to assess the inter-observer agreement for diagnosis of esophageal motility disorders using this technology. Practitioners registered on the HRM Working Group website were invited to review and classify (i) 147 individual water swallows and (ii) 40 diagnostic studies comprising 10 swallows using a drop-down menu that followed the Chicago Classification system. Data were presented using a standardized format with pressure contours without a summary of HRM metrics. The sequence of swallows was fixed for each user but randomized between users to avoid sequence bias. Participants were blinded to other entries. (i) Individual swallows were assessed by 18 practitioners (13 institutions). Consensus agreement (≤ 2/18 dissenters) was present for most cases of normal peristalsis and achalasia but not for cases of peristaltic dysmotility. (ii) Diagnostic studies were assessed by 36 practitioners (28 institutions). Overall inter-observer agreement was 'moderate' (kappa 0.51) being 'substantial' (kappa > 0.7) for achalasia type I/II and no lower than 'fair-moderate' (kappa >0.34) for any diagnosis. Overall agreement was somewhat higher among those that had performed >400 studies (n = 9; kappa 0.55) and 'substantial' among experts involved in development of the Chicago Classification system (n = 4; kappa 0.66). This prospective, randomized, and blinded study reports an acceptable level of inter-observer agreement for HRM diagnoses across the full spectrum of esophageal motility disorders for a large group of clinicians working in a range of medical institutions. Suboptimal agreement for diagnosis of peristaltic motility disorders highlights contribution of objective HRM metrics.

BackgroundMeasurement of esophago-gastric junction (EGJ) cross-sectional area (CSA) and distensibility by an Endolumenal Functional Lumen Imaging Probe (EndoFLIP((R))) may distinguish between gastro-esophageal reflux disease (GERD) patients and healthy volunteers (HV). We aimed to assess the agreement of EndoFLIP((R)) measurements with clinical and physiologic diagnosis of GERD.MethodsTwenty-one HV and 18 patients with typical GERD symptoms were studied. After gastroscopy, EGJ CSA, and distensibility were measured by EndoFLIP((R)). Forty-eight hour esophageal pH monitoring was then performed by a wireless system. The ability of EndoFLIP((R)) to discriminate GERD patient and HVs was assessed. Planned secondary analysis then assessed whether EGJ CSA and distensibility were increased in individuals with pathologic acid exposure.Key ResultsHealthy volunteers were younger and had lower body mass index (BMI; both p<0.001). Pathologic acid exposure was present in 3/21 (14%) HVs and 9/18 (50%) patients (p=0.126). At 30mL EndoFLIP((R)) bag volume, EGJ CSA was higher (p=0.058) and EGJ distensibility was lower (p=0.020) in HVs than patients. Secondary analysis showed that EGJ measurements were similar in participants with and without pathologic acid exposure (CSA 98mm(2)vs 107mm(2); p=0.789, distensibility; p=0.704). An inverse association between BMI and CSA (R-2= 0.2758, p=0.001) and distensibility (R-2=0.2005, p=0.005) was present.Conclusions & InferencesEndolumenal Functional Lumen Imaging Probe is not useful for GERD diagnosis because EGJ CSA and distensibility do not distinguish between HVs and GERD patients defined by clinical presentation or pH measurement. This unexpected result may be due to an important, confounding interaction of obesity.

Background: A TLESR is a major mechanism of acid reflux in healthy subjects and patients with reflux esophagitis and we have noticed that the amplitude of primary peristalsis and EGJ pressure, following a TLESR, is accompanied by a forceful contraction, when compared with before a TLESR.The aim of this study is to investigate whether or not primary peristalsis and EGJ pressure, when accompanied by a forceful contraction and following a TLESR, is a characteristic finding of a TLESR.Methods: 10 healthy subjects underwent esophageal high-resolution manometry with a 21-lumen perfused assembly, which monitored pressure in the pharynx, the upper esophageal sphincter, the esophageal body, LES and the proximal stomach.The EGJ was evaluated using ten side holes, spaced at 1-cm intervals.Recordings were then taken, in the sitting position, for 1 hour after a meal (692 kcal, 33 % fat).A TLESR is defined as previously described.Data were analyzed, using Trace!Software (Dr.G.S Hebbard, The Royal Melbourne Hospital, Australia).The contractile integral (CI) of the distal esophageal segment (D-CI: volume of the domain above 20 mmHg), excluding the EGJ segment, was measured both before and after a TLESR, and the CI of the EGJ (EGJ-CI) (volume of the domain above 0 mmHg), was measured for 8 seconds after primary peristalsis reached the EGJ, both before and after a TLESR.Results: 56 TLESRs were measured during the study.The D-CI (1603 mmHg s cm (1177-2120), median (interquartile range)) following a TLESR was significantly greater than before a TLESR (484 (323-1079)) and more than a 50% increase of D-CI in 35 (62.5%) of the 56 TLESRs was observed.The EGJ-CI (790 (465-1009)) following a TLESR was significantly greater than before a TLESR (238 (186-308)) and more than a 50% increase in the EGJ-CI in 48 (85.7%) of the 56 TLESRs was observed.Conclusions: The D-CI and the EGJ-CI following a TLESR, were significantly greater than before a TLESR and this tendency was evident in the EGJ-CI, although it can, at times, be difficult to evaluate a TLESR.If the focus is on a forceful contraction of primary peristalsis or on the EGJ, it may be easier to detect and evaluate a TLESR.

BACKGROUND:Colonic transit tests are used to manage patients with Functional Gastrointestinal Disorders. Some tests used expose patients to ionizing radiation. The aim of this study was to compare novel magnetic resonance imaging (MRI) tests for measuring orocecal transit time (OCTT) and whole gut transit time (WGT), which also provide data on colonic volumes. METHODS:21 healthy volunteers participated. Study 1: OCTT was determined from the arrival of the head of a meal into the cecum using MRI and the Lactose Ureide breath test (LUBT), performed concurrently. Study 2: WGT was assessed using novel MRI marker capsules and radio-opaque markers (ROMs), taken on the same morning. Studies were repeated 1 week later. KEY RESULTS:OCTT measured using MRI and LUBT was 225 min (IQR 180-270) and 225 min (IQR 165-278), respectively, correlation r(s) = 0.28 (ns). WGT measured using MRI marker capsules and ROMs was 28 h (IQR 4-50) and 31 h ± 3 (SEM), respectively, correlation r(s) = 0.85 (p < 0.0001). Repeatability assessed using the intraclass correlation coefficient (ICC) was 0.45 (p = 0.017) and 0.35 (p = 0.058) for MRI and LUBT OCTT tests. Better repeatability was observed for the WGT tests, ICC being 0.61 for the MRI marker capsules (p = 0.001) and 0.69 for the ROM method (p < 0.001) respectively. CONCLUSIONS & INFERENCES:The MRI WGT method is simple, convenient, does not use X-ray and compares well with the widely used ROM method. Both OCTT measurements showed modest reproducibility and the MRI method showed modest inter-observer agreement.

G A A b st ra ct s Forty-six subjects had biopsy to rule out EoE; 29 (63%) of these had normal WEPM. The maximum eos/hpf ranged between 1 and 75 with 19 patients having between 1-15 eos/hpf (mean ± sd: 4.5 ± 4.5) and 6 having .15 eos/hpf (mean ± sd: 41.3 ± 21.3). Of these, 2 patients, 4.3% (95% CI: 0.5, 14.8%) proved to have EoE and one had eosinophilic gastroenteritis with eosinophilic esophagitis. These 46 patients were significantly younger, more commonly female, more likely to have dysphagia, less likely to have abnormal EGD, BE, subepithelial tissue and lamina propia fibrosis than patients who had EB done for other reasons. Patients with abnormal WEPM were significantly more likely to have basal cell hyperplasia (57% vs. 23%; p=0.004). Abnormal histology was significantly more common in patients with abnormal WEPM than in those with normal WEPM (73% vs. 44%; p=0.011). Patients with abnormal histology were more likely to have heartburn and/or regurgitation than those with normal histology (p=0.019). CONCLUSION: Nearly 45% of patients with normal pH study have histologic findings that may affect patient management. EoE is an uncommon finding in patients undergoing WEPM for evaluation of atypical or refractory gastroesophageal reflux symptoms.

BACKGROUND:Rumination is the voluntary, albeit subconscious return of gastric contents to the mouth. Currently, rumination syndrome and repetitive belching disorders are considered separate diagnoses, as defined by Rome III criteria and high-resolution oesophageal manometry (HRM).AIM:To test the hypothesis that these conditions represent a common behavioural response to aversive digestive stimuli and that successful treatment can be directed at both the stimulus and the response.METHODS:Case-note review of consecutive patients with a final diagnosis of behavioural digestive disorders between August 2009 and October 2011.RESULTS:Thirty-five of 46 (76%) patients exhibited 'classical' rumination with abdomino-gastric strain (R-waves) driving gastric contents across the lower oesophageal sphincter; 5 (11%) had 'reflux-related' rumination with R-waves seen during gastro-oesophageal common cavity (reflux) events and 6 had (13%) supra-gastric belching. All received at least one biofeedback session at the time of diagnosis with a good response reported by 20/46 (43%) of the patients, which included 3 with supra-gastric belching. Additionally, rumination ceased in cases in which definitive treatment relieved the symptoms that triggered abnormal behaviour (e.g. fundoplication in 'reflux-rumination').CONCLUSIONS:Rumination and many of its variations, excluding only some cases of supra-gastric belching, are associated with abdomino-gastric strain, a generic abnormal behavioural response to a variety of aversive digestive stimuli. All types of rumination can respond to biofeedback. High-resolution oesophageal manometry identifies subgroups with distinct mechanisms of disease that respond to specific management targeted at the symptoms that trigger the abnormal behaviour.

acidic reflux (1 patient was negative for acid refluxes and weakly acidic refluxes separately, but was positive considering both refluxes as a whole).Twenty-eight (41%) patients had no association between reflux and symptoms.Identifying patients with symptomatic weakly acidic reflux reduces the number of patients with unexplained chest pain from 91 (46%) to 64 (32%) and from 51 (75%) to 28 (41%) among patients off-PPI and on-PPI, respectively (p<0.01).Conclusion: Monitoring for weakly acidic reflux in NCCP patients increases our ability to identify patients in whom symptoms are associated with reflux, mainly in patients on-PPI therapy.Our data support the use of ambulatory impedance-pH monitoring in a diagnostic algorithm for patients with unexplained chest pain.The impact of this improved diagnostic value on NCCP management remains to be investigated by outcome studies.

Objective To assess current management practice of heart failure with reduced ejection fraction (HFrEF) in multinational primary care (PC) and determine whether N-terminal-pro-B-type natriuretic peptide (NT-pro-BNP)-guided referral of HFrEF patients from PC to a cardiologist could improve care, defined as adherence to European Society of Cardiology (ESC) guideline-recommended pharmacotherapy. Methods PRospective Evaluation of natriuretic peptide-based reFERral of patients with chronic HF in PC (PREFER) study enrolled HFrEF patients from PC considered clinically stable and those with NT-pro-BNP ≥600 pg/mL were referred to a cardiologist for optimisation of HF treatment. The primary outcome of adherence to ESC HF guidelines after referral to specialist was assessed at the second visit within 4 weeks of cardiologist’s referral and no later than 6 months after the baseline visit. Based on futility interim analysis, the study was terminated early. Results In total, 1415 HFrEF patients from 223 PCs from 18 countries in Europe were enrolled. Of these, 1324 (96.9%) were considered clinically stable and 920 (65.0%) had NT-pro-BNP ≥600 pg/mL (mean: 2631 pg/mL). In total, 861 (60.8%) patients fulfilled both criteria and were referred to a cardiologist. Before cardiologist consultation, 10.1% of patients were on ESC guideline-recommended HFrEF medications and 2.7% were on recommended dosages of HFrEF medication (defined as ≥50% of ESC guideline-recommended dose). Postreferral, prescribed HFrEF drugs remained largely unchanged except for an increase in diuretics (+4.6%) and mineralocorticoid receptor antagonists (+7.9%). No significant increase in patients’ adherence to guideline-defined drug combinations (11.2% post-referral vs 10.1% baseline) or drug combinations and dosages (3.3% postreferral vs 2.7% baseline) was observed after cardiologist consultation. Conclusions PREFER demonstrates substantial suboptimal treatment of HFrEF patients in the real world. Referral of patients with elevated NT-pro-BNP levels from PC to cardiologist did not result in meaningful treatment optimisation for treatments with known mortality and morbidity benefit.

Singly positive cells (mCherry or eGFP) were more predominant, suggesting either the Lgr5-EGFP-IRES-CreERT2 transgene is intermittently expressed or the cells are lost by another mechanism.In support of this conclusion, EGFP (Lgr5)+ cells appeared during the imaging period in crypts that were previously only mCherry+.We also induced H2B-mCherry expression In Vitro with 4OHT introduction into the culture medium.No mCherry cells were noted initially, however mCherry+ cells began appearing within 20 hours, all in EGFP (Lgr5+) cells.By the end of the culture period, as the number of mCherry positive cells increased, some lost EGFP expression, possibly due to cell differentiation.Additional studies are underway to clarify this observation.Conclusion: Live imaging of enteroids reveals significant cellular and organoid movements, recapitulating In Vivo processes.Labeling of stem cells with H2B-mCherry using different Cre drivers will enable lineage tracing to be observed in real-time, helping establish relationships between different stem cell populations.