Effects of Amitriptyline and Escitalopram on Sleep and Mood in Patients With Functional Dyspepsia.

BACKGROUND & AIMS: Tricyclic antidepressants are effective in reducing symptoms of functional dyspepsia (FD). We performed a post hoc analysis of data from a previous randomized clinical trial to determine whether the benefits of an antidepressant on gastrointestinal symptoms in patients with FD were mediated by improving sleep or reducing anxiety. We explored the relationships between psychological measures, quality of sleep, and relief of symptoms. METHODS: We analyzed data from a multicenter, double-blind trial that evaluated the efficacy of antidepressants on symptoms of FD, from October 2006 through October 2012. Patients (n = 292) were randomly assigned to groups given 50 mg amitriptyline, 10 mg escitalopram, or placebo for 12 weeks. During the study, participants completed the following validated psychological questionnaires: Symptom Check List 90, Symptom Somatic Checklist, Hospital Anxiety Depression Scale, Profile of Mood States, State Trait Anxiety Inventory, and Pittsburgh Sleep Quality Index at baseline and 12 weeks following treatment. RESULTS: Baseline scores for the psychological and sleep measures were similar among groups; after 12 weeks there were no significant differences in scores among groups. Baseline mean global Pittsburgh Sleep Quality Index scores indicated poor sleep quality in all groups at baseline and after 12 weeks. Overall, antidepressants affected sleep duration scores: patients given amitriptyline had lower (better) scores than patients given placebo or escitalopram (P = .019). In all groups, responders had decreased anxiety and improvements in some sleep components. CONCLUSIONS: In a post hoc analysis of data from a clinical trial that evaluated the effects of antidepressants in patients with FD, amitriptyline was found to reduce symptoms of FD, but its mechanism is unlikely to involve reductions in psychological distress. The drug may modestly improve sleep. Clinicaltrials.gov no: NCT00248651.

Effects of NGM282, an FGF19 variant, on colonic transit and bowel function in functional constipation: a randomized phase 2 trial.

OBJECTIVE: NGM282 is an analog of fibroblast growth factor 19 (FGF19), a potent inhibitor of bile acid (BA) synthesis in animals and humans. In phase 2 trials in type 2 diabetes and primary biliary cholangitis, NGM282 was associated with dose-related abdominal cramping and diarrhea. We aimed to examine effects of NGM282 on colonic transit, stool frequency and consistency, hepatic BA synthesis (fasting serum C4), fecal fat, and BA in functional constipation (FC). METHODS: Two-dose NGM282 (1 and 6 mg, subcutaneously daily), parallel-group, randomized, placebo-controlled, 14-day study in patients with FC (Rome III criteria) and baseline colonic transit 24 h geometric center (GC) <3.0. We explored treatment interaction with SNPs in genes KLB, FGFR4, and TGR5 (GPBAR1). STATISTICAL ANALYSIS: overall ANCOVA at α = 0.025 (baseline as covariate where available), with three pairwise comparisons among the three groups (α = 0.008). RESULTS: Overall, NGM282 altered bowel function (number of bowel movements, looser stool form, and increased ease of passage) and significantly accelerated gastric and colonic transit. Dose-related effects were seen with GC 24 h, but not with gastric emptying (GE) and GC 48 h. There were no differences in fecal fat or weight, but there was reduced fecal total BA excretion with NGM282. The most common adverse events were increased appetite (n = 0 with placebo, 2 with 1 mg, 9 with 6 mg), injection site reaction (n = 2 placebo, 4 with 1 mg, 8 with 6 mg), and diarrhea (n = 1 with 1 mg and 4 with 6 mg NGM282). There was treatment interaction with KLB SNP, with greater increase in colonic transit in participants with the minor A allele (p = 0.056). CONCLUSION: NGM282 significantly impacts GE and colonic transit, consistent with the observed clinical symptoms. The specific mechanism of prokinetic activity requires further research.

Identification and validation of functional gastrointestinal disorder subtypes using latent class analysis: a population-based study.

OBJECTIVE: Attempts to categorize distinct functional gastrointestinal disorders based on reported symptoms continue but symptoms frequently overlap. The study objective was to use latent class analysis (LCA) which accommodates both continuous and discrete manifest variables to determine mutually exclusive subgroup assignments of a population-based sample using gastrointestinal symptom and patient data. MATERIALS AND METHODS: A validated bowel disease questionnaire and somatic symptom questionnaire were mailed to an age and gender stratified randomly selected community sample. Responses to the symptom questions were dichotomized as frequent vs. infrequent based on Rome IV criteria. A LCA model was developed using a calibration subset and the results applied to the validation subset. RESULTS: There were 3831 total respondents (48%) with 3425 having complete data. The LCA algorithm was run for each of 10 (random) splits of the dataset and 2-6 latent classes were specified. Using the values of Akaike's Information Criterion coefficient c to determine fit of the data, 4 latent classes yielded better values resulting in four subgroups: 'asymptomatic,' 'upper' abdominal symptoms, 'lower' abdominal symptoms, and 'mixed' (upper and lower abdomen). CONCLUSIONS: Latent class analysis identified 4 groups based on symptoms. This approach resulted in differentiation by anatomical region rather than the Rome IV classification of symptoms.

Relationship of gastric emptying or accommodation with satiation, satiety, and postprandial symptoms in health.

The contributions of gastric emptying (GE) and gastric accommodation (GA) to satiation, satiety, and postprandial symptoms remain unclear. We aimed to evaluate the relationships between GA or GE with satiation, satiety, and postprandial symptoms in healthy overweight or obese volunteers (total n = 285, 73% women, mean BMI 33.5 kg/m2): 26 prospectively studied obese, otherwise healthy participants and 259 healthy subjects with previous similar GI testing. We assessed GE of solids, gastric volumes, calorie intake at buffet meal, and satiation by measuring volume to comfortable fullness (VTF) and maximum tolerated volume (MTV) by using Ensure nutrient drink test (30 ml/min) and symptoms 30 min after MTV. Relationships between GE or GA with satiety, satiation, and symptoms were analyzed using Spearman rank (rs ) and Pearson (R) linear correlation coefficients. We found a higher VTF during satiation test correlated with a higher calorie intake at ad libitum buffet meal (rs = 0.535, P < 0.001). There was a significant inverse correlation between gastric half-emptying time (GE T1/2) and VTF (rs = -0.317, P < 0.001) and the calorie intake at buffet meal (rs = -0.329, P < 0.001), and an inverse correlation between GE Tlag and GE25% emptied with VTF (rs = -0.273, P < 0.001 and rs = -0.248, P < 0.001, respectively). GE T1/2 was significantly associated with satiation (MTV, R = -0.234, P < 0.0001), nausea (R = 0.145, P = 0.023), pain (R = 0.149, P = 0.012), and higher aggregate symptom score (R = 0.132, P = 0.026). There was no significant correlation between GA and satiation, satiety, postprandial symptoms, or GE. We concluded that GE of solids, rather than GA, is associated with postprandial symptoms, satiation, and satiety in healthy participants.NEW & NOTEWORTHY A higher volume to comfortable fullness postprandially correlated with a higher calorie intake at ad libitum buffet meal. Gastric emptying of solids is correlated to satiation (volume to fullness and maximum tolerated volume) and satiety (the calorie intake at buffet meal) and symptoms of nausea, pain, and aggregate symptom score after a fully satiating meal. There was no significant correlation between gastric accommodation and either satiation or satiety indices, postprandial symptoms, or gastric emptying.

Colonic Transit and Bile Acid Synthesis or Excretion in Patients With Irritable Bowel Syndrome-Diarrhea Without Bile Acid Malabsorption.

BACKGROUND AND AIMS: Bile acids (BAs) are passively absorbed to a different extent along the mammalian colon, so that levels are lower in the feces than in proximal colon. Our aim was to explore associations among total, primary, and secretory BA in stool and colonic transit in patients with irritable bowel syndrome-diarrhea (IBS-D) without overt BA malabsorption (BAM). METHODS: In a cross-sectional observational study of 116 patients with IBS-D recruited from local communities in Minnesota, we measured total and individual main fecal BA excretion, fecal fat and fecal weight over 48 hours, fasting serum levels of C4 (surrogate for BA synthesis), and overall colonic transit by scintigraphy (geometric center at 24 hours and 48 hours). Patients without overt BAM were assigned to groups based on total fecal BA level below 2337 µmol/48 hours (n = 86) or serum levels of C4 below 47.1 ng/mL (n = 91). We used Spearman correlations to test study hypotheses with correction for 14 correlations tested (P < .0036). Data from 30 healthy volunteers were used as control subjects. RESULTS: Patients with IBS-D who had increased or normal total BA excretion in stool or BA synthesis had higher stool proportions of primary BAs (especially chenodeoxycholate), compared with healthy control subjects. In patients with IBS-D without overt BAM (normal 48-hour total fecal BA or serum C4), there were significant positive correlations between total fecal BA, fecal primary and secretory BA, fecal weight, and increased geometric center at 24 and 48 hours (P < .0036). Normal and slightly increased levels of total fecal BA have greatest effects on colonic transit at 48 hours. CONCLUSIONS: In the absence of overt BAM, the total, primary, and secretory BAs in stool contribute to the acceleration of colonic transit and fecal weight in the diarrhea of patients with IBS-D.

High-resolution Anorectal Manometry for Identifying Defecatory Disorders and Rectal Structural Abnormalities in Women.

BACKGROUND & AIMS: Contrary to conventional wisdom, the rectoanal gradient during evacuation is negative in many healthy people, undermining the utility of anorectal high-resolution manometry (HRM) for diagnosing defecatory disorders. We aimed to compare HRM and magnetic resonance imaging (MRI) for assessing rectal evacuation and structural abnormalities. METHODS: We performed a retrospective analysis of 118 patients (all female; 51 with constipation, 48 with fecal incontinence, and 19 with rectal prolapse; age, 53 ± 1 years) assessed by HRM, the rectal balloon expulsion test (BET), and MRI at Mayo Clinic, Rochester, Minnesota, from February 2011 through March 2013. Thirty healthy asymptomatic women (age, 37 ± 2 years) served as controls. We used principal components analysis of HRM variables to identify rectoanal pressure patterns associated with rectal prolapse and phenotypes of patients with prolapse. RESULTS: Compared with patients with normal findings from the rectal BET, patients with an abnormal BET had lower median rectal pressure (36 vs 22 mm Hg, P = .002), a more negative median rectoanal gradient (-6 vs -29 mm Hg, P = .006) during evacuation, and a lower proportion of evacuation on the basis of MRI analysis (median of 40% vs 80%, P < .0001). A score derived from rectal pressure and anorectal descent during evacuation and a patulous anal canal was associated (P = .005) with large rectoceles (3 cm or larger). A principal component (PC) logistic model discriminated between patients with and without prolapse with 96% accuracy. Among patients with prolapse, there were 2 phenotypes, which were characterized by high (PC1) or low (PC2) anal pressures at rest and squeeze along with higher rectal and anal pressures (PC1) or a higher rectoanal gradient during evacuation (PC2). CONCLUSIONS: In a retrospective analysis of patients assessed by HRM, measurements of rectal evacuation by anorectal HRM, BET, and MRI were correlated. HRM alone and together with anorectal descent during evacuation may identify rectal prolapse and large rectoceles, respectively, and also identify unique phenotypes of rectal prolapse.

Low Risk of Pneumonia From Pneumocystis jirovecii Infection in Patients With Inflammatory Bowel Disease Receiving Immune Suppression.

BACKGROUND & AIMS: Use of immunosuppressants and inflammatory bowel disease (IBD) may increase the risk of pneumonia caused by Pneumocystis jirovecii (PJP). We assessed the risk of PJP in a population-based cohort of patients with IBD treated with corticosteroids, immune-suppressive medications, and biologics. METHODS: We performed a population-based cohort study of residents of Olmsted County, Minnesota, diagnosed with Crohn's disease (n = 427) or ulcerative colitis (n = 510) from 1970 through 2011. Records of patients were reviewed to identify all episodes of immunosuppressive therapies and concomitant PJP prophylaxis through February 2016. We reviewed charts to identify cases of PJP, cross-referenced with the Rochester Epidemiology Project database (using diagnostic codes for PJP) and the Mayo Clinic and Olmsted Medical Center databases. The primary outcome was risk of PJP associated with the use of corticosteroids, immune-suppressive medications, and biologics by patients with IBD. RESULTS: Our analysis included 937 patients and 6066 patient-years of follow-up evaluation (median, 14.8 y per patient). Medications used included corticosteroids (520 patients; 55.5%; 555.4 patient-years of exposure), immunosuppressants (304 patients; 32.4%; 1555.7 patient-years of exposure), and biologics (193 patients; 20.5%; 670 patient-years of exposure). Double therapy (corticosteroids and either immunosuppressants and biologics) was used by 236 patients (25.2%), with 173 patient-years of exposure. Triple therapy (corticosteroids, immunosuppressants, and biologics) was used by 70 patients (7.5%) with 18.9 patient-years of exposure. There were 3 cases of PJP, conferring a risk of 0.2 (95% CI, 0.01-1.0) to corticosteroids, 0.1 (95% CI, 0.02-0.5) cases per 100 patient-years of exposure to immunosuppressants, 0.3 (95% CI, 0.04-1.1) cases per 100 patient-years of exposure to biologics, 0.6 (95% CI, 0.01-3.2) cases per 100 patient-years of exposure to double therapy, and 0 (95% CI, 0.0-19.5) cases per 100 patient-years of exposure to triple therapy. Primary prophylaxis for PJP was prescribed to 37 patients, for a total of 24.9 patient-years of exposure. CONCLUSIONS: In a population-based cohort of patients with IBD treated with corticosteroids, immunosuppressants, and biologics, there were only 3 cases of PJP, despite the uncommon use of PJP prophylaxis. Routine administration of PJP prophylaxis in these patients may not be warranted, although it should be considered for high-risk groups, such as patients receiving triple therapy.

Polymorphisms of 5-HTT LPR and GNß3 825C>T and Response to Antidepressant Treatment in Functional Dyspepsia: A Study from The Functional Dyspepsia Treatment Trial.

OBJECTIVES: The Functional Dyspepsia Treatment Trial reported that amitriptyline (AMI) was associated with adequate relief of functional dyspepsia (FD) symptoms, but the pharmacogenetics of antidepressant response in FD are not known. GNß3 825C>T CC genotype has been previously linked to FD and TT genotype to antidepressant response in depression. The ss genotype of the 5-HTT LPR variant of the serotonin transporter gene (SLC6A4) has been linked to selective serotonin reuptake inhibitor (SSRI) response. We aimed to examine whether GNß3 825C>T and 5-HTT LPR polymorphisms result in differential treatment effects in FD patients receiving antidepressant therapy. METHODS: Participants were randomized to receive placebo, 50 mg AMI, or 10 mg escitalopram (ESC). The primary end point was adequate relief for ≥5 weeks of the last 10 weeks. Genotyping of GNß3 825C>T and 5-HTT LPR was performed utilizing PCR-based methods. RESULTS: GNß3 825C>T and 5-HTT LPR genotype data were available for 256 (88%) and 246 (84%) patients, respectively. Both polymorphisms were in Hardy-Weinberg equilibrium. In tests for differential treatment, neither 5-HTT LPR nor GNß3 825C>T genotype influenced response to therapy (P=0.89 and P=0.54, respectively). Although there was a tendency for a more favorable response to ESC in the SS/LS genotype compared to the LL genotype groups (40% vs. 31% reporting adequate relief of FD symptoms) among those in the ESC treatment arm, this was not significant (P=0.43). CONCLUSIONS: GNß3 825C>T and 5-HTT LPR genetic variants do not alter treatment response to tricyclic and SSRI antidepressants in FD.

Cumulative Length of Bowel Resection in a Population-Based Cohort of Patients With Crohn's Disease.

BACKGROUND & AIMS: Little is known about the cumulative extent of bowel resection among patients with Crohn's disease. METHODS: Using the resources of the Rochester Epidemiology Project, we identified a cohort of 310 incident cases of Crohn's disease from Olmsted County, Minnesota who were diagnosed between 1970 and 2004. Operative and pathology reports were reviewed for bowel resection length. Median bowel resection lengths (with interquartile range [IQR]) were calculated per resection, cumulatively, and as a rate per year of follow-up. RESULTS: One hundred forty-seven patients underwent 1 or more bowel resections. The median follow-up time per patient was 13.6 years (range, 0.2-39 years). Among the 141 patients with resection data available, 211 resections were performed (100 patients with 1 resection, 24 with 2 resections, 9 with 3 resections, 6 with 4 resections, 1 with 5 resections, and 1 patient with 7 resections). The median length of bowel resected was 40 cm (IQR, 22-65 cm) at any resection. The median cumulative length of bowel resected was 64 cm (38-93 cm) during the follow-up period. The median (IQR) rate of bowel resected was 4.2 cm total bowel annually (2.8-7.7 cm). The median length resected was highest for the first resection (52 cm; IQR, 32-71 cm). A mixed regression analysis showed that the length of the first resection was significantly greater than that of the second (P = .002), without significant differences between the second and third or subsequent resections. CONCLUSIONS: In a population-based cohort of patients with Crohn's disease, the median cumulative length of total bowel resected was 64 cm during the follow-up period; the median rate of bowel loss due to resection was 4.2 cm annually.

Quantitative gastrointestinal and psychological traits associated with obesity and response to weight-loss therapy.

BACKGROUND & AIMS: Weight loss after pharmacotherapy varies greatly. We aimed to examine associations of quantitative gastrointestinal and psychological traits with obesity, and to validate the ability of these traits to predict responses of obese individuals to pharmacotherapy. METHODS: In a prospective study, we measured gastric emptying of solids and liquids, fasting and postprandial gastric volume, satiation by nutrient drink test (volume to fullness and maximal tolerated volume), satiety after an ad libitum buffet meal, gastrointestinal hormones, and psychological traits in 328 normal-weight, overweight, or obese adults. We also analyzed data from 181 previously studied adults to assess associations betwecen a subset of traits with body mass index and waist circumference. Latent dimensions associated with overweight or obesity were appraised by principal component analyses. We performed a proof of concept, placebo-controlled trial of extended-release phentermine and topiramate in 24 patients to validate associations between quantitative traits and response to weight-loss therapy. RESULTS: In the prospective study, obesity was associated with fasting gastric volume (P = .03), accelerated gastric emptying (P < .001 for solids and P = .011 for liquids), lower postprandial levels of peptide tyrosine tyrosine (P = .003), and higher postprandial levels of glucagon-like peptide 1 (P < .001). In a combined analysis of data from all studies, obesity was associated with higher volume to fullness (n = 509; P = .038) and satiety with abnormal waist circumference (n = 271; P = .016). Principal component analysis identified latent dimensions that accounted for approximately 81% of the variation among overweight and obese subjects, including satiety or satiation (21%), gastric motility (14%), psychological factors (13%), and gastric sensorimotor factors (11%). The combination of phentermine and topiramate caused significant weight loss, slowed gastric emptying, and decreased calorie intake; weight loss in response to phentermine and topiramate was significantly associated with calorie intake at the prior satiety test. CONCLUSIONS: Quantitative traits are associated with high body mass index; they can distinguish obesity phenotypes and, in a proof of concept clinical trial, predicted response to pharmacotherapy for obesity. ClinicalTrials.gov Number: NCT01834404.

Hidradenitis Suppurativa in Patients With Inflammatory Bowel Disease: A Population-Based Cohort Study in Olmsted County, Minnesota.

BACKGROUND & AIMS: Patients with inflammatory bowel disease (IBD) may be at higher risk for hidradenitis suppurativa (HS). We studied the risk and clinical characteristics of HS in a population-based cohort of patients with IBD. METHODS: We identified all cases of HS (confirmed by biopsy and/or dermatologic evaluation) in a population-based inception cohort of Olmsted County, Minnesota, residents diagnosed with IBD between 1970 and 2004 and followed up through August 2013. We estimated the incidence rate ratio of HS in patients with IBD compared with the general population, and described the clinical characteristics, risk factors, and management of HS. RESULTS: In 679 IBD patients followed up over a median of 19.8 years, we identified 8 patients with HS (mean age, 44.4 ± 8.3 y; 7 women; 6 obese). Compared with the general population, the incidence rate ratio of HS in IBD was 8.9 (95% confidence interval, 3.6-17.5). The 10- and 30-year cumulative incidence of HS was 0.85% and 1.55%, respectively. Five patients had Crohn's disease, 4 of whom had perianal disease; of 3 patients with ulcerative colitis, 2 had undergone ileal pouch-anal anastomosis. Axillae, groin, and thighs were the most common sites of involvement. Six patients had Hurley stage 2 disease (recurrent abscesses with sinus tracts and scarring, involving widely separated areas), and required a combination of antibiotics and surgery; none of the patients were treated with anti-tumor necrosis factor-α agents. CONCLUSIONS: In this population-based study, patients with IBD were approximately 9 times more likely to develop HS than the general population, with a female predisposition.

Delayed Gastric Emptying Is Associated With Early and Long-term Hyperglycemia in Type 1 Diabetes Mellitus.

BACKGROUND & AIMS: After the Diabetes Control and Complications Trial (DCCT), the Epidemiology of Diabetes Interventions and Complications (EDIC) study continued to show persistent benefit of prior intensive therapy on neuropathy, retinopathy, and nephropathy in type 1 diabetes mellitus (DM). The relationship between control of glycemia and gastric emptying (GE) is unclear. METHODS: We assessed GE with a (13)C-spirulina breath test and symptoms in 78 participants with type 1 diabetes at year 20 of EDIC. The relationship between delayed GE and glycated hemoglobin (HbA1c), complications of DM, and gastrointestinal symptoms were evaluated. RESULTS: GE was normal (37 participants; 50%), delayed (35 participants; 47%), or rapid (2 participants; 3%). The latest mean HbA1c was 7.7%. In univariate analyses, delayed GE was associated with greater DCCT baseline HbA1c and duration of DM before DCCT (P ≤ .04), greater mean HbA1c over an average of 27 years of follow-up evaluation (during DCCT-EDIC, P = .01), lower R-R variability during deep breathing (P = .03) and severe nephropathy (P = .05), and a greater composite upper gastrointestinal symptom score (P < .05). In multivariate models, retinopathy was the only complication of DM associated with delayed GE. Separately, DCCT baseline HbA1c (odds ratio [OR], 1.6; 95% confidence interval [CI], 1.1-2.3) and duration of DM (OR, 1.2; 95% CI, 1.01-1.3) before DCCT entry and mean HbA1c during DCCT-EDIC (OR, 2.2; 95% CI, 1.04-4.5) were associated independently with delayed GE. CONCLUSIONS: In the DCCT/EDIC study, delayed GE was remarkably common and associated with gastrointestinal symptoms and with measures of early and long-term hyperglycemia. ClinicalTrials.gov numbers NCT00360815 and NCT00360893.

Effect of Amitriptyline and Escitalopram on Functional Dyspepsia: A Multicenter, Randomized Controlled Study.

BACKGROUND & AIMS: Antidepressants are frequently prescribed to treat functional dyspepsia (FD), a common disorder characterized by upper abdominal symptoms, including discomfort or postprandial fullness. However, there is little evidence of the efficacy of these drugs in patients with FD. We performed a randomized, double-blind, placebo-controlled trial to evaluate the effects of antidepressant therapy on symptoms, gastric emptying (GE), and meal-induced satiety in patients with FD. METHODS: We performed a study at 8 North American sites of patients who met the Rome II criteria for FD and did not have depression or use antidepressants. Patients (n = 292; 44 ± 15 years old, 75% were female, 70% with dysmotility-like FD, and 30% with ulcer-like FD) were randomly assigned to groups given placebo, 50 mg amitriptyline, or 10 mg escitalopram for 10 weeks. The primary end point was adequate relief of FD symptoms for ≥5 weeks of the last 10 weeks (of 12). Secondary end points included GE time, maximum tolerated volume in Nutrient Drink Test, and FD-related quality of life. RESULTS: An adequate relief response was reported by 39 subjects given placebo (40%), 51 given amitriptyline (53%), and 37 given escitalopram (38%) (P = .05, after treatment, adjusted for baseline balancing factors including all subjects). Subjects with ulcer-like FD given amitriptyline were >3-fold more likely to report adequate relief than those given placebo (odds ratio = 3.1; 95% confidence interval: 1.1-9.0). Neither amitriptyline nor escitalopram appeared to affect GE or meal-induced satiety after the 10-week period in any group. Subjects with delayed GE were less likely to report adequate relief than subjects with normal GE (odds ratio = 0.4; 95% confidence interval: 0.2-0.8). Both antidepressants improved overall quality of life. CONCLUSIONS: Amitriptyline, but not escitalopram, appears to benefit some patients with FD, particularly those with ulcer-like (painful) FD. Patients with delayed GE do not respond to these drugs. ClinicalTrials.gov ID: NCT00248651.

Yield of Repeat Endoscopy in Barrett's Esophagus with No Dysplasia and Low-Grade Dysplasia: A Population-Based Study.

BACKGROUND: The yield of early repeat endoscopy in patients with Barrett's esophagus (BE) is not well established. AIMS: To determine how often early repeat endoscopy detected missed dysplasia or esophageal adenocarcinoma (EAC) in a population-based cohort of patients with BE. Secondary aims were to identify risk factors for missed dysplasia/EAC and compare detection of prevalent versus incident HGD/EAC. METHODS: A population-based cohort of BE subjects in Olmsted County, MN, was studied. Patients with initial non-dysplastic BE or low-grade dysplasia (LGD) who underwent repeat endoscopy within 24 months were included. Those with a worse histologic diagnosis on repeat endoscopy were considered to have missed dysplasia/EAC. Baseline characteristics among patients with and without missed dysplasia/EAC were compared. The absolute numbers of asymptomatic prevalent or missed, and incident HGD/EAC in the entire cohort were ascertained. RESULTS: Of 488 BE cases, 210 were included for the primary aim of this study. Repeat endoscopy revealed four HGD/EAC (1.9 %) and 16 LGD (8.8 %) for a combined miss rate of 9.5 %. Long-segment BE (LSBE) and lack of PPI use were predictors of missed dysplasia/EAC (P = 0.008), but adherence to biopsy protocol was not. Increased prevalent HGD/EAC (n = 30) rather than incident HGD/EAC (n = 22) was identified during a median 4.8 years of follow-up in this cohort. CONCLUSIONS: Dysplasia/EAC is commonly missed at initial BE diagnosis, particularly in patients with LSBE and no PPI use. Efforts should be made to enhance the sensitivity of detecting dysplasia/neoplasia around the time of initial BE diagnosis.

Outcomes of Ultrasound-Guided Trigger Point Injection for Abdominal Wall Pain.

BACKGROUND: Abdominal wall pain (AWP) is an important cause of chronic abdominal pain. History and physical examination are critical to the diagnosis of AWP. Trigger point injection (TPI) using either a steroid or a local anesthetic or a combination of both is often used to treat AWP. AIM: To determine the efficacy of ultrasound-guided TPI and to determine the predictors of a successful response. METHODS: Patients who received ultrasound-guided TPI between July 2010 and June 2011 were surveyed. The primary outcome was determined using the Treatment Efficacy Questionnaire (TEQ). Electronic medical records were reviewed to determine patient, pain and TPI characteristics. Linear regression was used to determine the predictors of a successful response on the TEQ. RESULTS: Right upper quadrant was the most common site of AWP, and the median pain duration was 12 months. Pain was rated as >8 (1-10 scale) by 57 % and 30 % described it as an ache. Narcotic use was reported in 38 %, and 73 % had a history of at least one abdominal surgery. Forty-four of the 120 (37 %) patients met the criteria for responder on the TEQ. Compared to before treatment, 36 % reported being "significantly better" and 22 % "slightly better." Multiple linear regression analysis showed that higher somatization negatively predicted response. None of the other historical, examination or TPI characteristics were associated with response to the TPI. CONCLUSION: TPI can provide significant, long-term symptom relief in a third of patients with chronic abdominal pain attributed to AWP. Somatization was inversely related to the treatment success.

Relationship between glycemic control and gastric emptying in poorly controlled type 2 diabetes.

BACKGROUND & AIMS: Acute hyperglycemia delays gastric emptying in patients with diabetes. However, it is not clear whether improved control of glycemia affects gastric emptying in these patients. We investigated whether overnight and short-term (6 mo) improvements in control of glycemia affect gastric emptying. METHODS: We studied 30 patients with poorly controlled type 2 diabetes (level of glycosylated hemoglobin, >9%). We measured gastric emptying using the [(13)C]-Spirulina platensis breath test on the patients' first visit (visit 1), after overnight administration of insulin or saline, 1 week later (visit 2), and 6 months after intensive therapy for diabetes. We also measured fasting and postprandial plasma levels of C-peptide, glucagon-like peptide 1, and amylin, as well as autonomic functions. RESULTS: At visit 1, gastric emptying was normal in 10 patients, delayed in 14, and accelerated in 6; 6 patients had gastrointestinal symptoms; vagal dysfunction was associated with delayed gastric emptying (P < .05). Higher fasting blood levels of glucose were associated with shorter half-times of gastric emptying (thalf) at visits 1 (r = -0.46; P = .01) and 2 (r = -0.43; P = .02). Although blood levels of glucose were lower after administration of insulin (132 ± 7 mg/dL) than saline (211 ± 15 mg/dL; P = .0002), gastric emptying thalf was not lower after administration of insulin, compared with saline. After 6 months of intensive therapy, levels of glycosylated hemoglobin decreased from 10.6% ± 0.3% to 9% ± 0.4% (P = .0003), but gastric emptying thalf did not change (92 ± 8 min before, 92 ± 7 min after). Gastric emptying did not correlate with plasma levels of glucagon-like peptide 1 and amylin. CONCLUSIONS: Two-thirds of patients with poorly controlled type 2 diabetes have mostly asymptomatic yet abnormal gastric emptying. Higher fasting blood levels of glucose are associated with faster gastric emptying. Overnight and sustained (6 mo) improvements in glycemic control do not affect gastric emptying.

A randomized trial of 5-hydroxytryptamine4-receptor agonist, YKP10811, on colonic transit and bowel function in functional constipation.

BACKGROUND & AIMS: YKP10811, a selective agonist of the serotonin 5-hydroxytryptamine-4 receptor, increases gastrointestinal (GI) motility. We investigated the safety and effects of YKP10811 on GI and colonic transit and bowel movements (BMs) in patients with functional constipation in a randomized, double-blind, placebo-controlled study. METHODS: Patients with functional constipation, based on the Rome III criteria, were assigned randomly to groups given YKP10811 10 mg (n = 15), 20 mg (n = 16), 30 mg (n = 15), or placebo (n = 11) daily for 8 days. Transit of solids was measured by validated scintigraphy at baseline and on days 7 to 9. Patients kept diaries on days 1 to 9, recording time to first BM, number of BMs/day, and stool consistency (based on the Bristol Stool Form Scale). To evaluate safety, we collected data on adverse events and clinical laboratory test and electrocardiograms results. The primary efficacy end points were determined from an intent-to-treat analysis assessing colonic transit at 24 hours and the half-time (t1/2) of gastric emptying, using analysis of covariance models. Secondary efficacy end points included measures of colonic transit (geometric center at 4 and 24 hours), small-bowel transit (based on colon filling at 6 hours), t1/2 of ascending colon emptying, and bowel functions. We used the Dunnett test to compare the effects of each dose with placebo. A per-protocol analysis (PPA) assessed the t1/2 of gastric emptying and time to first BM using proportional hazards models. RESULTS: Fifty-five participants completed the study. YKP10811 was associated with a significant acceleration in colon filling at 6 hours (P < .05), t1/2 of ascending colon emptying, and colonic transit at 24 and 48 hours, as well as increased stool consistency over 8 days (based on intent-to-treat analysis). In general, the 10-mg and 20-mg doses were the most effective in accelerating colonic transit. No serious adverse events were observed. CONCLUSIONS: YKP10811, a selective agonist of the serotonin receptor 5-hydroxytryptamine-4, accelerates GI and colonic transit and improves bowel functions in patients with functional constipation, compared with placebo. ClinicalTrial.Gov: NCT01523184.

Relationship Among Anal Sphincter Injury, Patulous Anal Canal, and Anal Pressures in Patients With Anorectal Disorders.

BACKGROUND & AIMS: The anal sphincters and puborectalis are imaged routinely with an endoanal magnetic resonance imaging (MRI) coil, which does not assess co-aptation of the anal canal at rest. By using a MRI torso coil, we identified a patulous anal canal in some patients with anorectal disorders. We aimed to evaluate the relationship between anal sphincter and puborectalis injury, a patulous anal canal, and anal pressures. METHODS: We performed a retrospective analysis of data from 119 patients who underwent MRI and manometry analysis of anal anatomy and pressures, respectively, from February 2011 through March 2013 at the Mayo Clinic. Anal pressures were determined by high-resolution manometry, anal sphincter and puborectalis injury was determined by endoanal MRI, and anal canal integrity was determined by torso MRI. Associations between manometric and anatomic parameters were evaluated with univariate and multivariate analyses. RESULTS: Fecal incontinence (55 patients; 46%) and constipation (36 patients; 30%) were the main indications for testing; 49 patients (41%) had a patulous anal canal, which was associated with injury to more than 1 muscle (all P ≤ .001), and internal sphincter (P < .01), but not puborectalis (P = .09) or external sphincter (P = .06), injury. Internal (P < .01) and external sphincter injury (P = .02) and a patulous canal (P < .001), but not puborectalis injury, predicted anal resting pressure. A patulous anal canal was the only significant predictor (P < .01) of the anal squeeze pressure increment. CONCLUSIONS: Patients with anorectal disorders commonly have a patulous anal canal, which is associated with more severe anal injury and independently predicted anal resting pressure and squeeze pressure increment. It therefore is important to identify a patulous anal canal because it appears to be a marker of not only anal sphincter injury but disturbances beyond sphincter injury, such as damage to the anal cushions or anal denervation.

Clinical and histologic determinants of mortality for patients with Barrett's esophagus-related T1 esophageal adenocarcinoma.

BACKGROUND & AIMS: Superficial (T1) esophageal adenocarcinoma (EAC) commonly is treated by endoscopic resection, yet little is known about factors that predict outcomes of this approach. We assessed clinical and histologic variables associated with the overall survival times of patients with T1 EAC who received therapy. METHODS: In a retrospective analysis, we collected data from patients who underwent endoscopic mucosal resection (EMR) for T1 EAC (194 patients with T1a and 75 patients with T1b) at the Mayo Clinic, from 1995 through 2011. EMR specimens were reviewed systematically for depth of invasion, presence of lymphovascular invasion, grade of differentiation, and status of resection margins. Kaplan-Meier curves and proportional hazards regression models were used in statistical analyses. RESULTS: Demographic characteristics were similar between patients with T1a and T1b EAC. Overall survival at 5 years after EMR was 74.4% for patients with T1a (95% confidence interval [CI], 67.6%-81.8%) and 53.2% for patients with T1b EAC (95% CI, 40.3%-70.1%). Of surviving patients with T1a EAC, 94.1% remained free of cancer (95% CI, 89.8%-98.5%), and 94.7% of surviving patients with T1b EAC remained free of cancer (95% CI, 85.2%-100%). A multivariable model associated older age (per 10-year increment), evidence of lymphovascular invasion, and deep margin involvement with reduced overall survival in patients with T1 EAC. CONCLUSIONS: Systematic assessment of EMR specimens can help predict mortality and potentially guide treatment options for patients with T1 EAC.

Relamorelin Relieves Constipation and Accelerates Colonic Transit in a Phase 2, Placebo-Controlled, Randomized Trial.

BACKGROUND & AIMS: Ghrelin receptors are located in the colon. Relamorelin is a pentapeptide selective agonist of ghrelin receptor 1a with gastric effects, but its effects in the colon are not known. We aimed to evaluate the effects of relamorelin on bowel movements (BMs) and gastrointestinal and colonic transit (CT) in patients with chronic constipation. METHODS: We performed a study of 48 female patients with chronic constipation who fulfilled the Rome III criteria and had 4 or fewer spontaneous BMs (SBMs)/wk. In a randomized (1:1), double-blind, parallel-group, placebo-controlled trial, the effects of relamorelin (100 µg/d, given subcutaneously) were tested during 14 days after a 14-day baseline, single-blind phase in which patients were given placebo at 2 Mayo Clinic sites. The participants' mean age was 40.6 ± 1.5 y, with a mean body mass index of 25.7 ± 0.6 kg/m(2), with 1.7 ± 0.1 SBM/wk, and a mean stool consistency of 1.2 ± 0.1 on the Bristol scale during this baseline period. The effect of treatment on transit was measured in 24 participants with colonic transit of less than 2.4 (geometric center at 24 h) during the baseline period. Gastric emptying, small-bowel transit, and CT were measured during the last 2 days that patients received relamorelin or placebo. Bowel function was determined from daily diaries kept by patients from days 1 through 28. Study end points were time to first BM, SBMs/wk, complete SBMs/wk, stool form, and ease of stool passage. Effects of relamorelin were assessed by analysis of covariance. RESULTS: Compared with placebo, relamorelin accelerated gastric emptying half-time (P = .027), small-bowel transit (P = .051), and CT at 32 hours (P = .040) and 48 hours (P = .017). Relamorelin increased the number of SBMs (P < .001) and accelerated the time to first BM after the first dose was given (P = .004) compared with placebo, but did not affect stool form. Adverse events associated with relamorelin included increased appetite, fatigue, and headache. CONCLUSIONS: Relamorelin acts in the colon to significantly reduce symptoms of constipation and accelerate CT in patients with chronic constipation, compared with placebo. ClinicalTrial.Gov registration number: NCT01781104.