Superficial oesophageal mucosal innervation may contribute to severity of symptoms in oesophageal motility disorders.

BACKGROUND: Mechanisms underlying perception of dysphagia and chest pain have not been completely elucidated, although oesophageal mucosal afferent nerves might play an important role. AIMS: To evaluate the relationship between oesophageal mucosal afferent nerves and the severity of dysphagia and chest pain in oesophageal motility disorders. METHODS: We prospectively recruited patients with oesophageal motility disorders having dysphagia and/or chest pain from whom oesophageal biopsies were obtained. High-resolution manometry classified patients into disorders of oesophagogastric junction (OGJ) outflow and disorders of peristalsis. Symptom severity was assessed using validated questionnaires including Brief Oesophageal Dysphagia Questionnaire (BEDQ). Immunohistochemistry was performed on oesophageal biopsies to evaluate the location of calcitonin gene-related peptide (CGRP)-immunoreactive mucosal afferent nerves. Findings were compared to existing data from 10 asymptomatic healthy volunteers. RESULTS: Of 79 patients, 61 patients had disorders of OGJ outflow and 18 had disorders of peristalsis. CGRP-immunoreactive mucosal nerves were more superficially located in the mucosa of patients with oesophageal motility disorders compared to healthy volunteers. Within disorders of OGJ outflow, the location of CGRP-immunoreactive nerves negatively correlated with BEDQ score both in the proximal (ρ = -0.567, p < 0.001) and distal oesophagus (ρ = -0.396, p = 0.003). In the proximal oesophagus, strong chest pain was associated with more superficially located mucosal nerves than weak chest pain (p = 0.04). Multivariate analysis showed superficial nerves in the proximal oesophagus was independently associated with severe dysphagia in disorders of OGJ outflow (p = 0.008). CONCLUSIONS: Superficial location of mucosal nerves in the proximal oesophagus might contribute to symptoms, especially severe dysphagia, in disorders of OGJ outflow.

Identification of novel immune cell signature in gastroesophageal reflux disease: altered mucosal mast cells and dendritic cell profile.

Introduction: Heartburn pathogenesis in GERD remains incompletely understood. We aimed to identify differences in the immune cell signature and sensory mucosal markers between reflux phenotypes and healthy asymptomatic subjects. Methods: Thirty-seven patients with heartburn symptoms were phenotyped endoscopically and with objective reflux studies into erosive reflux disease (ERD) (N=10), nonerosive reflux disease (NERD) (N=9), functional heartburn (FH) (N=9), and Barrett's esophagus (BO) (N=9). Bulk mRNA-sequencing(RNA-seq) was conducted on RNA extracted from endoscopic biopsies, and immune cell deconvolution analysis was performed using CIBERSORT. RNA-seq findings were validated by immunofluorescent staining for CD1a, nerve growth factor (NGF), and mast cell tryptase in corresponding patient biopsies. Results: Transcriptomic analysis detected higher mast cell abundance in BO, ERD, and NERD compared to healthy controls (p<0.05), with decreased dendritic cell infiltration in BO, ERD, and NERD patients compared to healthy controls and FH patients. CD1a-positive dendritic cell infiltration was significantly higher in the healthy esophageal mucosa at protein level compared to BO (p=0.0005), ERD (p=0.0004), and FH patients (p=0.0096). Moreover, NGF co-expression on mast cells in GERD patients was significantly higher than in healthy controls (p=0.0094). Discussion: The mucosa in patients with GERD had a significant increase in NGF expression on mast cells, suggesting an upregulation of signalling for neuronal sprouting in GERD. Moreover, decreased dendritic cell abundance in GERD esophageal mucosa may play a role in reduced oral tolerance and development of subsequent immune responses which may participate in esophageal sensitivity.

Sensory Phenotype of the Oesophageal Mucosa in Gastro-Oesophageal Reflux Disease.

Gastroesophageal reflux disease (GORD) affects up to 20% of Western populations, yet sensory mechanisms underlying heartburn pathogenesis remain incompletely understood. While central mechanisms of heartburn perception have been established in earlier studies, recent studies have highlighted an important role of neurochemical, inflammatory, and cellular changes occurring in the oesophageal mucosa itself. The localization and neurochemical characterisation of sensory afferent nerve endings differ among GORD phenotypes, and could explain symptom heterogeneity among patients who are exposed to similar levels of reflux. Acid-induced stimulation of nociceptors on pain-sensing nerve endings can regulate afferent signal transmission. This review considers the role of peripheral mechanisms of sensitization in the amplification of oesophageal sensitivity in patients with GORD.

Randomised clinical trial: the use of alginates during preinvestigation proton pump inhibitor wash-out and their impact on compliance and symptom burden.

BACKGROUND/AIMS: Investigation of gastro-oesophageal reflux disease is usually performed off proton pump inhibitors (PPIs). This can exacerbate symptoms, potentially impacting investigation accuracy if patients circumvent the preinvestigation instructions. There are no standard recommendations on how to manage PPI withdrawal. We aimed to assess the impact of structured alginate use on symptom burden. METHODS: Participants were already established on ≥4 weeks of PPI therapy and being referred for manometry and 24-hour pH/impedance testing. Preinvestigation instructions involved stopping PPIs and H2 receptor antagonists for 1 week, but antacids and alginates were allowed until the night before. Participants were randomised to follow these standard instructions (control group), or the same instructions with the provision of Gaviscon Advance to be taken four times daily (treatment group). The primary outcome assessed change in Gastro-Oesophageal Reflux Disease Health-Related Quality of Life Score. KEY RESULTS: Data for 48 patients were available for primary outcome assessment. While patients in the control group had a significant increase in symptoms (median difference 6.5, 95% CI (1 to 7), p=0.04), no change occurred in the treatment arm (median difference -1.5, 95% CI (-2, 3.5), p=0.54). There were no serious adverse events. CONCLUSIONS: Structured alginate use prevents symptom exacerbation during preinvestigation PPI wash-out. These findings are limited to the 1-week wash-out period but can benefit thousands of patients undergoing investigation for gastro-oesophageal reflux each year. Further research is required to assess this effect in other settings, such as sustained PPI deprescription. The trial was funded by Reckitt Benckiser. TRIAL REGISTRATION NUMBER: EudraCT registration 2019-004561-41.

Clonal Transitions and Phenotypic Evolution in Barrett's Esophagus.

BACKGROUND & AIMS: Barrett's esophagus (BE) is a risk factor for esophageal adenocarcinoma but our understanding of how it evolves is poorly understood. We investigated BE gland phenotype distribution, the clonal nature of phenotypic change, and how phenotypic diversity plays a role in progression. METHODS: Using immunohistochemistry and histology, we analyzed the distribution and the diversity of gland phenotype between and within biopsy specimens from patients with nondysplastic BE and those who had progressed to dysplasia or had developed postesophagectomy BE. Clonal relationships were determined by the presence of shared mutations between distinct gland types using laser capture microdissection sequencing of the mitochondrial genome. RESULTS: We identified 5 different gland phenotypes in a cohort of 51 nondysplastic patients where biopsy specimens were taken at the same anatomic site (1.0-2.0 cm superior to the gastroesophageal junction. Here, we observed the same number of glands with 1 and 2 phenotypes, but 3 phenotypes were rare. We showed a common ancestor between parietal cell-containing, mature gastric (oxyntocardiac) and goblet cell-containing, intestinal (specialized) gland phenotypes. Similarly, we have shown a clonal relationship between cardiac-type glands and specialized and mature intestinal glands. Using the Shannon diversity index as a marker of gland diversity, we observed significantly increased phenotypic diversity in patients with BE adjacent to dysplasia and predysplasia compared to nondysplastic BE and postesophagectomy BE, suggesting that diversity develops over time. CONCLUSIONS: We showed that the range of BE phenotypes represents an evolutionary process and that changes in gland diversity may play a role in progression. Furthermore, we showed a common ancestry between gastric and intestinal-type glands in BE.

Changes in UK medical trainees' perceptions of workplace-based assessments across 10 years: results from two cross-sectional studies.

OBJECTIVES: Workplace-based assessments (WPBAs) have become embedded in the training and assessment of UK medical trainees since the onset of the 21st century. When first introduced WPBA required a significant adjustment in both trainees' and educators' training behaviour, and was met with scepticism in some quarters. In this study, we aimed to evaluate how trainees' perceptions of WPBAs have evolved over a 10-year period, as experience with them has increased. DESIGN: Two online questionnaires were constructed and distributed to UK trainees. The first was distributed in 2008, the second in 2018. Questions related to trainees' perception of WPBAs as a learning process and as a reflection of their competence. SETTING AND PARTICIPANTS: All UK medical trainees were eligible to respond. In 2008, 482 trainees from 96 hospitals completed the questionnaire. In 2018, 356 trainees from 103 hospitals completed the questionnaire. MAIN OUTCOME MEASURES: Data were analysed both quantitatively and qualitatively. A comparison between the numbers of each WPBA modality completed in 2008 and 2018 was assessed using chi-squared test. Comparisons of Likert scale values between 2008 and 2018 were assessed using unpaired t-test. Thematic analysis was carried out on free-text answers. RESULTS: The number of forms completed per participant increased significantly from 2008 to 2018. In 2008, forms were most commonly completed immediately after a learning observation (34%). In 2018, forms were most commonly completed between 1 week and 1 month after observation (58%). In 2018, significantly fewer WPBAs were followed by an educational/beneficial discussion in comparison to 2008 data. The most common free-text theme in the 2008 data set was 'supervisor issues' whereas in 2018 the most commonly noted theme was 'limited educational benefit'. CONCLUSIONS: Our study suggests trainees' perspectives of WPBAs have not changed in the 10 years since implementation. Trainees do not perceive WPBA as an accurate reflection of their competency but instead as a 'tick-box' bureaucratic exercise to enable career progression. Development of educator training and trainer and trainee job-planning is required to ensure that WPBAs are genuinely educational activities that offer an accurate reflection of trainees' medical competence.

A distributed optimisation framework combining natural gradient with Hessian-free for discriminative sequence training.

This paper presents a novel natural gradient and Hessian-free (NGHF) optimisation framework for neural network training that can operate efficiently in a distributed manner. It relies on the linear conjugate gradient (CG) algorithm to combine the natural gradient (NG) method with local curvature information from Hessian-free (HF). A solution to a numerical issue in CG allows effective parameter updates to be generated with far fewer CG iterations than usually used (e.g. 5-8 instead of 200). This work also presents a novel preconditioning approach to improve the progress made by individual CG iterations for models with shared parameters. Although applicable to other training losses and model structures, NGHF is investigated in this paper for lattice-based discriminative sequence training for hybrid hidden Markov model acoustic models using a standard recurrent neural network, long short-term memory, and time delay neural network models for output probability calculation. Automatic speech recognition experiments are reported on the multi-genre broadcast data set for a range of different acoustic model types. These experiments show that NGHF achieves larger word error rate reductions than standard stochastic gradient descent or Adam, while requiring orders of magnitude fewer parameter updates.

Combination of deep speaker embeddings for diarisation.

Significant progress has recently been made in speaker diarisation after the introduction of d-vectors as speaker embeddings extracted from neural network (NN) speaker classifiers for clustering speech segments. To extract better-performing and more robust speaker embeddings, this paper proposes a c-vector method by combining multiple sets of complementary d-vectors derived from systems with different NN components. Three structures are used to implement the c-vectors, namely 2D self-attentive, gated additive, and bilinear pooling structures, relying on attention mechanisms, a gating mechanism, and a low-rank bilinear pooling mechanism respectively. Furthermore, a neural-based single-pass speaker diarisation pipeline is also proposed in this paper, which uses NNs to achieve voice activity detection, speaker change point detection, and speaker embedding extraction. Experiments and detailed analyses are conducted on the challenging AMI and NIST RT05 datasets which consist of real meetings with 4-10 speakers and a wide range of acoustic conditions. For systems trained on the AMI training set, relative speaker error rate (SER) reductions of 13% and 29% are obtained by using c-vectors instead of d-vectors on the AMI dev and eval sets respectively, and a relative SER reduction of 15% in SER is observed on RT05, which shows the robustness of the proposed methods. By incorporating VoxCeleb data into the training set, the best c-vector system achieved 7%, 17% and 16% relative SER reduction compared to the d-vector on the AMI dev, eval and RT05 sets respectively.

Esophageal Mucosa Innervation in Children With Nonerosive Reflux Disease.

INTRODUCTION: Esophageal mucosa innervation in adults with nonerosive reflux disease (NERD) is more superficial compared with healthy volunteers. We delineated the esophageal mucosal innervation in pediatric NERD and controls. METHODS: Distal and proximal pediatric esophageal biopsies were immunohistochemically stained with calcitonin gene-related peptide and transient receptor potential cation channel subfamily V member 1. RESULTS: Mucosal innervation was assessed in 18 controls (9M:9F, median age: 9 years) and 11 NERD patients (6M:5F, median age: 5 years). Calcitonin gene-related peptide positive nerve fibers were lying deep in the mucosa in both groups, P > 0.05 and did not coexpress transient receptor potential cation channel subfamily V member 1. DISCUSSION: The pediatric esophageal mucosa in NERD displays deep lying nerve fibers, in contrast to adults.

Esophageal afferent innervation and its role in gastro-esophageal reflux disease symptoms.

PURPOSE OF REVIEW: Despite the wide prevalence of gastro-esophageal reflux disease (GERD), the neurophysiological mechanisms underlying heartburn perception in the esophagus of patients with GERD remains incompletely understood. Recent studies have highlighted the potential influence sensory afferent nerves innervating the oesophageal epithelium may have on heartburn pathogenesis. The purpose of this review is to consider the current understanding of esophageal afferent neuronal innervation, including the nociceptive role of acid-sensing receptors expressed on these sensory nerves, in relation to pain perception in the esophagus of GERD patients. RECENT FINDINGS: Central and peripheral pathways of sensitization following noxious stimulation of nociceptive receptors expressed on afferent nerves can regulate the strength of sensory nerve activation in the esophagus, which can result in the amplification or suppression of afferent signal transmission. The localization and characterization of mucosal sensory afferent nerves vary between GERD phenotypes and may explain the heterogeneity of symptom perception in patients with apparently similar levels of reflux. SUMMARY: In this review, we discuss the relevance of afferent esophageal innervation in heartburn perception, with a particular focus on the pathways of reflux-induced activation of nociceptive nerves.

Heartburn sensation in nonerosive reflux disease: pattern of superficial sensory nerves expressing TRPV1 and epithelial cells expressing ASIC3 receptors.

The underlying causes of heartburn, characteristic symptom of gastroesophageal reflux disease (GERD), remain incompletely understood. Superficial afferent innervation of the esophageal mucosa in nonerosive reflux disease (NERD) may drive nociceptive reflux perception, but its acid-sensing role has not yet been established. Transient receptor potential vanilloid subfamily member-1 (TRPV1), transient receptor potential melastatin 8 (TRPM8), and acid-sensing ion channel 3 (ASIC3) are regulators of sensory nerve activity and could be important reflux-sensing receptors within the esophageal mucosa. We characterized TRPV1, TRPM8, and ASIC3 expression in esophageal mucosa of patients with GERD. We studied 10 patients with NERD, 10 with erosive reflux disease (ERD), 7 with functional heartburn (FH), and 8 with Barrett's esophagus (BE). Biopsies obtained from the distal esophageal mucosa were costained with TRPV1, TRPM8, or ASIC3, and CGRP, CD45, or E-cadherin. RNA expression of TRPV1, TRPM8, and ASIC3 was assessed using qPCR. Patients with NERD had significantly increased expression of TRPV1 on superficial sensory nerves compared with ERD (P = 0.028) or BE (P = 0.017). Deep intrapapillary nerve endings did not express TRPV1 in all phenotypes studied. ASIC3 was exclusively expressed on epithelial cells most significantly in patients with NERD and ERD (P ≤0.0001). TRPM8 was expressed on submucosal CD45+ leukocytes. Superficial localization of TRPV1-immunoreactive nerves in NERD, and increased ASIC3 coexpression on epithelial cells in NERD and ERD, suggests a mechanism for heartburn sensation. Esophageal epithelial cells may play a sensory role in acid reflux perception and act interdependently with TRPV1-expressing mucosal nerves to augment hypersensitivity in patients with NERD, raising the enticing possibility of topical antagonists for these ion channels as a therapeutic option.NEW & NOTEWORTHY We demonstrate for the first time that increased pain perception in patients with nonerosive reflux disease likely results from expression of acid-sensitive channels on superficial mucosal afferents and esophageal epithelial cells, raising the potential for topical therapy.

Identification of Different Phenotypes of Esophageal Reflux Hypersensitivity and Implications for Treatment.

BACKGROUND & AIMS: Reflux hypersensitivity (RH), a functional esophageal disorder, is detected in 14%-20% of patients who present with typical esophageal symptoms. As many as 40% of patients with RH do not respond to treatment with pain modulators or proton pump inhibitors (PPIs); behavior disorders might contribute to lack of treatment efficacy. We aimed to assess the prevalence of behavioral disorders and their effects on typical reflux symptoms in patients with RH. METHODS: We performed a retrospective study of 542 patients with PPI-refractory esophageal symptoms (heartburn, regurgitation, or chest pain) or with symptoms that responded to PPI therapy, evaluated for anti-reflux surgery from January 2016 through August 2019 at a single center in London, United Kingdom. We collected data on symptoms, motility, and impedance-pH monitoring and assigned patients to categories of RH (n = 116), functional heartburn (n = 126), or non-erosive reflux disease (n = 300). RESULTS: Of the 116 patients with a diagnosis of RH, 59 had only hypersensitivity, whereas 57 patients (49.2%) had either excessive supragastric belching (SGB, 39.7%), based on 24-hour impedance-pH monitoring, or rumination (9.5%), based on postprandial manometry combined with impedance. The prevalence of SGB and rumination in patients with RH was significantly higher than in patients with functional heartburn (22%; P < .001). Patients with RH and rumination were significantly younger (P = .005) and had the largest number of non-acid reflux episodes (P = .023). In patients with RH with SGB, SGB episodes were associated with 40.6% of marked reflux symptoms (heartburn, regurgitation, or chest pain), based on impedance-pH monitoring. In patients with RH and rumination, 40% of reflux-related symptoms (mostly regurgitation) were due to possible rumination episodes. CONCLUSIONS: Almost half of patients with a diagnosis of RH have behavior disorders, including excessive SGB or rumination. Episodes of SGB or rumination are associated with typical reflux symptoms. Segregation of patients with diagnosis of RH into those with vs without behavioral disorders might have important therapeutic implications.

Mucosal pathogenesis in gastro-esophageal reflux disease.

BACKGROUND: Despite gastro-esophageal reflux disease affecting up to 20% of Western populations, relatively little is known about the molecular mechanisms underlying its most troublesome symptom: heartburn. Recent findings have unveiled the role of components of the esophageal mucosa in the pathogenesis of GERD including sensory nociceptive nerves and inflammatory mediators. Erosive esophagitis was long believed to develop as a result of acid injury at the esophageal lumen, but novel concepts suggest the generation of reflux-induced esophageal injury as a result of cytokine-mediated inflammation. Moreover, the localization and characterization of mucosal afferent nerves vary between GERD phenotypes and could explain the heterogeneity of symptom perception between patients who experience similar levels of acid reflux. PURPOSE: The purpose of this review is to consider the crosstalk of different factors of the esophageal mucosa in the pathogenesis of GERD, with a particular focus on mucosal innervation and molecular basis of acid-induced cytokine response. We discuss the current understanding of the mucosal response to acid injury, the nociceptive role of acid-sensitive receptors expressed in the esophageal mucosa, and the role of esophageal epithelial cells in initiating the onset of erosive esophagitis.

Duration of adhesion of swallowed alginates to distal oesophageal mucosa: implications for topical therapy of oesophageal diseases.

BACKGROUND: We have previously shown, ex vivo, that alginate solutions can have a topical protective effect on oesophageal mucosal biopsies exposed to simulated gastric juice. Oesophageal mucosal impedance can measure the duration of mucosal adherence of ionic solutions since the impedance drops when the solution is present, and rises to baseline as the solution clears. AIM: To investigate the in vivo duration of adhesion of swallowed alginate solution to distal oesophageal mucosa. METHODS: We studied 20 healthy volunteers and 10 patients with heartburn. A pH-impedance catheter was inserted, and baseline distal channel oesophageal impedance measured. Healthy volunteers received 10 mL of either sodium alginate (Gaviscon Advance), Gaviscon placebo (no alginate) or viscous slurry (saline mixed with sucralose), given in a randomised, single-blinded order over three visits. Patients received either sodium alginate or placebo on two visits. Initial impedance drop was measured, then 1-minute mean impedance was measured each minute until ≥75% recovery to baseline. RESULTS: In healthy volunteers, sodium alginate adhered to the oesophageal mucosa for longer than placebo or viscous slurry (10.4 [8.7] minutes vs 1.1 [1.6] vs 3.6 [4.0], P < 0.01). In patients, sodium alginate adhered to the oesophageal mucosa for longer than placebo (9.0 (5.4) vs 3.7 (4.1), P < 0.01). CONCLUSIONS: Sodium alginate solution adhered to the oesophageal mucosa for significantly longer than placebo or viscous slurry. This demonstrates that alginates could confer a protective benefit due to mucoadhesion and can be a basis for further development of topical protectants and for topical drug delivery in oesophageal disease.

Measurement of Esophageal Nocturnal Baseline Impedance: A Simplified Method.

BACKGROUND/AIMS: Mean nocturnal baseline impedance (MNBI) during multichannel intraluminal impedance pH-monitoring (MII-pH) reflects the status of esophageal mucosal integrity. MNBI is suggested as an adjunctive method to distinguish patients with true gastroesophageal reflux disease (GERD) from functional heartburn (FH) and might predict outcomes for anti-reflux treatment. However, current methodology for calculation of MNBI is time-consuming and subject to operator-dependent selection bias. We aim to simplify and provide a more objective method to calculate MNBI. METHODS: We retrospectively analyzed 100 MII-pH tracings from 20 patients with erosive reflux disease, 20 with non-erosive reflux disease (NERD), 20 with reflux hypersensitivity, 20 with functional heartburn (FH), and 20 healthy asymptomatic volunteers. We compared the current "conventional" MNBI analysis with our "simple" MNBI analysis measured by selecting the whole supine period using the impedance average calculation function in the MII-pH software. RESULTS: Absolute values were very similar and there was a strong correlation between conventional and simple MNBI values in the most distal channel in all groups (r ≥ 0.8, P < 0.001) including patients with increased supine acid reflux. Distal esophageal simple MNBI negatively correlated with acid exposure time (r = -0.695, P < 0.001). Patients with erosive reflux disease and NERD had lower simple MNBI values in the most distal channel compared to other groups (P < 0.001). With a cutoff value of 1785 ohms, simple MNBI can discriminate patients with GERD from those with reflux hypersensitivity and FH (sensitivity 80.0% and specificity 89.7%). CONCLUSION: Simple MNBI analysis provides very similar values and has an excellent correlation with conventional MNBI analysis.

Rumination Syndrome in Children Presenting With Refractory Gastroesophageal Reflux Symptoms.

OBJECTIVES: Up to 40% of children presenting with reflux symptoms do not respond to standard medical interventions. In adults, 20% of patients presenting with Proton Pump Inhibitors refractory Gastro-Esophageal Reflux Disease (GERD) have rumination syndrome. The management of GERD and rumination differ significantly. Our study aimed to identify rumination syndrome amongst children presenting with persistent GERD symptoms based on a distinct pattern on impedance-pH monitoring. METHODS: The parameters of impedance-pH monitoring were compared between children with rumination syndrome (n = 12), diagnosed on high-resolution manometry impedance (HRM/Z), children with GERD (n = 18), children with an alternative diagnosis (non-GERD, n = 12) and children negative for rumination based on HRM/Z (n = 14). The parameters that distinguish the rumination group were identified and incorporated into a scoring system, which was blindly applied on a separate group of children with refractory GERD (n = 18) to define its sensitivity and specificity. RESULTS: Rumination syndrome presents in 44% of children with refractory GERD. Children with rumination syndrome present with a large number of proximal reflux episodes (>57.5 episodes/24 hours); a high frequency of nonacid reflux events in the postprandial period (>2/hour); and a highly positive symptom-reflux association analysis (SAP ≥ 95%). A score of ≥2 out of the 3 points distinguishes children with rumination syndrome with 75% sensitivity and 80% specificity. CONCLUSIONS: Children with rumination syndrome have a distinct pattern of impedance-pH monitoring and can be distinguished amongst children presenting with refractory GERD. Applying a simple scoring system during impedance-pH analysis could lead to early diagnosis of children with rumination syndrome.

Patients with dyspepsia have impaired mucosal integrity both in the duodenum and jejunum: in vivo assessment of small bowel mucosal integrity using baseline impedance.

BACKGROUND: Recent studies reported that impaired proximal duodenal mucosa, assessed by duodenal biopsy, could play an important role in the development of dyspeptic symptoms. The aims of this study were (a) to develop a method to measure "in vivo" duodenal and jejunal baseline impedance (BI) and (b) to assess small bowel mucosal integrity in patients with functional dyspepsia (FD) and healthy controls (HC). METHODS: We recruited 16 patients with FD and 15 HC. All subjects underwent ambulatory duodeno-jejunal manometry combined with impedance (HRM/Z), BI were determined by measuring impedance immediately after the passage of nocturnal migrating motor complex (MMC) phase IIIs. RESULTS: The number of MMC phase IIIs in FD was significantly lower than that in HC (2.6 ± 1.4 vs 4.8 ± 1.7, p < 0.001). The BI in patients was significantly lower than that in HC in D1(164.2 ± 59.8 Ω in FD and 243.1 ± 40.5 Ω in HC, p = 0.0061), D2 (191.2 ± 34.1 and 256.5 ± 91.4 Ω, p = 0.01), D3 (214.0 ± 76.9 and 278.1 ± 45.3 Ω, p = 0.009), D4 (270.8 ± 54.2 and 351.8 ± 50.2 Ω, p < 0.001), and J1 (312.2 ± 55.4 and 379.3 ± 38.3 Ω, p = 0.001). CONCLUSIONS: This is the first study reporting the duodenal and jejunal BI in vivo. The results have shown significantly lowered BI in the proximal small intestine in patients with FD compared to HC. Furthermore it suggests that measurements of small bowel BI could be used as a biomarker for diagnosis and follow up of patients with FD.

Exacerbation of gastroesophageal reflux symptoms after discontinuation of proton pump inhibitors is not associated with increased esophageal acid exposure.

BACKGROUND: Discontinuation of long-term proton pump inhibitors (PPIs) on patients with reflux symptoms can be challenging, as symptoms often exacerbate after stopping. The mechanism remains unknown. Our aim was to evaluate the impact of stopping long-term PPIs on patients with heartburn, and its association with esophageal acid exposure. METHODS: Patients with heartburn on long-term PPIs underwent symptom questionnaire, high-resolution manometry, and 24h ambulatory impedance-pH studies, following a 7-day PPIs discontinuation. We investigated the association between exacerbation of symptoms and findings on ambulatory reflux studies. KEY RESULTS: We studied 37 patients. After stopping PPIs, 27 patients (73%) had exacerbation of heartburn. Esophageal acid exposure time% (AET) in patients with exacerbation of heartburn was not significantly higher than in patients without (3.5% [1.3-9.7] vs 2.5% [1.3-8.7], NS). Fourteen of 27 patients with exacerbation had physiological AET (<4%) as compared with 6 of 10 patients with physiological AET (NS). All questioned symptoms (heartburn, regurgitation, epigastric discomfort/pain, bloating/belch) worsened after stopping PPIs (NS). CONCLUSIONS & INFERENCES: Exacerbation of heartburn after discontinuation of PPIs does not appear to be due to increased esophageal acid exposure.