Improving the Diagnostic Yield of High-Resolution Esophageal Manometry for GERD: The "Straight Leg-Raise" International Study.

BACKGROUND & AIMS: The straight leg raise (SLR) maneuver during high-resolution manometry (HRM) can assess esophagogastric junction (EGJ) barrier function by measuring changes in intraesophageal pressure (IEP) when intra-abdominal pressure is increased. We aimed to determine whether increased esophageal pressure during SLR predicts pathologic esophageal acid exposure time (AET). METHODS: Adult patients with persistent gastroesophageal reflux disease (GERD) symptoms undergoing HRM and pH-impedance or wireless pH study off proton pump inhibitor were prospectively studied between July 2021 and March 2022. After the HRM Chicago 4.0 protocol, patients were requested to elevate 1 leg at 45º for 5 seconds while supine. The SLR maneuver was considered effective when intra-abdominal pressure increased by 50%. IEPs were recorded 5 cm above the lower esophageal sphincter at baseline and during SLR. GERD was defined as AET greater than 6%. RESULTS: The SLR was effective in 295 patients (81%), 115 (39%) of whom had an AET greater than 6%. Hiatal hernia (EGJ type 2 or 3) was seen in 135 (46%) patients. Compared with patients with an AET less than 6%, peak IEP during SLR was significantly higher in the GERD group (29.7 vs 13.9 mm Hg; P < .001). Using receiver operating characteristic analysis, an increase of 11 mm Hg of peak IEP from baseline during SLR was the optimal cut-off value to predict an AET greater than 6% (area under the receiver operating characteristic curve, 0.84; sensitivity, 79%; and specificity, 85%), regardless of the presence of hiatal hernia. On multivariable analysis, an IEP pressure increase during the SLR maneuver, EGJ contractile integral, EGJ subtype 2, and EGJ subtype 3, were found to be significant predictors of AET greater than 6% CONCLUSIONS: The SLR maneuver can predict abnormal an AET, thereby increasing the diagnostic value of HRM when GERD is suspected. CLINICALTRIALS: gov ID: NCT04813029.

Breathing new life into clinical testing and diagnostics: perspectives on volatile biomarkers from breath.

Human breath offers several benefits for diagnostic applications, including simple, noninvasive collection. Breath is a rich source of clinically-relevant biological information; this includes a volatile fraction, where greater than 1,000 volatile organic compounds (VOCs) have been described so far, and breath aerosols that carry nucleic acids, proteins, signaling molecules, and pathogens. Many of these factors, especially VOCs, are delivered to the lung by the systemic circulation, and diffusion of candidate biomarkers from blood into breath allows systematic profiling of organismal health. Biomarkers on breath offer the capability to advance early detection and precision medicine in areas of global clinical need. Breath tests are noninvasive and can be performed at home or in a primary care setting, which makes them well-suited for the kind of public screening program that could dramatically improve the early detection of conditions such as lung cancer. Since measurements of VOCs on breath largely report on metabolic changes, this too aids in the early detection of a broader range of illnesses and can be used to detect metabolic shifts that could be targeted through precision medicine. Furthermore, the ability to perform frequent sampling has envisioned applications in monitoring treatment responses. Breath has been investigated in respiratory, liver, gut, and neurological diseases and in contexts as diverse as infectious diseases and cancer. Preclinical research studies using breath have been ongoing for some time, yet only a few breath-based diagnostics tests are currently available and in widespread clinical use. Most recently, tests assessing the gut microbiome using hydrogen and methane on breath, in addition to tests using urea to detect Helicobacter pylori infections have been released, yet there are many more applications of breath tests still to be realized. Here, we discuss the strengths of breath as a clinical sampling matrix and the technical challenges to be addressed in developing it for clinical use. Historically, a lack of standardized methodologies has delayed the discovery and validation of biomarker candidates, resulting in a proliferation of early-stage pilot studies. We will explore how advancements in breath collection and analysis are in the process of driving renewed progress in the field, particularly in the context of gastrointestinal and chronic liver disease. Finally, we will provide a forward-looking outlook for developing the next generation of clinically relevant breath tests and how they may emerge into clinical practice.

Performance and Interpretation of Hydrogen and Methane Breath Testing Impact of North American Consensus Guidelines.

BACKGROUND: Hydrogen and methane breath tests (HMBT) are widely used clinical investigations but lack standardization. To address this, the North American Consensus (NAC) group published evidence-based recommendations for HMBT. AIMS: To evaluate results obtained using NAC recommendations for HMBT, compared to retrospective data that utilized guidelines previously recommended. METHODS: HMBT data from 725 patients referred for small intestinal bacterial overgrowth (SIBO) and/or carbohydrate malabsorption (CM) testing were analyzed. Data were compared regarding dose of substrate for SIBO testing (16 vs. 10 g lactulose, and 50 vs. 75 g glucose) and the effect of post-ingestion sampling period for malabsorption testing. The effect of different recommended cut-off values for SIBO were examined. RESULTS: Substrate dose did not affect methane production. 10 g lactulose significantly reduced positive SIBO results compared to 16 g lactulose (42 vs. 53%, p = 0.04). 75 g glucose significantly increased positive results compared to 50 g glucose (36 vs. 22%, p = 0.04). Provoked symptoms were significantly more prevalent in patients testing positive by both North American Consensus and Ledochowski cut-off values. 34.5% of patients tested positive for CM at 180-min compared to 28% at 120-min (not significant, p = 0.19). CONCLUSIONS AND INFERENCES: 10 g lactulose substrate produces fewer positive SIBO results than 16 g lactulose, while 75 g glucose dose produces more positive SIBO results than 50 g. Performing CM breath tests for 180 min increases number of positive results when compared to 120 min. SIBO cut-off timings require further investigation, but our findings broadly support the NAC recommendations for SIBO and CM testing.

The prevalence of intestinal dysbiosis in patients referred for antireflux surgery.

BACKGROUND: Prior to antireflux surgery, most patients with symptoms of gastroesophageal reflux disease (GERD) have been taking long-term proton pump inhibitors (PPIs). PPIs have been shown to cause changes to the intestinal microbiota, such as small intestinal bacterial overgrowth (SIBO), which is characterised by symptoms of gas bloating. Patients undergoing antireflux surgery are not routinely screened for SIBO, yet many patients experience gas-related symptoms postoperatively. METHODS: Data from consecutive patients (n = 104) referred to a speciality reflux centre were retrospectively assessed. Patients underwent a routine diagnostic workup for GERD including history, endoscopy, oesophageal manometry and 24-h pH-impedance monitoring off PPIs. Intestinal dysbiosis was determined by hydrogen and methane breath testing with a hydrogen-positive result indicative of SIBO and a methane-positive result indicative of intestinal methanogen overgrowth (IMO). RESULTS: 60.6% of patients had intestinal dysbiosis (39.4% had SIBO and 35.6% had IMO). Patients with dysbiosis were more likely to report bloating (74.6% vs 48.8%; P = 0.01) and belching (60.3% vs 34.1%; P = 0.01). The oesophageal acid exposure time and number of reflux episodes were similar between dysbiosis and non-dysbiosis groups, but patients with dysbiosis were more likely to have a positive reflux-symptom association (76.2% vs 31.7%; P < 0.001), especially for regurgitation in those with SIBO (P = 0.01). Hydrogen gas production was significantly greater in patients with a positive reflux-symptom association for regurgitation (228.8 ppm vs 129.1 ppm, P = 0.004) and belching (mean AUC 214.8 ppm vs 135.9 ppm, P = 0.02). CONCLUSIONS: The prevalence of intestinal dysbiosis is high in patients with GERD, and these patients are more likely to report gas-related symptoms prior to antireflux surgery. Independently, SIBO may be a contributory factor to refractory reflux symptoms and gas bloating in antireflux surgery candidates.

The prevalence of gastro-esophageal reflux disease and esophageal dysmotility in Chinese patients with idiopathic pulmonary fibrosis.

BACKGROUND: The cause of idiopathic pulmonary fibrosis (IPF) remains unknown, yet gastro-esophageal reflux disease (GERD) is highly prevalent in this population. GERD prevalence was studied, and esophageal function tests (EFT) were assessed in Chinese IPF patients. METHODS: We prospectively studied 69 IPF patients who undertook both stationary High Resolution esophageal Manometry/Impedance (HRiM) and 24-hour esophageal Multi-Channel Intraluminal Impedance with pH Recordings (MII/pH). Patients were divided into GERD+ and GERD- groups according to pH results. Controls were HRiM treated healthy volunteers, and patients without IPF received HRiM and MII/pH diagnosed with GERD. RESULTS: 69 IPF patients, 62 healthy volunteers, and 88 IPF negative GERD patients were selected. GERD prevalence in IPF was 43/69 (62.3%), and 58.1% of patients presented with at least one typical symptom. Symptoms had a sensitivity of 58.1%, a specificity of 61.6%, a positive predictive value of 71.4% and a negative predictive of 47.1%. Compared with healthy volunteers, IPF patients had significantly decreased lower esophageal sphincter pressure (LESP), upper esophageal sphincter pressure (UESP) and complete bolus transit rate (CBTR). By contrast, IPF patients had increased total bolus transit time and prevalence of weak peristalsis. MII/pH showed that one third of IPF patients had abnormal distal and proximal reflux, especially non-acid reflux. Compared with GERD patients without IPF, GERD patients with IPF had significantly decreased CBTR and UESP with increased bolus exposure time. CONCLUSIONS: GERD prevalence in IPF was high, but symptoms alone were an unreliable predictor of reflux. IPF patients had lower LESP and UESP, impaired esophageal peristalsis and bolus clearance function with more proximal reflux events.

The prevalence of rumination syndrome and rumination disorder: A systematic review and meta-analysis.

BACKGROUND: Rumination is characterized by the repeated regurgitation of food. Rumination syndrome is a disorder of gut-brain interaction diagnosed by Rome criteria, whereas rumination disorder is a feeding and eating disorder diagnosed by DSM-5 criteria. We aimed to determine the global prevalence of rumination according to these criteria across all age groups. METHODS: We performed a systematic review and meta-analysis of studies reporting the prevalence of rumination syndrome according to Rome III and Rome IV and rumination disorder according to the following validated DSM-5 assessments: PARDI, EDA-5, EDY-Q, STEP, and STEP-CHILD. We searched MEDLINE, EMBASE, and PsychINFO (from January 1, 2006, to June 1, 2023) to identify studies reporting the prevalence of rumination in community settings in participants of any age. We did a meta-analysis to estimate the pooled prevalence and odds ratio (OR) of rumination according to diagnostic criteria, country, and characteristics such as age and sex. KEY RESULTS: The search strategy generated 1243 studies, of which 147 studies appeared to be relevant. Thirty studies were included, with a total of 114,228 participants, of whom 61,534 of these were adults and 52,694 were children. The pooled prevalence of rumination syndrome in children of all ages according to Rome III criteria was 1.0% (95% CI 0.3-1.6; I2 91.1%), but no data were available for adults. According to Rome IV criteria, the pooled prevalence of rumination syndrome in children of all ages was 0.4% (95% CI 0.2-0.6; I2 56.4%) and 3.7% in adults (95% CI 2.3-5.1; I2 91.4%). The pooled prevalence of rumination disorder in children of all ages according to EDY-Q was 2.1% (95% CI 0.9-3.4; I2 = 78.1%), but only one study utilizing EDY-Q in adults was included (0.7% [95% CI 0.4-1.0]). No data were available for children or adults using any other validated DSM-5 assessments for rumination disorder. Irrespective of diagnostic criteria, the pooled prevalence of rumination was higher in adults compared to children and adolescents (3.0% [95% CI 1.4-4.7; I2 = 98.1%] vs. 0.8% [95% CI 0.4-1.3; I2 = 90.8%]), but higher in adolescents than in children (1.1% [95% CI 0.3-2.0; I2 = 92.8%] vs. 0.1% [95% CI 0.0-0.2; I2 = 24.5%]). In adults, factors independently associated with rumination were female gender (OR 1.4 [95% CI 1.0-2.0]), anxiety (OR 2.3 [95% CI 2.1-2.6]), and depression (OR 1.8 [95% CI 1.2-2.9]). No association between gender and rumination was seen in children. CONCLUSIONS AND INFERENCES: The prevalence of rumination is more common in adults than in children. In adults, rumination is associated with female gender, anxiety, and depression. Future population studies should aim to better understand why this behavior is more common in adults and also compare validated DSM-5 assessments for rumination disorder with Rome criteria for rumination syndrome as prevalence may differ.

The Milan score: A novel manometric tool for a more efficient diagnosis of gastro-esophageal reflux disease.

OBJECTIVE: A definitive diagnosis of gastroesophageal reflux disease (GERD) depends on endoscopic and/or pH-study criteria. However, high resolution manometry (HRM) can identify factors predicting GERD, such as ineffective esophageal motility (IEM), esophago-gastric junction contractile integral (EGJ-CI), evaluating esophagogastric junction (EGJ) type and straight leg raise (SLR) maneuver response. We aimed to build and externally validate a manometric score (Milan Score) to stratify the risk and severity of the disease in patients undergoing HRM for suspected GERD. METHODS: A population of 295 consecutive patients undergoing HRM and pH-study for persistent typical or atypical GERD symptoms was prospectively enrolled to build a model and a nomogram that provides a risk score for AET > 6%. Collected HRM data included IEM, EGJ-CI, EGJ type and SLR. A supplemental cohort of patients undergoing HRM and pH-study was also prospectively enrolled in 13 high-volume esophageal function laboratories across the world in order to validate the model. Discrimination and calibration were used to assess model's accuracy. Gastroesophageal reflux disease was defined as acid exposure time >6%. RESULTS: Out of the analyzed variables, SLR response and EGJ subtype 3 had the highest impact on the score (odd ratio 18.20 and 3.87, respectively). The external validation cohort consisted of 233 patients. In the validation model, the corrected Harrel c-index was 0.90. The model-fitting optimism adjusted calibration slope was 0.93 and the integrated calibration index was 0.07, indicating good calibration. CONCLUSIONS: A novel HRM score for GERD diagnosis has been created and validated. The MS might be a useful screening tool to stratify the risk and the severity of GERD, allowing a more comprehensive pathophysiologic assessment of the anti-reflux barrier. TRIAL REGISTRATION: ClinicalTrials.gov (Identifier: NCT05851482).

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.

An insight into the functional alterations in the gut microbiome of healthy adults in response to a multi-strain probiotic intake: a single arm open label trial.

Background: Probiotic supplements, by definition, provide a benefit to the host, but few studies have investigated the effect of probiotic supplements in healthy adult populations. Purpose: The present, single arm, open label clinical trial, evaluated compositional and functional changes in the fecal microbiome of healthy adults after supplementation with a 14-strain probiotic. Methods: We analysed the effect of a 14-strain probiotic blend (Bacillus subtilis NCIMB 30223, Bifidobacterium bifidum NCIMB 30179, B. breve NCIMB 30180, B. infantis NCIMB 30181, B. longum NCIMB 30182, Lactobacillus helveticus NCIMB 30184, L. delbrueckii subsp. bulgaricus NCIMB 30186, Lacticaseibacillus paracasei NCIMB 30185, Lactiplantibacillus plantarum NCIMB 30187, Lacticaseibacillus rhamnosus NCIMB 30188, L. helveticus NCIMB 30224, Lactobacillus salivarius NCIMB 30225, Lactococcus lactis subsp. lactis NCIMB 30222, and Streptococcus thermophilus NCIMB 30189), on the faecal microbiota of healthy young adults (n=41) in a single arm study. The adults consumed 4 capsules daily of the 14 strain blend(8 billion colony forming units/day) for 8 weeks. Compositional and functional changes in faecal microbiota before and after supplementation were assessed using shotgun metagenomic sequencing. Fasting breath analysis, faecal biochemistry and bowel habits were also assessed. Results: In healthy adult participants, no significant changes to the overall alpha- or beta-diversity was observed after 8 weeks of multi-strain probiotic supplementation. However, in a simplified model that considered only time and individual differences, significant decreases (p < 0.05) in family Odoribacteraceae and Bacteroidaceae abundance and a significant increase (p < 0.05) in genus Megamonas abundance were observed. At a functional level, there were significant changes in functional gene abundance related to several functional pathways, including phenylalanine metabolism, O-antigen nucleotide sugar biosynthesis, bacterial chemotaxis, and flagellar assembly. No significant changes in stool form or frequency, fecal biochemistry, or methane and hydrogen breath tests were observed. Conclusion: In healthy young adults, overall alpha- and beta-diversity did not change in response to probiotic intake even though modest compositional changes at the family and genus level were observed. However, at functional level, results identified changes in gene abundance for several functional pathways.

Principles and clinical methods of body surface gastric mapping: Technical review.

BACKGROUND AND PURPOSE: Chronic gastric symptoms are common, however differentiating specific contributing mechanisms in individual patients remains challenging. Abnormal gastric motility is present in a significant subgroup, but reliable methods for assessing gastric motor function in clinical practice are lacking. Body surface gastric mapping (BSGM) is a new diagnostic aid, employs multi-electrode arrays to measure and map gastric myoelectrical activity non-invasively in high resolution. Clinical adoption of BSGM is currently expanding following studies demonstrating the ability to achieve specific patient subgrouping, and subsequent regulatory clearances. An international working group was formed in order to standardize clinical BSGM methods, encompassing a technical group developing BSGM methods and a clinical advisory group. The working group performed a technical literature review and synthesis focusing on the rationale, principles, methods, and clinical applications of BSGM, with secondary review by the clinical group. The principles and validation of BSGM were evaluated, including key advances achieved over legacy electrogastrography (EGG). Methods for BSGM were reviewed, including device design considerations, patient preparation, test conduct, and data processing steps. Recent advances in BSGM test metrics and reference intervals are discussed, including four novel metrics, being the 'principal gastric frequency', BMI-adjusted amplitude, Gastric Alimetry Rhythm Index™, and fed: fasted amplitude ratio. An additional essential element of BSGM has been the introduction of validated digital tools for standardized symptom profiling, performed simultaneously during testing. Specific phenotypes identifiable by BSGM and the associated symptom profiles were codified with reference to pathophysiology. Finally, knowledge gaps and priority areas for future BSGM research were also identified by the working group.

Human visceral afferent recordings: preliminary report.

BACKGROUND: Conditions characterised by chronic visceral pain represent a significant healthcare burden with limited treatment options. While animal models have provided insights into potential mechanisms of visceral nociception and identified candidate drug targets, these have not translated into successful treatments in humans. OBJECTIVE: To develop an in vitro afferent nerve preparation using surgically excised freshly isolated human colon and vermiform appendix-mesentery tissues. METHODS: Non-inflamed appendix (n=18) and colon (n=9) were collected from patients undergoing right and left hemicolectomy. Electrophysiological recordings were made from mesenteric nerves and the tissue stimulated chemically and mechanically. RESULTS: Ongoing neuronal activity was sparse and where units occurred peak firing rates were: colon (2.0±0.4 spikes/s, n=4) and appendix (2.4±0.6 spikes/s, n=9). Afferent nerves innervating the appendix responded with a significant increase in activity following stimulation with inflammatory mediators (73±10.6 vs 3.0±0.3 spikes/s, n=6, p<0.001, inflammatory mediator vs baseline) and capsaicin (63±15.8 vs 2±0.3 spikes/s, n=3, p<0.001, capsaicin vs buffer). Afferent nerves innervating the colon responded with increased activity to blunt probing of the serosal surface. CONCLUSIONS: This first-in-human study demonstrates afferent nerve recordings from human gut tissue ex vivo and shows that tissue may be stimulated both chemically and mechanically to study neuronal responses. Collectively, the results provide preliminary evidence to validate this in vitro human tissue model as one that may aid future disease mechanistic studies and candidate drug testing.

Primary and secondary somatosensory cortex responses to anticipation and pain: a magnetoencephalography study.

Several brain regions, including the primary and secondary somatosensory cortices (SI and SII, respectively), are functionally active during the pain experience. Both of these regions are thought to be involved in the sensory-discriminative processing of pain and recent evidence suggests that SI in particular may also be involved in more affective processing. In this study we used MEG to investigate the hypothesis that frequency-specific oscillatory activity may be differentially associated with the sensory and affective components of pain. In eight healthy participants (four male), MEG was recorded during a visceral pain experiment comprising baseline, anticipation, pain and post-pain phases. Pain was delivered via intraluminal oesophageal balloon distension (four stimuli at 1 Hz). Significant bilateral but asymmetrical changes in neural activity occurred in the ß-band within SI and SII. In SI, a continuous increase in neural activity occurred during the anticipation phase (20-30 Hz), which continued during the pain phase but at a lower frequency (10-15 Hz). In SII, oscillatory changes only occurred during the pain phase, predominantly in the 20-30 Hz ß band, and were coincident with the stimulus. These data provide novel evidence of functional diversity within SI, indicating a role in attentional and sensory aspects of pain processing. In SII, oscillatory changes were predominantly stimulus-related, indicating a role in encoding the characteristics of the stimulus. We therefore provide objective evidence of functional heterogeneity within SI and functional segregation between SI and SII, and suggest that the temporal and frequency dynamics within cortical regions may offer valuable insights into pain processing.

Distinct neurophysiological profiles in irritable bowel syndrome.

The objective of this study was to determine whether cortical evoked potentials (CEPs) can define neurophysiological patterns in irritable bowel syndrome (IBS). In this prospective study of consecutive patients attending secondary and tertiary centers, patients with Rome II-defined IBS underwent rectal sensory and pain threshold (RST and RPT, respectively) testing with electrical stimulation on three separate visits. CEPs were collated for 75% pain thresholds, and anxiety [Spielberger State-Trait Anxiety Inventory (SSTAI)] questionnaires were completed. Subjects were 33 IBS patients (27 female, mean age 40.1 yr) and 21 healthy controls (14 female, mean age 31.4 yr). At visit 3, RPT was significantly lower [mean (95% CI)] in IBS patients than in control subjects: 58.2 mA (48.0-68.5) vs. 79.5 mA (69.3-89.6) (P < 0.01). No significant differences were observed in CEP latencies and amplitudes between visits 1, 2, and 3 within each group, except P2 latency for controls (P = 0.04) and N2 latency (P = 0.04) and N2 amplitude (P = 0.02) for IBS patients. Group comparisons showed significant differences in 3-day mean RPT, CEP amplitudes, and CEP latencies between IBS patients and controls. RPT <50 mA and P1 latency >106 ms were identified four IBS subgroups: 24% were hypersensitive, 12% were hypervigilant, 15% were hyposensitive, and 49% exhibited normal P1 latency and pain threshold. CEPs are reliable and reproducible measures of early sensory processing. Identification of four IBS neurophysiological patterns highlights its heterogeneous nature. These findings mark the first step toward personalized medicine in IBS, whereby therapy may be directed at the underlying physiological process.

Neurophysiological evaluation of convergent afferents innervating the human esophagus and area of referred pain on the anterior chest wall.

Noxious stimuli in the esophagus cause pain that is referred to the anterior chest wall because of convergence of visceral and somatic afferents within the spinal cord. We sought to characterize the neurophysiological responses of these convergent spinal pain pathways in humans by studying 12 healthy subjects over three visits (V1, V2, and V3). Esophageal pain thresholds (Eso-PT) were assessed by electrical stimulation and anterior chest wall pain thresholds (ACW-PT) by use of a contact heat thermode. Esophageal evoked potentials (EEP) were recorded from the vertex following 200 electrical stimuli, and anterior chest wall evoked potentials (ACWEP) were recorded following 40 heat pulses. The fear of pain questionnaire (FPQ) was administered on V1. Statistical data are shown as point estimates of difference +/- 95% confidence interval. Pain thresholds increased between V1 and V3 [Eso-PT: V1-V3 = -17.9 mA (-27.9, -7.9) P < 0.001; ACW-PT: V1-V3 = -3.38 degrees C (-5.33, -1.42) P = 0.001]. The morphology of cortical responses from both sites was consistent and equivalent [P1, N1, P2, N2 complex, where P1 and P2 are is the first and second positive (downward) components of the CEP waveform, respectively, and N1 and N2 are the first and second negative (upward) components, respectively], indicating activation of similar cortical networks. For EEP, N1 and P2 latencies decreased between V1 and V3 [N1: V1-V3 = 13.7 (1.8, 25.4) P = 0.02; P2: V1-V3 = 32.5 (11.7, 53.2) P = 0.003], whereas amplitudes did not differ. For ACWEP, P2 latency increased between V1 and V3 [-35.9 (-60, -11.8) P = 0.005] and amplitudes decreased [P1-N1: V1-V3 = 5.4 (2.4, 8.4) P = 0.01; P2-N2: 6.8 (3.4, 10.3) P < 0.001]. The mean P1 latency of EEP over three visits was 126.6 ms and that of ACWEP was 101.6 ms, reflecting afferent transmission via Adelta fibers. There was a significant negative correlation between FPQ scores and Eso-PT on V1 (r = -0.57, P = 0.05). These data provide the first neurophysiological evidence of convergent esophageal and somatic pain pathways in humans.

Linaclotide increases cecal pH, accelerates colonic transit, and increases colonic motility in irritable bowel syndrome with constipation.

BACKGROUND: Linaclotide is efficacious in the management of irritable bowel syndrome with constipation (IBS-C), yet relatively little is known regarding its effect on human gastrointestinal physiology. The primary aim of the study was to examine the effect of linaclotide on change in pH across the ileocecal junction (ICJ), a proposed measure of cecal fermentation, and its relationship to symptoms and quality of life (QoL) in IBS-C. METHODS: A total of 13 participants with Rome III IBS-C underwent a standardized wireless motility capsule (WMC). Stool consistency was measured using the Bristol stool form scale (BSFS) and frequency with spontaneous bowel movements (SBM). Gastrointestinal symptoms and QoL were assessed using validated questionnaires. The WMC and questionnaires were repeated after 28 days of linaclotide 290 g po od. KEY RESULTS: Linaclotide reduced the change in pH across the ICJ (-2.4 ± 0.2 vs -2.1 ± 0.4, P = 0.01) as a function of a relative alkalinization of the cecum (5.2 ± 0.2 vs 5.5 ± 0.3, P = 0.02). Linaclotide accelerated colonic transit time (2650 minutes (2171-4038) vs. 1757 (112-3011), P = 0.02), increased colonic log motility index (15 ± 1.8 vs. 16.5 ± 1.8, P = 0.004) but had no effect of gastric emptying or small bowel transit. Change in pH across the ICJ correlated with improvement in symptom intensity, unpleasantness, and visceral sensitivity index (r = 0.62, P = 0.03, r = 0.63, P = 0.02, r = 0.62, P = 0.02) and with increases in BSFS type and SBM (r = 0.9, P < 0.0001, r = 0.6, P = 0.02). CONCLUSIONS & INFERENCES: Linaclotide's effects are confined to the colon where it increases cecal pH, potentially representing a reduction in cecal fermentation and accelerates colonic motility.

Endoscopic measurement of gastric pH associates with persistent acid reflux in patients treated with proton-pump inhibitors for gastroesophageal reflux disease.

Background: Proton-pump inhibitors (PPIs) are the mainstay of gastroesophageal reflux disease (GERD) treatment, however, up to 30% of patients have a poor symptomatic response. PH-impedance is the gold standard to assess whether this is due to persistent acid reflux. We aimed to characterize clinical predictors of persistent esophageal acid reflux on PPIs including gastric pH measured during endoscopy. Methods: We prospectively recruited patients with GERD and/or Barrett's esophagus (BE) on PPIs. All patients completed a symptom questionnaire (RDQ) and underwent gastroscopy with gastric pH analysis, immediately followed by ambulatory 24-hour pH-impedance. We used a modified cut-off of 1.3% for pathological esophageal acid exposure time (AET). Multiple linear regression model was used to analyze the correlation between AET and predictive variables. Results: We recruited 122 patients, of which 92 (75.4%) were included in the final analysis [44 male (47.8%), median age 53 years (IQR: 43-66)]. Forty-four patients (47.8%) had persistent acid reflux with a median total AET of 2.2 (IQR1.2-5.0), as compared to 0.1 (IQR 0.0-0.2) in patients without persistent reflux (n=48; P<.001). There was no difference in age, gender, BMI, PPI-regimen, diagnosis of hiatus hernia or BE, and severity of symptoms between patients with normal and abnormal AET. Median gastric pH was significantly lower in patients with abnormal AET (5.8 vs 6.6, P=0.032) and it correlated with the total AET (P=.045; R2=12.0%). With a pH cut-off of 5.05, single point endoscopic gastric pH analysis had an area under the ROC curve (AUC) of 63.0% (95%CI 51.3-74.7) for prediction of pathological esophageal AET. Conclusions: Symptoms and clinical characteristics are not useful to predict persistent acid reflux in patients on PPIs. One-point gastric pH correlates with 24-hour esophageal AET and could guide clinicians to assess response to PPIs, however, its utility needs validation in larger studies.

Driving plasticity in human adult motor cortex is associated with improved motor function after brain injury.

Changes in somatosensory input can remodel human cortical motor organization, yet the input characteristics that promote reorganization and their functional significance have not been explored. Here we show with transcranial magnetic stimulation that sensory-driven reorganization of human motor cortex is highly dependent upon the frequency, intensity, and duration of stimulus applied. Those patterns of input associated with enhanced excitability (5 Hz, 75% maximal tolerated intensity for 10 min) induce stronger cortical activation to fMRI. When applied to acutely dysphagic stroke patients, swallowing corticobulbar excitability is increased mainly in the undamaged hemisphere, being strongly correlated with an improvement in swallowing function. Thus, input to the human adult brain can be programmed to promote beneficial changes in neuroplasticity and function after cerebral injury.

Modulation of visceral nociceptive pathways.

Increased sensitivity of visceral nociceptive pathways contributes to symptoms in an array of clinical gastrointestinal conditions, however, the search for a consistently effective pharmacological agent to treat these conditions remain elusive. Modulation of visceral nociceptive pathways can occur at peripheral, spinal and supra-spinal sites and a dizzying array of potential drug targets exists. Till date, only tricyclic anti-depressants (TCAs) such as amitriptyline and, more recently, selective serotonin reuptake inhibitors (SSRIs) such as citalopram have demonstrated convincing visceral anti-nociceptive properties and clinical benefit in a limited population of patients with visceral hypersensitivity. Unfortunately, there is an incomplete understanding of the receptors and/or primary site of action at which these compounds exert their effects and significant side effects are often encountered. There is a continuing and concerted effort underway to develop target-specific visceral analgesic/anti-hyperalgesic compounds and the aim of this article is to provide a concise update on the most recent advances in this area.

Constitutive cyclo-oxygenase-2 does not contribute to the development of human visceral pain hypersensitivity.

BACKGROUND AND AIMS: Central sensitisation (CS), contributes to the development and maintenance of gastrointestinal pain hypersensitivity. Constitutive cyclo-oxygenase-2 (COX-2) contributes to central sensitisation in somatic pain hypersensitivity but its role in mediating visceral pain hypersensitivity is unknown. We therefore conducted a study to determine if COX-2 inhibition with Valdecoxib attenuates the development or early maintenance of CS in a validated human oesophageal pain hypersensitivity model. METHODS: Healthy volunteers were studied in two randomised, double blind, crossover studies in which pain thresholds (PT) to electrical stimulation were assessed in the proximal oesophagus, chest wall and foot, prior to and following a distal oesophageal acid infusion. Protocol 1: Valdecoxib, (40 mg) or matching placebo was given orally for 4 days prior to oesophageal acid infusion. Protocol 2: IV Parecoxib (40 mg) or saline was given 120 min after oesophageal acid infusion. RESULTS: Valdecoxib did not prevent the induction of secondary allodynia in the proximal oesophagus nor did it attenuate it following its establishment. Chest wall PT fell following oesophageal acid but foot PT remained unchanged; highlighting the development viscero-somatic convergence due to CS. Valdecoxib had no analgesic or anti-hyperalgesic effect on chest wall or foot PT. CONCLUSIONS: Neither the induction nor initial maintenance of acid induced oesophageal pain hypersensitivity is prevented by Valdecoxib, suggesting that constitutive spinal COX-2 does not contribute to the development or early maintenance of acute visceral central sensitisation.