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Background: Genetic polymorphisms in G-protein beta-3 subunit (GNβ3) and beta-2 adrenergic receptor (ADRB2) are associated with pain and gut hypersensitivity, which can overlap with gastroesophageal reflux disease (GERD)., Aim: To evaluate relationships between single nucleotide polymorphisms (SNPs) within GNβ3 and ADRB2 systems, and reflux symptom burden, GERD phenotypes from ambulatory reflux monitoring, and quality of life., Methods: Symptomatic adults undergoing ambulatory reflux testing were recruited and phenotyped based on acid burden and symptom reflux association; major oesophageal motor disorders and prior foregut surgery were exclusions. A comparison asymptomatic control cohort was also identified. Subjects and controls completed questionnaires assessing symptom burden on visual analog scales, short-form health survey-36 (SF-36), and Beck Anxiety and Depression Inventories (BAI and BDI). Genotyping was performed from saliva samples; 6 SNPs selected from each of the two genes of interest were compared., Results: Saliva from 151 study subjects (55.3 ± 1.2 years, 63.6% F) and 60 control subjects (50.9 ± 2.2 years, 66.7%) had sufficient genetic material for genotyping. Study subjects had higher symptom burden, worse total and physical health, and higher anxiety scores compared to controls (P ≤ .002). Tested SNPs within ADRB2 were similar between study subjects and controls (P > .09). Study subjects with recessive alleles in 3 GNβ3 SNPs (Rs2301339, Rs5443, and Rs5446) had worse symptom severity (P = .011), worse mental health (P = .03), and higher depression scores (P = .005) despite no associations with GERD phenotypes or reflux metrics., Conclusions: Genetic variation within GNβ3 predicts oesophageal symptom burden and affect, but not oesophageal acid burden or symptom association with reflux episodes., (© 2017 John Wiley & Sons Ltd.)

Background: The upper esophageal sphincter (UES) reflexively responds to bolus presence within the esophageal lumen, therefore UES metrics can vary in achalasia., Methods: Within consecutive patients undergoing esophageal high-resolution manometry (HRM), 302 patients (58.2±1.0 year, 57% F) with esophageal outflow obstruction were identified, and compared to 16 asymptomatic controls (27.7±0.7 year, 56% F). Esophageal outflow obstruction was segregated into achalasia subtypes 1, 2, and 3, and esophagogastric junction outflow obstruction (EGJOO with intact peristalsis) using Chicago Classification v3.0. UES and lower esophageal sphincter (LES) metrics were compared between esophageal outflow obstruction and normal controls using univariate and multivariate analysis. Linear regression excluded multicollinearity of pressure metrics that demonstrated significant differences across individual subtype comparisons., Key Results: LES integrated relaxation pressure (IRP) had utility in differentiating achalasia from controls (P<.0001), but no utility in segregating between subtypes (P=.27). In comparison to controls, patients collectively demonstrated univariate differences in UES mean basal pressure, relaxation time to nadir, recovery time, and residual pressure (UES-RP) (P≤.049). UES-RP was highest in type 2 achalasia (P<.0001 compared to other subtypes and controls). In multivariate analysis, only UES-RP retained significance in comparison between each of the subgroups (P≤.02 for each comparison). Intrabolus pressure was highest in type 3 achalasia; this demonstrated significant differences across some but not all subtype comparisons., Conclusions and Inferences: Nadir UES-RP can differentiate achalasia subtypes within the esophageal outflow obstruction spectrum, with highest values in type 2 achalasia. This metric likely represents a surrogate marker for esophageal pressurization., (© 2017 John Wiley & Sons Ltd.)

Background: Inpatient care is a fundamental part of gastroenterology training and involves the recommendation, performance, and interpretation of diagnostic tests. However, test results are not always communicated to patients or treating providers. We determined the process of communication of test results and recommendations in our inpatient gastroenterology (GI) consult service., Methods: Test recommendations on 304 consecutive new GI consults (age 60.2 ± 1.0 year) over a 2-month period were recorded. Demographic factors (age, race, gender, zip code, insurance status) were extracted from the electronic medical record (EMR). Charts were independently reviewed 6 months later to determine results of recommended tests, follow-up of actionable test results, 30-day readmission rates, and predictors of suboptimal communication., Results: Of 490 recommended tests, 437 (89.2%) were performed, and 199 (45.5%) had actionable findings. Of these, 48 (24.1%) did not have documented follow-up. Failure of follow-up was higher for upper endoscopy (31.9%) compared to colonoscopy (18.0%, p = 0.07). Women (p = 0.07), patients on Medicare (p = 0.05), and procedures supervised by advanced GI fellows (p = 0.06) were less likely to receive follow-up. Median income and identification of a primary provider did not influence follow-up rates; 30-day readmission rates were not impacted. Female gender, insurance (Medicare) status, and attending type remained independent predictors of failure of follow-up on multivariate regression (p ≤ 0.03)., Conclusions: Failure to follow up test results on inpatient services at a large academic center was unacceptably high. Maximizing personnel participation together with diligence and technology (EMR) will be required to improve communication.

While functional dyspepsia (FD) is an exceedingly common disorder, the number of treatment options remains limited, and strategies for the individualized implementation of these therapies largely are lacking. In the current issue of American Journal of Gastroenterology, Saito and colleagues report on a secondary analysis of data from the Functional Dyspepsia Treatment Trial, specifically examining the role of two candidate genetic markers in predicting FD response to antidepressant treatments. Though the current study yielded a negative result, it nevertheless emphasizes the importance of our continued pursuit of therapeutic biomarkers in order to move beyond "one-size-fits-all" approaches to the treatment of FD and related disorders.

Objectives: Irritable bowel syndrome (IBS) is a functional bowel disorder characterized by symptoms including abdominal pain and altered bowel function. Up to 75% of individuals with IBS may be undiagnosed. The aim of this study was to characterize symptoms, healthcare utilization, and treatments in populations with both diagnosed and undiagnosed IBS., Methods: An online survey was conducted to compare gastrointestinal (GI) symptoms, healthcare visits, well-being, symptom management, and treatment satisfaction in individuals with and without medically diagnosed IBS (Rome III criteria). Symptom severity, disruptiveness, and treatment satisfaction were rated using a 7-point scale. Adjustments to daily life were determined by predefined survey responses., Results: A total of 1,924 individuals with a history of GI symptoms were eligible and completed the survey. Of these, 1,094 individuals (56.9%) met the criteria for IBS; 830 individuals (43.1%) had no medical diagnosis of IBS despite meeting diagnostic criteria. Most participants received a diagnosis from either gastroenterologists (45%) or primary care physicians (42%). A greater percentage of diagnosed patients had severe GI symptoms (score ≥6) vs. undiagnosed individuals (16% vs. 8%, respectively; P<0.05); diagnosed patients were more likely to report that GI symptoms adversely affected their quality of life. Approximately 40% of participants received IBS-related treatment from primary care physicians; 26% and 43% of diagnosed and undiagnosed individuals, respectively, were not receiving treatment for GI symptoms., Conclusions: Many individuals with IBS-related symptoms have not been medically diagnosed with IBS. IBS-related symptoms impact quality of life, yet more than one-third of individuals are not receiving treatment for IBS.

Background: Mean nocturnal baseline impedance (MNBI), a novel pH-impedance metric, may be a surrogate marker of reflux burden., Aim: To assess the predictive value of MNBI on symptomatic outcomes after anti-reflux therapy., Methods: In this prospective observational cohort study, pH-impedance studies performed over a 5-year period were reviewed. Baseline impedance was extracted from six channels at three stable nocturnal 10-min time periods, and averaged to yield MNBI. Distal and proximal oesophageal MNBI values were calculated by averaging MNBI values at 3, 5, 7 and 9 cm, and 15 and 17 cm respectively. Symptomatic outcomes were measured as changes in global symptom severity (GSS, rated on 100-mm visual analogue scales) on prospective follow-up after medical or surgical anti-reflux therapy. Univariate and multivariate analyses assessed the predictive value of MNBI on symptomatic outcomes., Results: Of 266 patients, 135 (50.8%) were tested off proton pump inhibitor (PPI) therapy and formed the study cohort (52.1 ± 1.1 years, 63.7% F). The 59 with elevated acid exposure time (AET) had lower composite and distal MNBI values than those with physiological AET (P < 0.0001), but similar proximal MNBI (P = 0.62). Linear AET negatively correlated with distal MNBI, both individually and collectively (Pearson's r = -0.5, P < 0.001), but not proximal MNBI (Pearson's r = 0, P = 0.72). After prospective follow-up (94 patients were followed up for 3.1 ± 0.2 years), univariate and multivariate regression models showed that distal MNBI, but not proximal MNBI, was independently predictive of linear GSS improvement., Conclusions: Distal oesophageal MNBI negatively correlates with AET and, when assessed off PPI therapy, is independently predictive of symptomatic improvement following anti-reflux therapy., (© 2016 John Wiley & Sons Ltd.)

Background: Irritable bowel syndrome (IBS) is a common abdominal pain disorder without an organic explanation. Abuse histories (physical, sexual, emotional) are prevalent in IBS. While abuse relates to mood disorders (depression and anxiety) also common in IBS, the influence of abuse on gastrointestinal (GI) symptoms and health-related quality of life (HRQOL) and its independence from psychological symptom comorbidity has not been studied., Methods: Consecutive GI outpatients completed the ROME III Research Diagnostic Questionnaire and questionnaires on trauma (Life-Stress Questionnaire), mood (Beck Depression/Anxiety Inventories), somatic symptoms (PHQ-12), and HRQOL (SF-36). Current GI symptom severity and bother were assessed using 10-cm Visual Analog Scales., Key Results: 272 ROME-defined IBS (47.6 ± 0.9 years, 81% female) and 246 non-FGID (51.6 ± 1.0 years, 65% female) subjects participated. IBS patients reported greater rates of physical, sexual, and emotional abuse (p < 0.006 each), and higher depression, anxiety, and somatic symptoms (p < 0.001). Greater bowel symptom bother (7.4 ± 0.2 vs 6.7 ± 0.2, p = 0.040), severity (7.7 ± 0.2 vs 6.5 ± 0.2, p < 0.001), recent symptomatic days (9.8 ± 0.4 vs 8.5 ± 0.3, p = 0.02), and poorer HRQOL (40.9 ± 2.3 vs 55.5 ± 1.7, p < 0.001) were noted in IBS with abuse. Abuse effects were additive, with greater IBS symptom severity and poorer HRQOL noted in cases with multiple forms of abuse. Mediation analyses suggested that abuse effects on GI symptoms and HRQOL were partially mediated by mood., Conclusions & Inferences: Abuse experiences common among IBS sufferers are associated with reports of greater GI symptoms and poorer HRQOL, particularly in those with multiple forms of abuse; this relationship may be partially mediated by concomitant mood disturbances., (© 2016 John Wiley & Sons Ltd.)

Background: Positive symptom association probability (SAP) with physiologic esophageal acid exposure time (AET) on pH-impedance monitoring defines reflux hypersensitivity (RH), a correlate of acid sensitivity on pH monitoring. We evaluated prevalence, clinical characteristics, and symptomatic outcomes of RH in a prospective observational cohort with reflux symptoms undergoing pH-impedance monitoring., Methods: Reflux hypersensitivity was diagnosed when SAP was positive with pH- and/or impedance-detected reflux events with physiologic AET. Symptom burden was assessed using dominant symptom intensity (DSI, product of symptom severity and frequency on 5-point Likert scales) and global symptom severity (GSS, global esophageal symptoms on 100-mm visual analog scales) by questionnaire, both at baseline and on prospective follow-up. Clinical characteristics and predictors of symptomatic improvement were assessed with univariate and multivariate analyses., Key Results: Seventy-seven patients (29%) met criteria for RH, of which 53 patients (53.7 ± 1.8 years, 66% F) were contacted after 3.3 ± 0.2 years for follow-up. Reflux hypersensitivity was detected on pH-impedance testing both on and off antisecretory therapy; pH alone missed 51% of RH. About 57% reported ≥50% GSS improvement. Sixteen patients undergoing antireflux surgery (ARS) reported better symptom improvement compared to 37 patients treated medically (GSS change: p = 0.005; DSI change: p = 0.04). Hiatus hernia (p = 0.03) and surgical management (p ≤ 0.04) predicted symptom improvement on univariate analysis, while acid sensitivity was a negative predictor for outcome on both univariate (p = 0.02) and multivariate analyses (p ≤ 0.04)., Conclusions & Inferences: Reflux hypersensitivity is a mechanism for persistent reflux symptoms in almost one-third of patients undergoing pH-impedance testing. While acid sensitivity predicts suboptimal symptom improvement, antireflux therapy may improve RH in select settings., (© 2016 John Wiley & Sons Ltd.)

Background: Sleep disturbances are common, and perhaps are even more prevalent in irritable bowel syndrome (IBS)., Aims: To determine the effect of measured sleep on IBS symptoms the following day, IBS-specific quality of life (IBS-QOL) and non-GI pain symptoms., Methods: IBS patients' sleep patterns were compared to healthy individuals via wrist-mounted actigraphy over 7 days. Daily bowel pain logs (severity, distress; 10-point Likert) stool pattern (Bristol scale) and supporting symptoms (e.g. bloating, urgency; 5-point Likert) were kept. Validated measures, including the GI Symptom Rating Scale-IBS, Visceral Sensitivity Index, Pittsburgh Sleep Quality Index and the IBS-Quality of Life were collected. Mediation analysis explored the relationship between sleep, mood and bowel symptoms., Results: Fifty subjects (38.6 ± 1.0 years old, 44 female; 24 IBS and 26 healthy controls) completed sleep monitoring. IBS patients slept more hours per day (7.7 ± 0.2 vs. 7.1 ± 0.1, P = 0.008), but felt less well-rested. IBS patients demonstrated more waking episodes during sleep (waking episodes; 12.1 vs. 9.3, P < 0.001). Waking episodes predicted worse abdominal pain (P ≤ 0.01) and GI distress (P < 0.001), but not bowel pattern or accessory IBS symptoms (P > 0.3 for each). Waking episodes negatively correlated with general- and IBS-specific QOL in IBS (r = -0.58 and -0.52, P < 0.001 for each). Disturbed sleep effects on abdominal pain were partially explained by mood as an intermediate., Conclusions: Sleep disturbances are more common in irritable bowel syndrome, and correlate with IBS-related pain, distress and poorer irritable bowel syndrome-related quality of life. Disturbed sleep effects extend beyond the bowel, leading to worse mood and greater somatic pain in patients with the irritable bowel syndrome., Competing Interests: None of the authors have any conflicts of interest to report. No writing assistance was obtained., (© 2016 John Wiley & Sons Ltd.)

Background: Combinations of reflux parameters (acid exposure time, AET; symptom association probability, SAP) on pH-impedance monitoring describe varying confidence in reflux evidence. We compared outcomes between phenotypes with distinct pre-identified reflux parameters., Methods: In this observational cohort study, patients undergoing pH-impedance testing over a 5-year period were phenotyped by strength of reflux evidence as strong (abnormal AET, positive SAP), good (abnormal AET, negative SAP), reflux hypersensitivity (RH, normal AET, positive SAP), and equivocal evidence of reflux, and compared to two historical institutional pH monitoring cohorts. Symptom burden (dominant symptom intensity, DSI; global symptom severity, GSS) was assessed by questionnaire at baseline and on prospective follow-up and compared between phenotypes., Key Results: Of 94 patients tested off proton pump inhibitor (PPI) therapy, baseline symptom burden was highest with strong reflux evidence and lowest when equivocal (DSI: p = 0.01; GSS: p = 0.03 across groups). After 3.1 ± 0.2 years follow-up, symptomatic improvement with surgical or medical therapy was highest with strong or good evidence, and lowest when equivocal (DSI: p = 0.008; GSS: p = 0.005 across groups). This was most pronounced for typical symptoms (DSI: p = 0.001; GSS: 0.016 across groups), but not atypical symptoms (DSI: p = 0.6; GSS: p = 0.2). For testing on PPI therapy, only GSS followed a similar trend (GSS: p = 0.057, DSI: p = 0.3). Compared to historical cohorts with pH monitoring alone, equivocal evidence for reflux was partly replaced by RH, especially off PPI (p < 0.0001)., Conclusions & Inferences: Phenotyping gastroesophageal reflux disease by the strength of reflux evidence on pH-impedance testing off PPI efficiently stratifies symptomatic outcome, especially for typical symptoms, and could be useful in planning management., (© 2015 John Wiley & Sons Ltd.)

Background: Achalasia is classified into three HRM subtypes that predict outcomes from diverse management strategies. We assessed if symptomatic response varied when a single management strategy-Heller myotomy (HM)-is employed., Methods: Treatment-naive subjects with achalasia referred for HM were followed in this observational cohort study. Chicago criteria designated achalasia subtypes (subtype I: no esophageal pressurization; subtype II: panesophageal pressurization in ≥20 % swallows; subtype III: premature contractions in ≥20 % swallows). Symptom questionnaires assessed symptom burden before and after HM on five-point Likert scales (0 = no symptoms, 4 = severe symptoms) and on 10-cm visual analog scales (global symptom severity, GSS); satisfaction with HM was recorded similarly. Data were analyzed to determine predictors of GSS change across subtypes., Results: Sixty achalasia subjects (56.1 ± 2.4 years, 55 % female) fulfilled inclusion criteria, 15 % with subtype I, 58 % with subtype II, and 27 % with subtype III achalasia. Baseline symptoms included dysphagia (solids: 85 %, liquids: 73 %), regurgitation (84 %), and chest pain (35 %); mean GSS was 7.1 ± 0.3. Upon follow-up 2.1 ± 0.2 years after HM, GSS declined to 1.9 ± 0.4 (p < 0.001), with surgical satisfaction score of 8.7 ± 0.3 out of 10; these were similar across achalasia subtypes. On univariate analysis, female gender, Eckardt score, severity of transit symptoms, and maximal IRP predicted linear GSS improvement; female gender (p = 0.003) and dysphagia for liquids (p = 0.043) remained predictive on multivariate analysis., Conclusions: When a uniform surgical approach is utilized, symptomatic outcome and satisfaction with therapy are similar across achalasia subtypes. Female gender and severity of dysphagia for solids may predict better HM outcome.

Background: The calcium-sensing receptor (CaSR) is a calcium (Ca(2+)) sensitive G protein-coupled receptor implicated in various biological processes. In particular, it regulates Ca(2+)/Mg(2+)- homeostasis and senses interstitial Ca(2+) levels and thereby controls downstream signalling cascades. Due to its expression in the gut epithelium, the enteric nervous system and smooth muscles and its key function in regulation and coordination of muscular contraction and secretion, it represents an excellent candidate gene to be investigated in the pathophysiology of irritable bowel syndrome (IBS). Disturbed CaSR structure and function may impact gastrointestinal regulation of muscular contraction, neuronal excitation and secretion and consequently contribute to symptoms seen in IBS, such as disordered defecation as well as disturbed gut motility and visceral sensitivity., Methods: We have therefore genotyped the functional CASR SNP rs1801725 in three case control samples from the UK, Belgium and the USA., Results: Genotype frequencies showed no association in the three genotyped case-control samples, neither with IBS nor with IBS subtypes., Conclusions: Although we could not associate the SNP to any of the established bowel symptom based IBS subtypes we cannot rule out association to altered Ca(2+) levels and disturbed secretion and gut motility which were unfortunately not assessed in the patients genotyped. This underlines the necessity of a more detailed phenotyping of IBS patients and control individuals in future studies.

Objectives: Pharmacotherapy is a mainstay in functional gastrointestinal (GI) disorder (FGID) management, but little is known about patient attitudes toward medication regimens. Understanding patient concerns and adherence to pharmacotherapy is particularly important for off-label medication use (e.g., antidepressants) in FGID., Methods: Consecutive tertiary GI outpatients completed the Beliefs About Medications questionnaire (BMQ). Subjects were categorized as FGID and structural GI disease (SGID) using clinician diagnoses and Rome criteria; GI-specific medications and doses were recorded, and adherence to medication regimens was determined by patient self-report. BMQ domains (overuse, harm, necessity, and concern) were compared between FGID and SGID, with an interest in how these beliefs affected medication adherence. Psychiatric measures (depression, anxiety, and somatization) were assessed to gauge their influence on medication beliefs., Results: A total of 536 subjects (mean age 54.7±0.7 years, range 22-100 years; n=406, 75.7% female) were enrolled over a 5.5-year interval: 341 (63.6%) with FGID (IBS, 64.8%; functional dyspepsia, 51.0%, ≥2 FGIDs, 38.7%) and 142 (26.5%) with SGID (IBD, 28.9%; GERD, 23.2%). PPIs (n=231, 47.8%), tricyclic antidepressants (TCAs) (n=167, 34.6%), and anxiolytics (n=122, 25.3%) were common medications prescribed. FGID and SGID were similar across all BMQ domains (P>0.05 for overuse, harm, necessity, and concern). SGID subjects had higher necessity-concern framework (NCF) scores compared with FGID subjects (P=0.043). FGID medication adherence correlated negatively with concerns about medication harm (r=-0.24, P<0.001) and overuse (r=-0.15, P=0.001), whereas higher NCF differences predicted medication compliance (P=0.006). Medication concern and overuse scores correlated with psychiatric comorbidity among FGID subjects (P<0.03 for each). FGID patients prescribed TCAs (n=142, 41.6%) expressed a greater medication necessity (17.4±0.4 vs. 16.2±0.4, P=0.024) and found their GI regimen to be more helpful (P=0.054). FGID subjects not on TCAs expressed a greater apprehension about medication overuse (10.7±0.3 vs. 9.7±0.2, P=0.002) on the BMQ., Conclusions: FGID subjects report medication necessity and concern scores comparable to patients with SGID but have negative perceptions about medications, particularly in the presence of psychiatric comorbidity; these factors may affect treatment adherence and willingness to initiate neuromodulator regimens.

Background: Resect and discard is a new paradigm for management of diminutive polyps. It is unknown whether patients will embrace this new paradigm in which small polyps would not be sent for histopathologic review., Objective: To determine whether patients would be willing to pay for pathology costs with their own money and which factors influence patients' decisions to pay or not pay for pathology costs with their own money., Design: Single-center, prospective, survey study., Setting: Hospital outpatient endoscopy center., Patients: Adults undergoing colonoscopy for screening or routine polyp surveillance., Interventions: Patient survey., Main Outcome Measurements: Willingness to pay out-of-pocket for pathology costs when a diminutive polyp is found and factors that influence patients' decisions to pay or not pay for pathology costs with their own money., Results: A total of 500 participants completed the survey. A total of 360 respondents (71.9%) indicated a hypothetical willingness to pay out-of-pocket for histopathologic polyp analysis if this interpretation was not covered by insurance. Patient factors significantly associated with willingness to pay for polyp analysis included higher income and education and female sex., Limitations: Single center, hypothetical situation., Conclusion: Over two-thirds of patients were willing to pay to have their diminutive polyp sent for pathologic evaluation if their insurance carrier would not pay the cost. Factors associated with willingness to pay included higher income, higher education, and female sex. Patients who were unwilling to pay raised concerns about cost and are less concerned about cancer risk compared with those willing to pay. (, Clinical Trial Registration Number: NCT02305251.)., (Copyright © 2015 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Irritable bowel syndrome is the most common functional gastrointestinal disorder, manifesting as abdominal pain/discomfort and altered bowel function. Despite affecting as many as 20% of adults, a lack of understanding of etiopathogenesis and evaluation strategies results in diagnostic uncertainty, and in turn frustration of both the physician and the patient. This review summarizes the current literature on the diagnosis and management of irritable bowel syndrome, with attention to evidence-based approaches. A 4-step treatment strategy that has been used successfully in our tertiary referral practice is presented and should lead to successful therapeutic outcomes in the majority of patients with irritable bowel syndrome., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objectives: Enhanced characterization of esophageal peristaltic and sphincter function provided by esophageal pressure topography (EPT) offers a potential diagnostic advantage over conventional line tracings (CLT). However, high-resolution manometry (HRM) and EPT require increased equipment costs over conventional systems and evidence demonstrating a significant diagnostic advantage of EPT over CLT is limited. Our aim was to investigate whether the inter-rater agreement and/or accuracy of esophageal motility diagnosis differed between EPT and CLT., Methods: Forty previously completed patient HRM studies were selected for analysis using a customized software program developed to perform blinded independent interpretation in either EPT or CLT (six pressure sensors) format. Six experienced gastroenterologists with a clinical focus in esophageal disease (attendings) and six gastroenterology trainees with minimal manometry experience (fellows) from three academic centers interpreted each of the 40 studies using both EPT and CLT formats. Rater diagnoses were assessed for inter-rater agreement and diagnostic accuracy, both for exact diagnosis and for correct identification of a major esophageal motility disorder., Results: The total group agreement was moderate (κ=0.57; 95% CI: 0.56-0.59) for EPT and fair (κ=0.32; 0.30-0.33) for CLT. Inter-rater agreement between attendings was good (κ=0.68; 0.65-0.71) for EPT and moderate (κ=0.46; 0.43-0.50) for CLT. Inter-rater agreement between fellows was moderate (κ=0.48; 0.45-0.50) for EPT and poor to fair (κ=0.20; 0.17-0.24) for CLT. Among all raters, the odds of an incorrect exact esophageal motility diagnosis were 3.3 times higher with CLT assessment than with EPT (OR: 3.3; 95% CI: 2.4-4.5; P<0.0001), and the odds of incorrect identification of a major motility disorder were 3.4 times higher with CLT than with EPT (OR: 3.4; 2.4-5.0; P<0.0001)., Conclusions: Superior inter-rater agreement and diagnostic accuracy of esophageal motility diagnoses were demonstrated with analysis using EPT over CLT among our selected raters. On the basis of these findings, EPT may be the preferred assessment modality of esophageal motility.

Background: To date, genetic-association studies of single nucleotide polymorphisms (SNP) in selected candidate genes with the symptom phenotype of irritable bowel syndrome (IBS) have typically involved hundreds to 2000 patients. SNPs in immune-related genes, such as cytokine and cytokine receptor encoding genes, have been reported to associate with IBS risk., Methods: We conducted two independent case-control studies on 16 SNPs in IL1R1, IL4, IL6, IL8, IL10, IL23R, TNFA, and TNFSF15, one from the UK (194 patients and 92 healthy volunteers) and one from the USA (137 patients and 96 healthy volunteers). The main aim was to examine the relationship between inherited immunological diversity and IBS risk in a meta-analysis which included 12 additional, earlier studies. The meta-analysis comprised a total of 2894 patients (839 IBS-C, 1073 IBS-D, 502 IBS-M), and 3138 healthy volunteers with self-reported Caucasian ancestry., Key Results: The association of SNP rs4263839 (TNFSF15) was investigated in four studies and confirmed in the meta-analysis: IBS (OR 1.19, 95% CI 1.08-1.31), and IBS-C (OR 1.24, 95% CI 1.08-1.42). No additional SNPs residing in immunogenes associated with IBS symptom phenotypes., Conclusions & Inferences: Our meta-analysis could not confirm a major role of most investigated SNPs, but a moderate association between rs4263839 TNFSF15 and IBS, in particular IBS-C. The analysis emphasizes the importance of definition and phenotype homogeneity, adequate study size and representativeness of the patient and control collective., (© 2015 John Wiley & Sons Ltd.)

Background & Aims: pH-impedance monitoring detects acid and nonacid reflux events, but little is known about which parameters predict outcomes of different management strategies. We evaluated a cohort of medically and surgically managed patients after pH-impedance monitoring to identify factors that predict symptom improvement after therapy., Methods: In a prospective study, we followed up 187 subjects undergoing pH-impedance testing from January 2005 through August 2010 at Washington University in St. Louis, Missouri (mean age, 53.8 ± 0.9 y; 70.6% female). Symptom questionnaires assessed dominant symptom intensity (DSI) and global symptom severity (GSS) at baseline and at follow-up evaluation. Data collected from pH impedance studies included acid exposure time (AET), reflux exposure time (RET) (duration of impedance decrease 5 cm above lower esophageal sphincter, reported as the percentage of time similar to AET), symptom reflux correlation (symptom index and symptom association probability [SAP]), and the total number of reflux events. Univariate and multivariate analyses were performed to determine factors associated with changes in DSI and GSS after therapy., Results: Of the study subjects, 49.7% were tested on proton pump inhibitor (PPI) therapy and 68.4% were managed medically. After 39.9 ± 1.3 months of follow-up, DSI and GSS scores decreased significantly (P < .05). On univariate analysis, an abnormal AET predicted decreased DSI and GSS scores (P ≤ .049 for each comparison); RET and SAP from impedance-detected reflux events (P ≤ .03) also were predictive. On multivariate analysis, abnormal AET consistently predicted symptomatic outcome; other predictors included impedance-detected SAP, older age, and testing performed off PPI therapy. Abnormal RET, acid symptom index, or SAP, and numbers of reflux events did not independently predict a decrease in DSI or GSS scores., Conclusions: Performing pH-impedance monitoring off PPI therapy best predicts response to antireflux therapy. Key parameters with predictive value include increased AET, and correlation between symptoms and reflux events detected by impedance., (Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Objectives: Although screening colonoscopy is effective in preventing distal colon cancers, effectiveness in preventing right-sided colon cancers is less clear. Previous studies have reported that retroflexion in the right colon improves adenoma detection. We aimed to determine whether a second withdrawal from the right colon in retroflexion vs. forward view alone leads to the detection of additional adenomas., Methods: Patients undergoing screening or surveillance colonoscopy were invited to participate in a parallel, randomized, controlled trial at two centers. After cecal intubation, the colonoscope was withdrawn to the hepatic flexure, all visualized polyps removed, and endoscopist confidence recorded on a 5-point Likert scale. Patients were randomized to a second exam of the proximal colon in forward (FV) or retroflexion view (RV), and adenoma detection rates (ADRs) compared. Logistic regression analysis was used to evaluate predictors of identifying adenomas on the second withdrawal from the proximal colon., Results: A total of 850 patients (mean age 59.1±8.3 years, 59% female) were randomly assigned to FV (N=400) or RV (N=450). Retroflexion was successful in 93.5%. The ADR (46% FV and 47% RV) and numbers of adenomas per patient (0.9±1.4 FV and 1.1±2.1 RV) were similar (P=0.75 for both). At least one additional adenoma was detected on second withdrawal in similar proportions (10.5% FV and 7.5% RV, P=0.13). Predictors of identifying adenomas on the second withdrawal included older age (odds ratio (OR)=1.04, 95% confidence interval (CI)=1.01-1.08), adenomas seen on initial withdrawal (OR=2.8, 95% CI=1.7-4.7), and low endoscopist confidence in quality of first examination of the right colon (OR=4.8, 95% CI=1.9-12.1). There were no adverse events., Conclusions: Retroflexion in the right colon can be safely achieved in the majority of patients undergoing colonoscopy for colorectal cancer screening. Reexamination of the right colon in either retroflexed or forward view yielded similar, incremental ADRs. A second exam of the right colon should be strongly considered in patients who have adenomas discovered in the right colon, particularly when endoscopist confidence in the quality of initial examination is low.

Background: "Resect and discard" (RD) is a new paradigm for management of diminutive polyps., Aim: To compare concordance of surveillance interval recommendations and diagnostic performance between RD and standard of care in a hospital outpatient department with both academic and community gastroenterologists., Methods: Prospective, observational study conducted at a single outpatient endoscopy center over 12 months. Patients with diminutive polyps on screening or surveillance colonoscopy were included. Histology predictions for all diminutive polyps (≤5 mm) were made based on endoscopic imaging. Concordance of recommended surveillance intervals and diagnostic performance of histology predictions were compared to histopathological review., Results: A total of 606 diminutive polyps were found in 315 patients (mean age 62.4 years, 49 % female). Histological prediction was made in 95.7 % of polyps (97.4 % of patients), with high confidence in 74.3 %. The concordance for surveillance intervals was 82.1 % compared to histopathological review and was similar between community and academic gastroenterologists (80.2 vs. 76.3 %, p = 0.38). Overall, sensitivity, specificity, and accuracy of histological predictions made with high confidence were 0.81, 0.36, and 77.1 %. Predictions made with narrow-band imaging (NBI) had lower accuracy (73.9 % with NBI vs. 82.5 % with high-definition white light (HWDL) only, p = 0.017) as well as lower prediction confidence (score of 7.6 with NBI vs. 8.6 with HDWL only, p < 0.001)., Conclusions: Our surveillance interval concordance was below the 90 % threshold deemed acceptable by the ASGE Preservation and Incorporation of Valuable Endoscopic Innovations statement. Diagnostic performance using optical imaging to predict histology was equal between community and academic endoscopists.

Background: Crohn's disease (CD) is a chronic inflammatory disease of the gastrointestinal tract. Genetic polymorphisms can confer CD risk and influence disease phenotype. Indoleamine 2,3 dioxygenase-1 (IDO1) is one of the most over-expressed genes in CD and mediates potent anti-inflammatory effects via tryptophan metabolism along the kynurenine pathway. We aimed to determine whether non-synonymous polymorphisms in IDO1 or IDO2 (a gene paralog) are important either as CD risk alleles or as modifiers of CD phenotype., Methods: Utilizing a prospectively collected database, clinically phenotyped CD patients (n = 734) and non-IBD controls (n = 354) were genotyped for established IDO1 and IDO2 non-synonymous single nucleotide polymorphisms (SNPs) and novel genetic variants elucidated in the literature. Allelic frequencies between CD and non-IBD controls were compared. Genotype-phenotype analysis was conducted. IDO1 enzyme activity was assessed by calculating the serum kynurenine to tryptophan ratio (K/T)., Results: IDO1 SNPs were rare (1.7% non-IBD vs 1.1% CD; p = NS) and not linked to Crohn's disease diagnosis in this population. IDO1 SNPs did however associate with a severe clinical course, presence of perianal disease, extraintestinal manifestations and a reduced serum K/T ratio during active disease suggesting lower IDO1 function. IDO2 minor allele variants were common and one of them, rs45003083, associated with reduced risk of Crohn's disease (p = 0.025). No IDO2 SNPs associated with a particular Crohn's disease clinical phenotype., Conclusions: This work highlights the functional importance of IDO enzymes in human Crohn's disease and establishes relative rates of IDO genetic variants in a US population.

Background: Functional gastrointestinal disorders (FGID) patients report poor health-related quality of life (HRQOL) and experience high rates of psychiatric and extraintestinal functional disorder (EIFD) comorbidity. The independent influence of these comorbidities on HRQOL and symptom burden remains unknown. We sought to determine whether FGID with mood or EIFD comorbidity have poorer HRQOL and greater GI symptom burdens; to determine the influence of comorbidities on HRQOL in FGID independent of bowel symptoms., Methods: Subjects reported on comorbidities (anxiety, depression, somatization, EIFD), FGID criteria (irritable bowel syndrome, IBS; functional dyspepsia, FD) using ROME III Research questionnaire, GI symptom burden, and HRQOL. Differences in measures were assessed between subjects with and without ROME III criteria. Multiple regression determined the relative contribution of comorbidities to HRQOL, and mediation analysis explored whether comorbidity influences HRQOL., Key Results: In a cohort of 912 GI outpatients (47.2 ± 1.5 years, 75.8% female), 606 (66.4%) met Rome III IBS and/or FD criteria. Comorbidities were common in FGID (≥1 in 77.4%), leading to lower HRQOL and greater GI symptom burden (each p < 0.05). Poorer HRQOL was predicted by both psychiatric and EIFD comorbidity (each p < 0.05) independent of GI symptoms (p < 0.001). Comorbidities together exerted a greater effect on predicted variation in HRQOL (70.9%) relative to GI symptoms (26.5%)., Conclusions & Inferences: Psychiatric and EIFD comorbidities are common in FGID, decrease HRQOL and are associated with greater GI symptom burdens; these factors were stronger predictors of HRQOL than GI symptoms in FGID patients., (© 2014 John Wiley & Sons Ltd.)

Objectives: pH-impedance testing detects reflux events irrespective of pH, but its value in predicting treatment outcome is unclear. We prospectively evaluated subjects treated medically after pH-impedance testing to determine predictors of symptom improvement., Methods: Subjects referred for pH-impedance testing completed questionnaires in which dominant symptoms and global symptom severity (GSS) were recorded. Acid-reflux parameters (acid-exposure time, AET; symptom association by Ghillebert probability estimate, GPE; symptom index, SI) and impedance reflux parameters (reflux-exposure time, RET; number of reflux events; GPE and SI with impedance data) were extracted. Symptoms and GSS were prospectively reevaluated after medical therapy. Univariate and multivariate analyses determined predictors of GSS improvement following medical management., Results: Over 5 years, 128 subjects (mean 53.3±1.3 years, 66.4% female; typical symptoms 57.0%, 53.9% tested on therapy) underwent pH-impedance testing and subsequent medical therapy for reflux symptoms, and completed required questionnaires. On follow-up 3.35±0.14 years later, mean GSS declined by 45.0%, with 42.2% patients reporting ≥50% GSS improvement. On univariate analysis, total AET, AET≥4.0%, and GPE for all reflux events predicted both linear and ≥50% GSS improvement, but RET and number of reflux events did not. On multivariate analysis, controlling for testing on or off therapy, only AET (P=0.003) and GPE for all reflux events (P=0.029) predicted GSS improvement., Conclusions: Acid-based reflux parameters offer greater value over impedance-based nonacid-reflux parameters in predicting symptomatic responses to proton pump inhibitor (PPI) therapy. Our findings support conducting pH-impedance studies off PPI therapy to maximize clinical utility in predicting outcome.

Background: Tricyclic antidepressants (TCAs) have efficacy in treating irritable bowel syndrome (IBS). Some clinicians use TCAs to treat residual symptoms in inflammatory bowel disease (IBD) patients already on decisive IBD therapy or with quiescent inflammation, although this strategy has not been formally studied., Goals: The aim of this study was to examine the efficacy of TCA therapy in IBD patients with residual symptoms, despite controlled inflammation, in a retrospective cohort study., Study: Inclusion required initiation of TCA for persistent gastrointestinal symptoms. IBD patients had inactive or mildly active disease with persistent symptoms despite adequate IBD therapy as determined by their physician. Symptom response was compared with IBS patients. Established Likert scales were used to score baseline symptom severity (0=no symptoms, 3=severe symptoms) and TCA response (0=no improvement; 3=complete satisfaction)., Results: Eighty-one IBD [41.3±1.7 y, 56F; 58 Crohn's disease/23 ulcerative colitis (UC)] and 77 IBS (46.2±1.7 y, 60F) patients were initiated on a TCA therapy. Baseline symptom scores (IBD, 2.06±0.03; IBS, 2.12±0.04; P=0.15) and symptom response to TCA therapy (IBD, 1.46±0.09; IBS, 1.30±0.09; P=0.2) were similar in both the groups. At least moderate improvement (Likert score ≥2) on TCA was achieved by comparable proportions of patients (59.3% IBD vs. 46% IBS; P=0.09). Within IBD, response was better with UC than Crohn's disease (1.86±0.13 vs. 1.26±0.11, respectively, P=0.003)., Conclusions: In a clinical practice setting, TCA use led to moderate improvement of residual gastrointestinal symptoms in IBD patients for whom escalation of IBD therapy was not planned. UC patients demonstrated higher therapeutic success. IBD symptom responses were similar to IBS patients.

Background: While it is established that cirrhosis results in a decrease in liver volume (LV), whether LV itself predicts patient survival is unknown. We hypothesize that estimated LV is an important prognostic indicator in patients with cirrhosis., Methods: Data was gathered retrospectively from consecutive patients evaluated for a liver transplant from January 2001 to June 2006. Of 500 patients identified, 323 patients met both inclusion and exclusion criteria. LV per ideal body weight (IBW) was used to correct for body size, and LV/IBW was stratified by median split for survival analyses. Patients were classified into one of three clinical groups: hepatocellular disease (n = 229), cholestatic disease (n = 56), and miscellaneous (n = 38). One of three possible clinical outcomes (survival, liver transplantation, or death) was recorded during the 5-year follow-up, the latter two grouped together as "transplant/death.", Results: Transplant/death occurred in 283 (88 %) subjects. Overall, there was a significant increase in transplant/death in those with lower LV/IBW (χ(2) = 5.27, p = 0.022). When considering the subset with hepatocellular disease, lower LV/IBW was a robust predictor of transplant/death (χ(2) = 9.62, p = 0.002). In multivariate analyses, the LV/IBW trended toward predicting transplant/death (ExpB = 0.943, p = 0.053) independent of Model for End stage Liver Disease (MELD) (ExpB = 1.13, p = 0.001)., Discussion: LV has important predictive value in patients with cirrhosis from hepatocellular disease. This observation appears to be independent of MELD, suggesting LV may impart important prognostic information that is not captured by the MELD score alone. Thus, LV may serve as an important adjunct to the MELD score in patients with hepatocellular disease.

Background: Suboptimal colon preparation is a significant barrier to quality colonoscopy. The impact of pharmacologic agents associated with gastrointestinal dysmotility on quality of colon preparation has not been well characterized., Aims: Evaluate impact of opiate pain medication and psychoactive medications on colon preparation quality in outpatients undergoing colonoscopy., Methods: Outpatients undergoing colonoscopy at a single medical centre during a 6-month period were retrospectively identified. Demographics, clinical characteristics and pharmacy records were extracted from electronic medical records. Colon preparation adequacy was evaluated using a validated composite colon preparation score., Results: 2600 patients (57.3 ± 12.9 years, 57% female) met the inclusion and exclusion criteria. 223 (8.6%) patients were regularly using opioids, 92 antipsychotics, 83 tricyclic antidepressants and 421 non-tricyclic antidepressants. Opioid use was associated with inadequate colon preparation both with low dose (OR = 1.4, 95%CI 1.0-2.1, p = 0.05) and high dose opioid users (OR = 1.7, 95%CI 1.1-2.9, p = 0.039) in a dose dependent manner. Other significant predictors of inadequate colon preparation included use of tricyclics (OR = 1.9, 95%CI 1.1-3.0, p = 0.012), non-tricyclic antidepressants (OR = 1.5, 95%CI 1.1-2.0, p = 0.013), and antipsychotic medications (OR = 2.2, 95%CI 1.4-3.4, p = 0.001)., Conclusions: Opiate pain medication use independently predicts inadequate quality colon preparation in a dose dependent fashion; furthermore psychoactive medications have even more prominent effects and further potentiates the negative impact of opiates with concurrent use., (Copyright © 2013 Editrice Gastroenterologica Italiana S.r.l. All rights reserved.)

Objectives: Alterations in 5-hydroxytryptamine (5-HT) signaling have been implicated as a factor contributing to the altered bowel habit of irritable bowel syndrome (IBS) patients. Tryptophan hydroxylase 1 (TPH1) is the rate-limiting enzyme in enterochromaffin cell 5-HT biosynthesis. We hypothesized that genetic variants affecting TPH1 gene expression might alter intestinal 5-HT bioavailability and subsequently the propensity for distinct bowel habit subtypes in IBS. In this study, we assessed the only common TPH1 proximal promoter variant (-347C/A; rs7130929) and its association with bowel habit predominance in IBS., Methods: Electrophoretic mobility shift assays were performed to assess whether the -347C/A-allele variant affects the DNA binding of nuclear factors. Genotype distribution was determined for 422 IBS patients subtyped using the Rome III criteria and for 495 healthy controls recruited from two university medical centers. Association with bowel habit was tested using a multinomial logistic regression model controlling for race, anxiety, depression, and study site., Results: Early growth response factor 1 (EGR-1) bound with higher affinity to a site comprising the minor A-allele of single-nucleotide polymorphism (SNP) -347C/A. TPH1 genotype frequencies did not differ between IBS patients and controls overall. The CC genotype was more prevalent in the IBS-D subtype (47%) than in the IBS-C (25%) and IBS-M (37%) subtypes (P=0.039) after adjusting for race and other covariates. Colonic biopsies from a small cohort of IBS patients from one center were tested for higher TPH1 mRNA expression in samples with CC compared with the CA genotype, but the results did not reach statistical significance., Conclusions: The TPH1 promoter SNP -347C/A differentially binds EGR-1 and correlates with IBS bowel habit subtypes and possibly colonic TPH1 expression consistent with its role in modulating intestinal 5-HT signaling.

Background: The beta-2 adrenergic receptor (ADRB2) is an important target for epinephrine, a neurotransmitter in pain signalling. ADRB2 haplotypes affect receptor expression and ligand response, and have been linked to painful non-GI disorders., Aims: To assess whether ADRB2 polymorphisms (rs1042713, rs1042714) are risk alleles for functional GI (FGID) and extraintestinal functional (EIFD) diagnoses, and whether ADRB2 predicts GI symptoms and health-related quality of life (HRQOL)., Methods: Of 398 subjects (49.6 ± 2.9 years, 68.0% female), 170 (42.5%) met Rome III criteria for ≥1 FGID [IBS (n = 139, 34.9%); functional dyspepsia (FD, n = 136, 34.1%), functional chest pain (FCP, n = 25, 6.2%)], while 228 were healthy controls. FGID subjects reported on bowel symptom severity and burden (10-cm VAS), frequency (days/last 2 weeks), EIFD, psychiatric diagnoses and HRQOL (SF 36). Multivariable models determined the contribution of ADRB2 polymorphisms to HRQOL, and mediational analyses assessed functional diagnoses as potential intermediates., Results: rs1042714 minor G alleles were associated with FGID diagnoses (OR 1.8; 95% CI 1.2-2.7; P = 0.009), particularly FD (OR 2.1, 95% CI 1.3-3.3), with trends towards IBS (P = 0.19) and FCP (P = 0.06) diagnoses. Within IBS, G allele carriers had more severe bowel symptoms (P = 0.025), and symptomatic days (P = 0.009). G allele carriers had greater numbers of EIFD (1.0 ± 0.1 vs. 0.4 ± 0.07, P < 0.001) and poorer HRQOL. The effect of ADRB2 on HRQOL was partially mediated by FGID, EIFD and psychiatric diagnoses., Conclusions: ADRB2 minor alleles at rs1042714 predict FGID and EIFD, and may influence bowel symptom severity and HRQOL. These findings provide indirect evidence of sympathetic nervous system role in FGID pathophysiology., (© 2013 John Wiley & Sons Ltd.)

Background: Tricyclic antidepressants (TCAs) are known to benefit subjects with functional nausea and vomiting (FNV), but it is not known if alternate neuromodulators are also beneficial. We retrospectively evaluated outcomes and clinical predictors of response in FNV subjects treated with any neuromodulator, including TCAs., Methods: We identified 94 subjects (43.8±1.4 year, 79 F) with FNV (Rome III criteria) over a 12 year period, treated with neuromodulators and followed up for 8.5±1.1 months. Clinical presentation, demographics and gastric emptying study (GES) findings (when available) were extracted. Likert scales determined symptom severity at baseline and symptom response or remission at follow-up. Outcomes and predictors of response were evaluated using univariate and multivariate analyses., Results: At least moderate symptom improvement was reported by 72.3%, and 22.3% had symptom remission. Proportions achieving moderate improvement and remission, and mean outcome Likert scores were similar regardless of neuromodulator agent used or GES status. On univariate and multivariate logistic regression analysis, baseline symptom severity affected symptom response, and pain negatively impacted symptom remission to treatment (p≤0.04 for each); GES status failed to predict treatment response or remission., Conclusions: Symptom improvement with neuromodulators may be seen in over two-thirds of subjects with FNV regardless of the specific agent administered. Response may be suboptimal in pain predominant presentations.

Background and Objectives: Clinics licensed to provide pharmacotherapy for opiate dependence disorder are required to perform random urine drug screen (RUDS) tests. The results provide the empirical basis of individual treatment and programmatic effectiveness, and public health policy. Patients consent to witnessed testing but most tests are unwitnessed. The purpose of the present study was to compare treatment effectiveness estimates derived from witnessed versus unwitnessed urine samples., Methods: We adopted a policy requiring visually witnessed urine drug screens (WUDS) and studied its impact (a single group, pretest-posttest design) on the RUDS test results in 115 male veterans enrolled in the St. Louis VA Opioid Treatment Program., Results: The percentage of opioid-positive urine samples increased significantly following implementation of WUDS (25% vs. 41%, χ(2) = 66.5, p < .001)., Conclusions and Scientific Significance: Results of this preliminary study suggest that random testing alone does not ensure the integrity of UDS testing. Outcome calculations based on random unwitnessed tests may overestimate the effectiveness of opioid dependence disorder treatment., (Copyright © American Academy of Addiction Psychiatry.)

Background: Multiple rapid swallows (MRS) inhibit esophageal peristalsis and lower esophageal sphincter (LES) tone; a rebound excitatory response then results in an exaggerated peristaltic sequence. Multiple rapid swallows responses are dependent on intact inhibitory and excitatory neural function and could vary by subtype in achalasia spectrum disorders., Methods: Consecutive subjects with incomplete LES relaxation on high-resolution manometry (HRM) (Sierra Scientific, Los Angeles, CA, USA) in the absence of mechanical obstruction were prospectively identified. Achalasia spectrum disorders were classified and HRM plots reviewed according to Chicago criteria. Esophageal peristaltic performance and LES function were assessed after 10 wet swallows and MRS (five 2 mL water swallows 2-3 s apart). Findings were compared with 18 healthy controls (28.5 ± 0.6 years, 44% women)., Key Results: A total of 46 subjects (57.1 ± 2.1 years, 52.2% women) met inclusion criteria. There was complete failure of peristalsis with MRS in all subjects with achalasia subtypes 1 and 2. In contrast, 80% of achalasia subtype 3 and incomplete LES relaxation (EGJ outflow obstruction) with preserved esophageal body peristalsis had a contractile response to MRS (P < 0.001 compared with subtypes 1 and 2); controls demonstrated 94.4% peristalsis. Percent decrease in LES residual pressure during MRS (compared to wet swallows) segregated achalasia subtypes; those with aperistalsis (subtypes 1 and 2) had a lesser decline (22.6%) compared to those with retained esophageal body peristalsis (40.5%) and controls (51.3%, P < 0.001 across groups)., Conclusions & Inferences: Multiple rapid swallow responses segregate achalasia spectrum disorders into two patterns differentiated by presence or absence of esophageal body contraction response to wet swallows. These findings support subtyping of achalasia, with pathophysiologic implications., (© 2012 Blackwell Publishing Ltd.)

Purpose: Somatization disorder has been described in several comorbid functional syndromes of urological chronic pelvic pain syndrome, such as irritable bowel syndrome. We investigated whether a subset of patients with urological chronic pelvic pain syndrome may have the polysymptomatic, polysyndromic presentation pattern that is common in somatization disorder., Materials and Methods: A total of 70 male and female patients with urological chronic pelvic pain syndrome and 35 age matched controls without the syndrome completed a 59-item symptom checklist to assess the classic polysymptomatic, polysyndromic symptom pattern. The 2 operational tools used were the Perley-Guze derived symptom checklist and the somatic symptom algorithm used for Diagnostic and Statistical Manual, 4th Edition, Text Revision somatization disorder criteria., Results: Female patients with urological chronic pelvic pain syndrome (interstitial cystitis/bladder pain syndrome) reported significantly more nonpain symptoms and pain symptoms outside the pelvis than control female urology patients (p=0.0016 and 0.0018, respectively). Female patients with urological chronic pelvic pain syndrome were more likely to endorse a polysymptomatic, polysyndromic symptom pattern than female controls (27% vs 0%, p=0.0071). In contrast, male patients with urological chronic pelvic pain syndrome (interstitial cystitis/bladder pain syndrome and/or chronic prostatitis/chronic pelvic pain syndrome) did not report more extrapelvic pain than male controls (p=0.89). Male patients with urological chronic pelvic pain syndrome were not more likely than male controls to have a polysymptomatic, polysyndromic symptom pattern., Conclusions: A subset of female patients with urological chronic pelvic pain syndrome endorses numerous extrapelvic symptoms across multiple organ systems. The checklist may be valuable to assess patients for this polysymptomatic, polysyndromic symptom pattern, which is common in somatization disorder. Recognizing this polysymptomatic, polysyndromic presentation will prompt clinicians to investigate further to determine whether somatization disorder may be an underlying diagnosis in a small subset of patients with urological chronic pelvic pain syndrome who complain of numerous extrapelvic symptoms., (Copyright © 2012 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Background: High resolution manometry (HRM) provides a colourful representation of oesophageal motility. Novice and intermediate learners were tested to compare HRM Clouse plots and conventional manometry for accuracy, ease of interpretation and knowledge retention., Methods: 36 learners evaluated 60 randomised motility sequences (30 HRM Clouse plots with corresponding line tracings) 4 months apart, following a tutorial. Learners rated prior knowledge of oesophageal pathophysiology and manometry and scored ease and speed of interpretation on 10 cm visual analogue scales (VAS)., Results: Understanding of oesophageal pathophysiology was low in all cohorts (2.9±0.4 on VAS) and knowledge of HRM and conventional motility studies was even lower (1.9±0.4 and 1.8±0.3, respectively, p=NS). After the tutorial, diagnostic accuracy was significantly higher with HRM Clouse plots than with line tracings (p<0.001). HRM gains in diagnostic accuracy were evident over line tracings (43.1%), particularly with aperistalsis (36.1%), oesophageal body hypomotility (25.8%) and relaxation of the lower oesophageal sphincter (21.0%) (p<0.001 for each comparison); these were maintained at the second evaluation. Gains were independent of academic level (F=0.56, p=0.5) and did not correlate with prior experience of learners (r=-0.18, p=0.29). Learners favoured HRM Clouse plots (80.6%) over line tracings and reported faster interpretation (94.4%)., Conclusions: HRM Clouse plots provide ease of interpretation that translates into higher diagnostic accuracy and better knowledge retention in novice and intermediate learners of oesophageal manometry. These results implicate the value of pattern recognition in HRM interpretation, irrespective of academic level and prior understanding of oesophageal motor function.

Background: Both simple proportions and statistical tests are utilised for symptom-reflux association. We systematically compared three such tests in a clinical setting., Aim: To compare the three commonly used symptom reflux association tests in a large cohort of patients undergoing ambulatory pH monitoring for the evaluation of oesophageal symptoms., Methods: Ambulatory pH data from 772 symptomatic subjects (49.1 ± 0.5 years; 479 F) tested off therapy were assessed for acid exposure time (AET, elevated when pH <4 for ≥4%), symptom index (SI, ≥50% when positive), and symptom association probability (SAP) and Ghillebert probability estimate (GPE, P < 0.05 when positive). Test concordance and discordance were individually assessed; discordance between statistical tests was minor if one had P < 0.1 while the other was positive. Logistic regression determined independent predictors of test discordance., Results: The SAP, GPE and SI were positive in 42.7%, 39.3% and 33.9% respectively. GPE performed extremely well compared to SAP (sensitivity 0.95, specificity 0.91), with major discordance in only 2.8%. Positive concordance was significantly higher when AET was abnormal. GPE underestimated symptom association compared to SAP, whereas SAP was subject to symptom over-counting in 33.3% of discordant cases. GPE-SAP discordance was associated with higher AET (7.5% vs. 5.1%) and more symptoms (19.3 vs. 10.7, P > 0.001 for each comparison with concordant tests); both remained significant on logistic regression analysis (P ≤ 0.003). SI was discordant with SAP when symptoms were extremely frequent (median 19, IQR 10-32) or limited (median 1, IQR 1-2), and concordant when median 6 symptoms (IQR 3-12) were recorded., Conclusions: The GPE can be used interchangeably with SAP in symptom reflux association. SI has uncertain value with very high and very low symptom counts., (© 2012 Blackwell Publishing Ltd.)

Background: Conventional catheter-based and wireless pH monitoring continue to be widely used for the evaluation of GERD symptoms despite the emergence of pH-impedance monitoring., Goals: We sought to identify patient- and test-related factors predicting objective GERD parameters on catheter-based and wireless pH monitoring., Study: Ambulatory pH studies in 2,067 subjects (50.4 ± 0.3 years, 66.3% female) were assessed for presenting symptoms, antireflux therapy status, test characteristics, distal esophageal total acid exposure time (AET), symptom index (SI), and symptom-reflux association (Ghillebert probability estimate, GPE). Univariate and multivariate logistic regression analyses were performed to identify predictors of GERD evidence, both off and on antireflux therapy., Results: Catheter-based pH monitoring was performed in 77.6%, and 90.1% of the studies were performed off antireflux therapy. The likelihood of finding GERD evidence was significantly higher off therapy (65.8 vs. 21.4% on therapy, p < 0.0001); this held true for both strong GERD evidence (elevated AET and positive GPE) and elevated AET alone. The SI did not complement AET and GPE. Extended pH recording with the wireless technique consistently increased diagnostic yield. On multivariate logistic regression, the status of antireflux therapy and frequency of symptoms dictated finding of GERD evidence, and yields were highest for perceptive symptoms (heartburn, chest pain, and cough)., Conclusions: Ambulatory pH testing off antireflux therapy improves detection of all degrees of GERD evidence. pH testing provides highest yields with frequent perceptive symptoms and least with isolated regurgitation and ENT symptoms. Extending pH-recording with wireless monitoring uniformly augments yield.

Objective: Major depressive disorder (MDD) and type 2 diabetes have independent adverse effects on sexual functioning (SF). Bupropion (BU) reportedly has few sexual side effects, but its use in diabetes has not been studied., Research Design and Methods: This article reports a planned secondary analysis of SF in 90 patients with type 2 diabetes treated with BU for MDD., Results: At baseline, 71.1% of patients had insufficient SF. Mean Sexual Energy Scale (SES) scores improved during treatment (P < 0.0001), as did the percentage with sufficient SF (30.6 vs. 68.1%, P = 0.001). Patients with persistent hyperglycemia had higher rates of sexual dysfunction; however, SES improvement was evident in some with persistent depression or hyperglycemia (18.2% and 25.9%, respectively)., Conclusions: Insufficient SF is prevalent and may be suspected in patients with MDD and type 2 diabetes. BU treatment of MDD had few sexual side effects and was associated with significant improvements in SF.

Objectives: The value of gastroesophageal reflux disease (GERD) indicators (acid exposure time (AET), symptom association probability (SAP), and symptom index (SI)) in predicting therapeutic success in noncardiac chest pain (NCCP) has not been systematically evaluated in outcome studies., Methods: We retrospectively identified 98 subjects with NCCP (age 51.8+/-1.2 years, 75 women, mean duration of symptoms 7.3+/-0.4 years) who underwent pH monitoring off antireflux therapy. Distal esophageal AET (abnormal if > or = 4.0%), SAP (measured as Ghillibert probability estimate, abnormal if P<0.05), and SI (abnormal if > or = 50%) were calculated; symptom severity and change after therapy were assessed on a 10-point Likert scale. Subjects were interviewed 2.8+/-0.9 years after the pH study to determine the degree of symptom change (high-degree response (HDR), with definite, sustained symptom improvement) after antireflux therapy. Regression analysis was used to determine the independent predictors of HDR., Results: GERD indicators were present in 61 subjects (62.2%); 52 subjects (53.1%) had abnormal AET, 26 (26.5%) had positive SAP, and 25 (25.5%) had positive SI. With therapy, mean symptom scores improved from 6.3+/-0.3 at the time of the pH study to 2.9+/-0.3 at the time of interview (P<0.001). A total of 58 subjects (59.2%) achieved HDR, and another 29.6% had moderate symptom improvement. On univariate analysis, HDR was associated with positive SAP (P=0.003) and elevated AET (P=0.015) but not with demographics, SI, or esophageal motor pattern. In regression analysis containing demographics, GERD indicators, psychiatric comorbidity, and esophageal motor pattern, positive SAP was retained as a significant predictor of HDR (P=0.003); elevated AET trended toward significance (P=0.055). Frequency of HDR was highest when subjects had all three GERD parameters abnormal (93.3% HDR) or both elevated AET and positive SAP (88.2% HDR, P<0.001 compared with only one or no GERD parameter abnormal)., Conclusions: Positive statistical tests of symptom association predict the therapeutic success of GERD management in NCCP. When used hierarchically, response to antireflux therapy is best predicted when GERD parameters are all abnormal and poorest when parameters are normal. These results support the importance of GERD, the relevance of symptom association testing during ambulatory pH monitoring, and the value of intensive antireflux therapy in NCCP.

Brunner gland cyst is a benign polypoid or nodular lesion of the duodenum that may not be familiar to gastroenterologists and pathologists because of its rarity. There have been only 9 cases documented in the world literature under various names. In this report, we describe the clinicopathologic features of three such cases to raise the awareness of its existence.

The definition of optimal therapeutic response has been evolving concurrent with the advancement of diagnostic tests. What once was considered "therapeutic success" is considered now disease persistence or relapse. As the laboratory tools become increasingly sensitive, it follows that the criteria of successful therapeutic response are becoming more stringent. The main objectives of chronic hepatitis B and C treatment are to achieve eradication of the virus and, with this, reduction or prevention of hepatic injury and disease progression. However, in the case of hepatitis B, viral suppression is for the moment a more realistic therapeutic objective, although eradication still remains the ultimate goal. In chronic hepatitis C, sustained virologic response, defined as the absence of HCV RNA 6 months post-antiviral treatment completion, is within reach. Better test sensitivity allows for additional levels of confidence in the achievements of virus eradication in patients with hepatitis C. Challenges persist despite great advances in the treatment of chronic viral hepatitis. Now that clearer therapeutic outcomes have been refined, more efficacious, and better-tolerated drugs may change the current therapeutic landscape of chronic viral hepatitis B and C.

Background & Aims: Unexplained, multi-system somatic symptoms and syndromes, the hallmark features of somatization, are prevalent in patients with functional gastrointestinal disorders (FGIDs). We studied outpatients attending a gastroenterology clinic to see whether current somatic symptom burdens (a somatization state measure) or number of prior functional diagnoses (a somatization trait measure) could predict the presence of an FGID over structural gastrointestinal disease, and whether the predictive value was dependent on comorbid depression or anxiety disorders., Methods: Clinical data from 327 consecutive new referrals to an outpatient gastroenterology practice were reviewed, 187 with an FGID and 140 with a structural illness. Somatization state and trait were measured by using self-reported current symptoms and functional diagnoses recorded in the medical history, respectively. Psychiatric comorbidity (depression or anxiety disorders) was extracted from chart review., Results: FGID subjects endorsed more somatization state symptoms, had more somatization trait diagnoses, and had greater likelihood of psychiatric comorbidity (P < .001 for each). Logistic regression analysis adjusting for age and sex differences showed that each of these features independently predicted the likelihood of an FGID over structural disease (P < .05 for each). When high ratings on the somatization measures were present together with psychiatric comorbidity, the positive predictive value exceeded 0.95., Conclusions: Higher burdens of either current somatic symptoms or functional diagnoses in the medical history are strong predictors of an FGID in outpatients presenting with gastrointestinal complaints. The mechanism is not solely dependent on a relationship with affective disorders, which independently predicts FGID, at least in part, through another path.

Background & Aims: Amyloidosis is characterized by the pathologic deposition of specific proteins throughout the body. Gastrointestinal involvement with amyloid associated with plasma cell dyscrasias (AL type amyloidosis) is common, but systematic description of the condition is lacking. The aim of this investigation was to characterize the clinical presentation, endoscopic findings, and histopathologic correlates in a series of patients with systemic AL amyloidosis of the luminal gastrointestinal tract., Methods: Eligible patients were identified by interrogating the histopathology database of our institution during a 14-year time period. Medical record, histopathologic, and laboratory data were collected, analyzed, and correlated with endoscopic findings., Results: Nineteen patients with systemic AL amyloidosis of the luminal gastrointestinal tract were identified. Gastrointestinal symptoms or signs related to amyloid involvement were noted in 95% of patients; abdominal pain, change in bowel habits, overt gastrointestinal bleeding, and complaints related to altered motility were the predominant presentations. Endoscopic abnormalities were found in nearly three fourths of patients, including ulcerations and submucosal hematomas. When gastrointestinal bleeding was the presenting symptom, submucosal hematomas were a common finding during endoscopic evaluation., Conclusions: AL type amyloidosis of the luminal gastrointestinal tract is a rare disease that presents with common, nonspecific complaints. The endoscopic detection of a submucosal hematoma in the setting of gastrointestinal bleeding in patients with plasma cell dyscrasias should raise suspicion for the disease.

Objective: Sertraline maintenance therapy effectively delays recurrence of major depressive disorder in adult diabetic patients when data are examined across all age-groups. A secondary analysis was performed to assess this effect in younger and older subsets of patients., Research Design and Methods: Younger (aged <55 years, n = 85) and older (aged > or =55 years, n = 67) subsets were identified from a multicenter, double-blind, placebo-controlled, maintenance treatment trial of sertraline in diabetic participants who achieved depression recovery with open-label sertraline treatment. Cox proportional hazards models were used to determine differences in time to depression recurrence between treatment arms (sertraline or placebo) for each age subset and between age subsets for each treatment., Results: In younger subjects, sertraline conferred significantly greater prophylaxis against depression recurrence than placebo (hazard ratio 0.37 [95% CI 0.20-0.71]; P = 0.003). Benefits of sertraline maintenance therapy were lost in older participants (0.94 [0.39-2.29]; P = 0.89). There was no difference in time to recurrence for sertraline-treated subjects between age subsets (P = 0.65), but older subjects had a significantly longer time to recurrence on placebo than younger subjects (P = 0.03)., Conclusions: While sertraline significantly increased the time to depression recurrence in the younger diabetic participants, there was no treatment effect in those aged > or =55 years because of a high placebo response rate. Further research is necessary to determine the mechanisms responsible for this effect and whether depression maintenance strategies specific for older patients with diabetes should be developed.