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1.  Colonic Diverticula are Not Associated with an Increased Risk of Colorectal Adenomas 
Background & Aims
Patients with missed colorectal cancer have been reported to be more likely to have colonic diverticulosis. Such an association could be due to either higher risk of neoplasia or difficulty examining the colon in patients with diverticulosis. The aim of this study was to determine whether colonic diverticula are associated with an increased risk for colonic neoplasia.
Methods
We analyzed data from a prospective study of patients undergoing screening colonoscopy that included detailed assessment of all colonic diverticula and colorectal polyps. We used logistic regression to estimate odds ratios and 95% confidence intervals while adjusting for confounding variables.
Results
Our analyses included 624 participants. Of these, 216 (35%) had one or more colorectal adenomas. Diverticula on colonoscopy were not associated with an increased risk of adenomas (OR 1.0, 95% CI 0.7–1.4) or advanced adenomas (OR 0.8, 95% CI 0.4–1.5). Those with the greatest burden of diverticula (10 or more) did not have an increased risk of adenomas (OR 1.1, 95% CI 0.7–1.8) compared with no diverticula. Colonic diverticula were not associated with an increased risk of proximal (OR 1.0, 95% CI 0.6–1.6) or distal adenomas (OR 1.0, 95% CI 0.6–1.7).
Conclusions
Patients with colonic diverticula do not have an increased risk of colorectal adenomas or advanced adenomas.
doi:10.1038/ajg.2015.359
PMCID: PMC4765899  PMID: 26526082
diverticular disease; colorectal cancer; interval colorectal cancer
2.  Association between affective-cognitive symptoms of depression and exacerbation of Crohn’s Disease 
Objectives
The prevalence of depression is high in patients with Crohn’s Disease (CD). We examined the influence of affective-cognitive symptoms of depression on the risk of exacerbation of CD.
Methods
We studied 2144 adult volunteers with a self-reported diagnosis of CD who completed a baseline survey that included demographics, CD status and an affective-cognitive index of depression. Linear and logistic regression analyses were used to determine if CD status at 12 months was associated with the baseline measure of depression. Analyses were adjusted for confounders including age, gender, race, baseline disease activity, disease duration, prior hospitalization and surgery, corticosteroid and anti-TNF use, medication adherence, BMI, current smoking, education, and sleep quality.
Results
Depression was significantly associated with subsequent increases in SCDAI score in both unadjusted (p<0.001) and adjusted (p< 0.001) analyses. This association was non-linear, with a shallower slope for lower levels of depression. A 10 point increase in depression t-scores from 55 to 65 was associated with a 18.6 point increase in SCDAI (95% CI 11.5–25.6) and an odds ratio of 1.27 for SCDAI > 150 at follow up (CI: 1.01–1.60). We also found a significant association between depressive symptoms and hospitalization.
Conclusion
Cognitive-affective depressive symptoms were significantly associated with a risk of exacerbation of CD and hospitalization.
doi:10.1038/ajg.2016.98
PMCID: PMC4965803  PMID: 27045927
3.  Fear of GI Symptoms has an Important Impact on Quality of Life in Patients With Moderate-to-Severe IBS 
OBJECTIVES
Because irritable bowel syndrome (IBS) is a functional medical condition for which there is no curative therapy, treatment goals emphasize relieving gastrointestinal (GI) symptoms and optimizing the quality of life (QOL). This study sought to characterize the magnitude of the associations between QOL impairment, fear of IBS symptoms, and confounding variables.
METHODS
Subjects included 234 Rome III-diagnosed IBS patients (mean age, 41 years, 79%, female) without comorbid organic GI disease who were referred to two specialty care clinics of an National Institutes of Health trial for IBS. Subjects completed a testing battery that included the IBS-specific QOL (IBS-QOL), SF-12 (generic QOL), the UCLA GI Symptom Severity Scale, the Visceral Sensitivity Index, Trait Anxiety Inventory, and Brief Symptom Inventory.
RESULTS
Multiple linear regression was used to develop a model for predicting QOL. Data supported an overall model that included sociodemographic, clinical (e.g., current severity of GI symptoms), and psychosocial (e.g., fear of GI symptoms, distress, neuroticism) variables, accounting for 48.7% of the variance in IBS-QOL (F=15.1, P <0.01). GI symptom fear was the most robust predictor of IBS-QOL (β=−0.45 P <0.01), accounting for 14.4% of the total variance.
CONCLUSIONS
Patients’ fear that GI symptoms have aversive consequences, is a predictor of QOL impairment that cannot be fully explained by the severity of their GI symptoms, overall emotional well-being, neurotic personality style, or other clinical features of IBS. An understanding of the unique impact that GI symptom fears have on QOL can inform treatment planning and help gastroenterologists to better manage more severe IBS patients seen in tertiary care clinics.
doi:10.1038/ajg.2014.241
PMCID: PMC5110208  PMID: 25223577
4.  The Relationship Between Proton Pump Inhibitor Use and Longitudinal Change in Bone Mineral Density: A Population-Based From the Canadian Multicentre Osteoporosis Study (CaMos) 
OBJECTIVES
Proton pump inhibitor (PPI) use has been identified as a risk factor for hip and vertebral fractures. Evidence supporting a relationship between PPI use and osteoporosis remains scant. Demonstrating that PPIs are associated with accelerated bone mineral density (BMD) loss would provide supportive evidence for a mechanism through which PPIs could increase fracture risk.
METHODS
We used the Canadian Multicentre Osteoporosis Study data set, which enrolled a population-based sample of Canadians who underwent BMD testing of the femoral neck, total hip, and lumbar spine (L1–L4) at baseline, and then again at 5 and 10 years. Participants also reported drug use and exposure to risk factors for osteoporosis and fracture. Multivariate linear regression was used to determine the independent association of PPI exposure and baseline BMD, and on change in BMD at 5 and 10 years.
RESULTS
In all, 8,340 subjects were included in the baseline analysis, with 4,512 (55%) undergoing year 10 BMD testing. After adjusting for potential confounders, PPI use was associated with significantly lower baseline BMD at the femoral neck and total hip. PPI use was not associated with a significant acceleration in covariate-adjusted BMD loss at any measurement site after 5 and 10 years of follow-up.
CONCLUSIONS
PPI users had lower BMD at baseline than PPI non-users, but PPI use over 10 years did not appear to be associated with accelerated BMD loss. The reasons for discordant findings between PPI use at baseline and during follow-up require further study.
doi:10.1038/ajg.2012.200
PMCID: PMC5104563  PMID: 22777336 CAMSID: cams6142
5.  Management of Patients with Acute Lower Gastrointestinal Bleeding 
This guideline provides recommendations for the management of patients with acute overt lower gastrointestinal hemorrhage. Hemodynamic status should be initially assessed with intravascular volume resuscitation started as needed. Risk stratification based upon clinical parameters should be performed to help distinguish patients at high and low-risk of adverse outcomes. Hematochezia associated with hemodynamic instability may be indicative of an upper GI bleeding source and thus warrants an upper endoscopy. In the majority of patients, colonoscopy should be the initial diagnostic procedure and should be performed within 24 hours of patient presentation after adequate colon preparation. Endoscopic hemostasis therapy should be provided to patients with high risk endoscopic stigmata of bleeding including active bleeding, non-bleeding visible vessel, or adherent clot. The endoscopic hemostasis modality used (mechanical, thermal, injection or combination) is most often guided by the etiology of bleeding, access to the bleeding site, and endoscopist experience with the various hemostasis modalities. Repeat colonoscopy, with endoscopic hemostasis performed if indicated, should be considered for patients with evidence of recurrent bleeding. Radiographic interventions (tagged red blood cell scintigraphy, CT angiography, angiography) should be considered in high-risk patients with ongoing bleeding who do not respond adequately to resuscitation, and who are unlikely to tolerate bowel preparation and colonoscopy. Strategies to prevent recurrent bleeding should be considered. NSAID use should be avoided in patients with a history of acute lower GI bleeding particularly if secondary to diverticulosis or angioectasia. In patients with established cardiovascular disease who require aspirin (secondary prophylaxis), aspirin should not be discontinued. The exact timing depends on the severity of bleeding, perceived adequacy of hemostasis and the risk of a thromboembolic event. Surgery for the prevention of recurrent lower gastrointestinal bleeding should be individualized and the source of bleeding should be carefully localized prior to resection.
doi:10.1038/ajg.2016.41
PMCID: PMC5099081  PMID: 26925883
6.  Proton pump inhibitors do not affect risk for Clostridium difficile infection in the intensive care unit 
Objectives
Patients in the intensive care unit (ICU) frequently receive proton pump inhibitors (PPIs) and have high rates of Clostridium difficile infection (CDI). PPIs have been associated with CDI in hospitalized patients, but ICU patients differ fundamentally from non-ICU patients and few studies have focused on PPI use exclusively in the critical care setting. We performed a retrospective cohort study to determine the associations between PPIs and healthcare facility–onset CDI in the ICU.
Methods
We analyzed data from all adult ICU patients at three affiliated hospitals (14 ICUs) between 2010–2013. Patients were excluded if they had recent CDI or an ICU stay of <3 days. We parsed electronic medical records for ICU exposures, focusing on PPIs and other potentially modifiable exposures that occurred during ICU stays. Healthcare facility–onset CDI in the ICU was defined as a newly positive PCR for the C. difficile toxin B gene from an unformed stool, with subsequent receipt of anti-CDI therapy. We analyzed PPIs and other exposures as time-varying covariates and used Cox proportional hazards modeling to adjust for demographics, comorbidities, and other clinical factors.
Results
Of 18,134 patients who met criteria for inclusion, 271 (1.5%) developed healthcare facility–onset CDI in the ICU. Receipt of antibiotics was the strongest risk factor for CDI (adjusted HR (aHR) 2.79; 95% confidence interval (CI), 1.50–5.19). There was no significant increase in risk for CDI associated with PPIs in those who did not receive antibiotics (aHR 1.56; 95% CI, 0.72–3.35), and PPIs were actually associated with a decreased risk for CDI in those who received antibiotics (aHR 0.64; 95% CI, 0.48–0.83). There was also no evidence of increased risk for CDI in those who received higher doses of PPIs.
Conclusions
Exposure to antibiotics was the most important risk factor for healthcare facility–onset CDI in the ICU. PPIs did not increase risk for CDI in the ICU regardless of use of antibiotics.
doi:10.1038/ajg.2016.343
PMCID: PMC5096970  PMID: 27575714
Clostridium difficile infection; proton pump inhibitors; antibiotics; intensive care unit; critical illness; microbiome; pharmacoepidemiology; outcomes research
7.  Fecal Gluten Peptides Reveal Limitations of Serological Tests and Food Questionnaires for Monitoring Gluten-Free Diet in Celiac Disease Patients 
Objectives:
Treatment for celiac disease (CD) is a lifelong strict gluten-free diet (GFD). Patients should be followed-up with dietary interviews and serology as CD markers to ensure adherence to the diet. However, none of these methods offer an accurate measure of dietary compliance. Our aim was to evaluate the measurement of gluten immunogenic peptides (GIP) in stools as a marker of GFD adherence in CD patients and compare it with traditional methods of GFD monitoring.
Methods:
We performed a prospective, nonrandomized, multicenter study including 188 CD patients on GFD and 84 healthy controls. Subjects were given a dietary questionnaire and fecal GIP quantified by enzyme-linked immunosorbent assay (ELISA). Serological anti-tissue transglutaminase (anti-tTG) IgA and anti-deamidated gliadin peptide (anti-DGP) IgA antibodies were measured simultaneously.
Results:
Of the 188 celiac patients, 56 (29.8%) had detectable GIP levels in stools. There was significant association between age and GIP in stools that revealed increasing dietary transgressions with advancing age (39.2% in subjects ≥13 years old) and with gender in certain age groups (60% in men ≥13 years old). No association was found between fecal GIP and dietary questionnaire or anti-tTG antibodies. However, association was detected between GIP and anti-DGP antibodies, although 46 of the 53 GIP stool-positive patients were negative for anti-DGP.
Conclusions:
Detection of gluten peptides in stools reveals limitations of traditional methods for monitoring GFD in celiac patients. The GIP ELISA enables direct and quantitative assessment of gluten exposure early after ingestion and could aid in the diagnosis and clinical management of nonresponsive CD and refractory CD. Trial registration number NCT02711397.
doi:10.1038/ajg.2016.439
PMCID: PMC5059698  PMID: 27644734
8.  Beliefs About GI Medications and Adherence to Pharmacotherapy in Functional GI Disorder Outpatients 
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., anti-depressants) 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.
doi:10.1038/ajg.2015.132
PMCID: PMC5051635  PMID: 25916226
9.  Persistent Liver Biochemistry abnormalities are more common in older patients and those with Cholestatic Drug induced Liver Injury 
OBJECTIVES
The long-term outcomes of patients with drug induced liver injury (DILI) are not well described. The aim of this study was to determine the frequency and severity of persistent liver biochemistry abnormalities in DILI patients followed over 2 years.
METHODS
Subjects with evidence of liver injury at 6 months after DILI onset were offered a month 12 and 24 study visit.
RESULTS
Amongst the 99 patients with definite, probable, or very likely DILI and available laboratory data at 12 months after DILI onset, 74 (75%) had persistent liver injury (persisters) defined as a serum AST or ALT > 1.5 × upper limit of normal (ULN) or an alkaline phosphatase > ULN, while 25 (25%) had resolved liver injury (resolvers). On multivariate analysis, month 12 persisters were significantly older (52.6 vs 43.7 years, p=0.01) and more likely to have a cholestatic lab profile at DILI onset (54% vs 20%, p < 0.01) than resolvers. The month 12 persisters also had significantly poorer SF-36 Physical summary scores at DILI onset and throughout follow-up compared to the resolvers (p < 0.01). Amongst the 17 subjects with a liver biopsy obtained at a median of 387 days after DILI onset, 9 had chronic cholestasis, 3 had steatohepatitis, and 3 had chronic hepatitis.
CONCLUSION
75% of subjects with liver injury at 6 months after DILI onset have laboratory evidence of persistent liver injury during prolonged follow-up. Higher serum alkaline phosphatase levels at presentation and older patient age were independent predictors of persistent liver injury. Subjects with persistent liver injury at 12 months after DILI onset should be carefully monitored and assessed for liver disease progression.
doi:10.1038/ajg.2015.283
PMCID: PMC4784423  PMID: 26346867
Hepatotoxicity; cholestasis; liver histology; ductular reaction
10.  Spatial Predisposition of Dysplasia in Barrett's Esophagus Segments: A Pooled Analysis of The SURF and AIM – Dysplasia Trials 
Introduction
Surveillance endoscopy detects dysplasia within Barrett's esophagus (BE) and dictates treatment. Current biopsy regimens recommend uniformly-spaced random biopsies. We assessed the distribution of dysplasia in BE to develop evidence-based biopsy regimens.
Methods
We performed analysis of the distribution of dysplasia within BE, using pre-treatment biopsy data from two randomized controlled trials (RCT) of radiofrequency ablation (RFA) for dysplastic BE: the SURF Trial and the AIM Dysplasia Trial. We used generalized linear models with generalized estimating equations to estimate prevalence differences for dysplasia depending on the standardized location of biopsies. We performed Monte Carlo simulation of biopsy regimens to estimate their yield for any dysplasia within segments.
Results
Dysplasia preferentially resides in the proximal-most half of the BE segment, which is almost twice as likely to demonstrate dysplasia as the distal-most quartile. In pooled analysis, compared to the distal-most quarter, the prevalence difference in the proximal-most quarter was 22.6%, in the second proximal-most quarter 23.1%, and in the second distal-most quarter 15.3%. The best performing biopsy regimen in simulation studies acquired 8 biopsies in the most proximal centimeter of BE, 8 biopsies in the second cm, and 2 biopsies in each cm thereafter q1cm - (8, 8, 2, 2…). A slightly simpler q2cm regimen q2cm - (12, 12, 4…) was nearly as effective.
Conclusion
Post-hoc analysis of two RCTs reveals a substantially increased prevalence of dysplasia proximally in BE segments. Our simulations suggest an altered biopsy regimen could increase sensitivity of biopsies in short-segment BE by >30%.
doi:10.1038/ajg.2015.263
PMCID: PMC4785998  PMID: 26346864
12.  Editorial: Clarity and Caution in the Natural History of Low-Grade Dysplasia in Ulcerative Colitis 
A substantial body of evidence supports the safety of conservative endoscopic polypectomy for discrete, adenomatous-appearing, colonic polyps in patients with ulcerative colitis. Much less is known about the clinicopathologic factors of low-grade dysplastic lesions at risk for subsequent high-grade dysplasia or colorectal cancer. In this issue of the American Journal of Gastroenterology, Choi and colleagues examine the outcome of patients with low-grade dysplasia participating in a surveillance cohort at St. Mark’s Hospital, one of the oldest and largest programs of its kind. Long-term follow-up of many, well-phenotyped, low-grade dysplasia cases sheds new light, and raises new questions, on our ulcerative colitis surveillance practice.
doi:10.1038/ajg.2015.315
PMCID: PMC4896161  PMID: 26465907
13.  The Impact of Physical Complaints, Social Environment, and Psychological Functioning on IBS Patients’ Health Perceptions: Looking Beyond GI Symptom Severity 
OBJECTIVES
In the absence of a reliable biomarker, clinical decisions for a functional gastrointestinal (GI) disorder like irritable bowel syndrome (IBS) depend on asking patients to appraise and communicate their health status. Self-ratings of health (SRH) have proven a powerful and consistent predictor of health outcomes, but little is known about how they relate to those relevant to IBS (e.g., quality of life (QOL), IBS symptom severity). This study examined what psychosocial factors, if any, predict SRH among a cohort of more severe IBS patients.
METHODS
Subjects included 234 Rome III-positive IBS patients (mean age = 41 years, female = 78%) without comorbid organic GI disease. Subjects were administered a test battery that included the IBS Symptom Severity Scale, Screening for Somatoform Symptoms, IBS Medical Comorbidity Inventory, SF-12 Vitality Scale, Perceived Stress Scale, Beck Depression Inventory, Trait Anxiety Inventory, and Negative Interactions Scale.
RESULTS
Partial correlations identified somatization, depression, fatigue, stress, anxiety, and medical comorbidities as variables with the strongest correlations with SRH (r values = 0.36–0.41, P values < 0.05). IBS symptom severity was weakly associated with SRH (r = 0.18, P < 0.05). The final regression model explained 41.3% of the variance in SRH scores (F = 8.49, P < 0.001) with significant predictors including fatigue, medical comorbidities, somatization, and negative social interactions.
CONCLUSIONS
SRH are associated with psychological (anxiety, stress, depression), social (negative interactions), and extraintestinal somatic factors (fatigue, somatization, medical comorbidities). The severity of IBS symptoms appears to have a relatively modest role in how IBS patients describe their health in general.
doi:10.1038/ajg.2013.410
PMCID: PMC5039032  PMID: 24419481
14.  Duration of Inflammatory Bowel Disease Is Associated With Increased Risk of Cholangiocarcinoma in Patients With Primary Sclerosing Cholangitis and IBD 
OBJECTIVES
Primary sclerosing cholangitis (PSC) often coexists with inflammatory bowel disease (IBD) and can be complicated by cholangiocarcinoma (CCA), a lethal malignancy for which reliable predictors remain unknown. We aimed to characterize the influence of colectomy and IBD duration on risk of CCA in patients with PSC-IBD.
METHODS
A retrospective review of patients with PSC-IBD seen at the Mayo Clinic, Rochester, between January 2005 and May 2013 was performed. The primary outcome was time to development of CCA and our goal was to determine whether the risk differed between patients with and without colectomy. Risk factors were assessed using univariable and multivariable Cox proportional hazard models where colectomy, IBD disease duration, and development of advanced liver disease were treated as time-dependent covariates.
RESULTS
A total of 399 patients with PSC-IBD were included in the study, of whom 137 had a colectomy and 123 patients developed CCA. Age-adjusted univariate Cox proportional hazard models demonstrated that colectomy (hazard ratio (HR) 1.53, 95% confidence interval (CI) 1.05–2.22, P =0.02) and duration of IBD (HR 1.37, 95% CI 1.15–1.63, P <0.01) were associated with an increased risk of CCA, and colonic neoplasia (HR 1.52, 95% CI 0.97–2.37, P =0.06) and colectomy for colonic neoplasia (HR 1.62, 95% CI 1.01–2.61, P =0.05) approached significance. Among patients with a history of colectomy, colonic neoplasia as the indication for surgery was associated with a particularly increased risk of CCA (HR 2.91, 95% CI 1.24–6.84, P =0.01) compared with medically refractory disease. On multivariate analysis, duration of IBD remained significantly associated with CCA (HR 1.33, 95% CI 1.11–1.60, P <0.01). The influence of IBD duration on CCA risk was not modified after colectomy (P =0.69).
CONCLUSIONS
Prolonged duration of IBD is associated with an increased risk of CCA in patients with PSC-IBD, and colectomy itself does not modify this risk. These findings identify a subset of patients who are at high risk of this lethal complication and in need of close surveillance.
doi:10.1038/ajg.2016.55
PMCID: PMC5027894  PMID: 27002801
15.  A clinical prediction tool identifies cases of eosinophilic esophagitis without endoscopic biopsy: A prospective study 
Objectives
Eosinophilic esophagitis (EoE) is difficult to distinguish from gastroesophageal reflux (GERD) and other causes of dysphagia. We assessed the utility of a set of clinical and endoscopic features for predicting EoE without obtaining esophageal biopsies.
Methods
We prospectively enrolled consecutive adults undergoing outpatient upper endoscopy at University of North Carolina from 7/2011–12/2013. Incident cases of EoE were diagnosed per consensus guidelines. Non-EoE controls had either GERD- or dysphagia-predominant symptoms. A predictive model containing clinical and endoscopic, but no histologic data was assessed. Receiver operator characteristic (ROC) curves were constructed and the area under the curve (AUC) was calculated.
Results
A total of 81 EoE cases (mean age 38 years; 60% male; 93% white; 141 eos/hpf) and 144 controls (mean age 52, 38% male; 82% white; 3 eos/hpf) were enrolled. A combination of clinical (age, sex, dysphagia, food allergy) and endoscopic (rings, furrows, plaques, hiatal hernia) features was highly predictive of EoE. The AUC was 0.944, with sensitivity, specificity, and accuracy of 84%, 97%, and 92%. Similar values were seen after limiting controls to those with only reflux or dysphagia, or to those with esophageal eosinophilia not due to EoE.
Conclusions
We validated a set of clinical and endoscopic features to predict EoE with a high degree of accuracy, and allow identification of those at very low risk of disease. Use of these predictors at the point-of-care will avoid the effort and expense of low-yield histological examinations for EoE.
doi:10.1038/ajg.2015.239
PMCID: PMC4586067  PMID: 26303128
Eosinophilic esophagitis; gastroesophageal reflux disease; clinical prediction tool; validation; diagnosis
16.  Altered Colonic Bacterial Fermentation as a Potential Pathophysiological Factor in Irritable Bowel Syndrome 
OBJECTIVES
Dysbiosis leading to abnormal intestinal fermentation has been suggested as a possible etiological mechanism in irritable bowel syndrome (IBS). We aimed to investigate the location and magnitude of altered intestinal bacterial fermentation in IBS and its clinical subtypes.
METHODS
One hundred fourteen IBS patients who satisfied Rome III criteria and 33 healthy controls (HC) were investigated. Intestinal fermentation was assessed using two surrogate measures: intestinal intraluminal pH and fecal short chain fatty acids (SCFAs). Intraluminal pH and intestinal transit time were measured in the small and large bowel using a wireless motility capsule (SmartPill™) in 47 IBS and 10 HC. Fecal SCFAs including acetate, propionate, butyrate and lactate were analyzed by capillary gas chromatography in all enrolled subjects. Correlations between intestinal pH, fecal SCFAs, intestinal transit time and IBS symptom scores were analyzed.
RESULTS
Colonic intraluminal pH levels were significantly lower in IBS patients compared to HC (total colonic pH, 6.8 for IBS vs. 7.3 for HC, P = 0.042). There were no differences in total and segmental pH levels in the small bowel between IBS patients and HC (6.8 vs. 6.8, P = NS). The intraluminal colonic pH differences were consistent in all IBS subtypes. Total SCFAs level was significantly lower in C-IBS patients than in D-IBS and M-IBS patients and HC. The total SCFAs level in all IBS subjects was similar with that of HC. Colonic pH levels correlated positively with colon transit time (CTT) and IBS symptoms severity. Total fecal SCFAs levels correlated negatively with CTT, and positively with stool frequency.
CONCLUSIONS
Colonic intraluminal pH is decreased, suggesting higher colonic fermentation, in IBS patients compared with HC. Fecal SCFAs are not a sensitive marker to estimate intraluminal bacterial fermentation.
doi:10.1038/ajg.2015.220
PMCID: PMC4983766  PMID: 26303129
Irritable Bowel Syndrome; Fermentation; Short chain fatty acids
18.  Diagnosis of esophageal motility disorders: esophageal pressure topography versus conventional line tracing 
Background
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 EPT (OR 3.4; 2.4–5.0; p<0.0001).
Conclusions
Superior inter-rater agreement and diagnostic accuracy of esophageal motility diagnoses was demonstrated with analysis using EPT over CLT among our selected raters. Based on these findings, EPT may be the preferred assessment modality of esophageal motility.
doi:10.1038/ajg.2015.159
PMCID: PMC4587659  PMID: 26032151
esophageal manometry; esophageal pressure topography; esophageal motility disorder
20.  Safety and Efficacy of Ombitasvir/Paritaprevir/Ritonavir Plus Dasabuvir With or Without Ribavirin in HCV-Infected Patients Taking Concomitant Acid-Reducing Agents 
OBJECTIVES:
Acid-reducing agents (ARAs) and proton-pump inhibitors (PPIs) that increase gastric pH can alter the bioavailability of antiviral drugs, particularly relevant in patients with advanced liver disease caused by chronic hepatitis C virus (HCV) infection seeking therapy. Using integrated data from six phase 3 studies, we report the safety and efficacy of the 3-direct-acting antiviral (DAA) regimen containing ombitasvir (OBV, an NS5A inhibitor), ritonavir-boosted paritaprevir (PTV/r, an NS3/4A protease inhibitor), and dasabuvir (DSV, an NS5B polymerase inhibitor) with or without ribavirin (RBV) for HCV genotype 1 patients taking concomitant ARAs and PPIs.
METHODS:
Treatment-naïve or peginterferon/RBV treatment-experienced patients with or without compensated cirrhosis received OBV/PTV/r and DSV with or without weight-based RBV. Rates of sustained virologic response (SVR), defined as HCV RNA below the lower limit of quantification, 12 weeks post-treatment (SVR12) and safety were evaluated in patients who were receiving concomitant ARAs.
RESULTS:
Among 2,053 patients enrolled and dosed with study drug, 410 (20%) were receiving concomitant ARAs; of these, 308 (15%) were taking concomitant PPIs. Rates of SVR12 were 95.9% (95% confidence interval (CI) 93.5–97.4%) among patients receiving an ARA, and 96.3% (95% CI 95.3–97.2%) in patients not receiving a concomitant ARA. Similarly, among patients receiving a PPI or not, SVR12 was achieved in 95.1% (95% CI 92.1–97.0%) and 96.4% (95% CI 95.5–97.2%), respectively. Response rates were high regardless of treatment regimen (with or without RBV), and among patients receiving a standard or high dose of PPIs. Regarding safety, adverse events and serious adverse events were more frequently reported in patients taking concomitant ARAs, though baseline population differences may have played a role.
CONCLUSIONS:
In phase 3 trials of OBV/PTV/r plus DSV and RBV in HCV genotype 1-infected patients, SVR12 rates were high regardless of ARA/PPI use or PPI dose. These data support the co-administration of this regimen with ARAs including PPIs.
doi:10.1038/ajg.2016.108
PMCID: PMC4897007  PMID: 27045929
21.  Metagenomics Reveals Dysbiosis and a Potentially Pathogenic N. flavescens Strain in Duodenum of Adult Celiac Patients 
OBJECTIVES:
Celiac disease (CD)-associated duodenal dysbiosis has not yet been clearly defined, and the mechanisms by which CD-associated dysbiosis could concur to CD development or exacerbation are unknown. In this study, we analyzed the duodenal microbiome of CD patients.
METHODS:
The microbiome was evaluated in duodenal biopsy samples of 20 adult patients with active CD, 6 CD patients on a gluten-free diet, and 15 controls by DNA sequencing of 16S ribosomal RNA libraries. Bacterial species were cultured, isolated and identified by mass spectrometry. Isolated bacterial species were used to infect CaCo-2 cells, and to stimulate normal duodenal explants and cultured human and murine dendritic cells (DCs). Inflammatory markers and cytokines were evaluated by immunofluorescence and ELISA, respectively.
RESULTS:
Proteobacteria was the most abundant and Firmicutes and Actinobacteria the least abundant phyla in the microbiome profiles of active CD patients. Members of the Neisseria genus (Betaproteobacteria class) were significantly more abundant in active CD patients than in the other two groups (P=0.03). Neisseria flavescens (CD-Nf) was the most abundant Neisseria species in active CD duodenum. Whole-genome sequencing of CD-Nf and control-Nf showed genetic diversity of the iron acquisition systems and of some hemoglobin-related genes. CD-Nf was able to escape the lysosomal compartment in CaCo-2 cells and to induce an inflammatory response in DCs and in ex-vivo mucosal explants.
CONCLUSIONS:
Marked dysbiosis and an abundance of a peculiar CD-Nf strain characterize the duodenal microbiome in active CD patients thus suggesting that the CD-associated microbiota could contribute to the many inflammatory signals in this disorder.
doi:10.1038/ajg.2016.95
PMCID: PMC4897008  PMID: 27045926
22.  Identification of Pseudolysin (lasB) as an Aciduric Gluten-Degrading Enzyme with High Therapeutic Potential for Celiac Disease 
OBJECTIVES
Immunogenic gluten proteins implicated in celiac disease (CD) largely resist degradation by human digestive enzymes. Here we pursued the isolation of gluten-degrading organisms from human feces, aiming at bacteria that would digest gluten under acidic conditions, as prevails in the stomach.
METHODS
Bacteria with gluten-degrading activities were isolated using selective gluten agar plates at pH 4.0 and 7.0. Proteins in concentrated bacterial cell sonicates were separated by diethylaminoethanol chromatography. Enzyme activity was monitored with chromogenic substrates and gliadin zymography. Elimination of major immunogenic gluten epitopes was studied with R5 and G12 enzyme-linked immunosorbent assays.
RESULTS
Gliadin-degrading enzyme activities were observed for 43 fecal isolates, displaying activities in the ~150–200 and <50 kDa regions. The active strains were identified as Pseudomonas aeruginosa. Gliadin degradation in gel was observed from pH 2.0 to 7.0. Liquid chromatography–electrospray ionization–tandem mass spectrometry analysis identified the enzyme as pseudolysin (lasB), a metalloprotease belonging to the thermolysin (M4) family proteases. Its electrophoretic mobility in SDS–polyacrylamide gel electrophoresis and gliadin zymogram gels was similar to that of a commercial lasB preparation, with tendency of oligomerization. Pseudolysin eliminated epitopes recognized by the R5 antibody, while those detected by the G12 antibody remained intact, despite destruction of the nearby major T-cell epitope QPQLPY.
CONCLUSIONS
Pseudolysin was identified as an enzyme cleaving gluten effectively at extremely low as well as near-neutral pH values. The potential to degrade gluten during gastric transport opens possibilities for its application as a novel therapeutic agent for the treatment of CD.
doi:10.1038/ajg.2015.97
PMCID: PMC4461489  PMID: 25895519
23.  Utility of a non-invasive serum biomarker panel for diagnosis and monitoring of eosinophilic esophagitis: A prospective study 
Objectives
Non-invasive biomarkers would be valuable for diagnosis and monitoring of eosinophilic esophagitis (EoE). The aim of this study was to determine the utility of a panel of serum biomarkers for the diagnosis and management of EoE.
Methods
We conducted a prospective cohort study of consecutive adults undergoing outpatient EGD. Incident cases of EoE were diagnosed per consensus guidelines; controls had GERD or dysphagia and did not meet EoE criteria. EoE cases were treated with topical steroids and had repeat endoscopy. Pre- and post-treatment serum samples were analyzed in a blinded fashion for: IL-4, IL-5, IL-6, IL-9, IL-13, TGF-α, TGF-β, TNF-α, eotaxin-1, -2, and -3, TSLP, major basic protein (MBP), and eosinophil-derived neurotoxin (EDN). Cases and controls were compared at baseline, and pre- and post-treatment assays were compared in cases.
Results
A total of 61 incident EoE cases and 87 controls were enrolled; 51 EoE cases had post-treatment serum analyzed. There were no significant differences in any of the biomarkers between EoE cases and controls at baseline. IL-13 and eotaxin-3 for cases and controls were 85 ±160 vs 43 ±161 pg/mL (p=0.12), and 41 ±159 vs 21 ±73 (p=0.30). There were no significant differences in assay values among cases before and after treatment. There were also no differences after stratification by atopic status or treatment response.
Conclusions
A panel of inflammatory factors known to be associated with EoE pathogenesis were not increased in the serum, nor were they responsive to therapy. None of these biomarkers are likely candidates for a serum test for EoE. Histologic analysis for diagnosis and management of EoE continues to be necessary, and novel, less invasive, biomarkers are needed.
doi:10.1038/ajg.2015.57
PMCID: PMC4578703  PMID: 25781367
Eosinophilic esophagitis; biomarkers; serum; inflammation; cytokines
24.  Cost-Utility of Competing Strategies to Prevent Endoscopic Transmission of Carbapenem-Resistant Enterobacteriaceae 
OBJECTIVES
Prior reports have linked patient transmission of carbapenem-resistant Enterobacteriaceae (CRE, or “superbug”) to endoscopes used during endoscopic retrograde cholangiopancreatography (ERCP). We performed a decision analysis to measure the cost-effectiveness of four competing strategies for CRE risk management.
METHODS
We used decision analysis to calculate the cost-effectiveness of four approaches to reduce the risk of CRE transmission among patients presenting to the hospital for symptomatic common bile duct stones. The strategies included: (1) perform ERCP followed by U.S. Food and Drug Administration (FDA)-recommended endoscope reprocessing procedures; (2) perform ERCP followed by “endoscope culture and hold”; (3) perform ERCP followed by ethylene oxide (EtO) sterilization of the endoscope; and (4) stop performing ERCP in lieu of laparoscopic cholecystectomy (LC) with common bile duct exploration (CBDE). Our outcome was incremental cost per quality-adjusted life year (QALY) gained.
RESULTS
In the base-case scenario, ERCP with FDA-recommended endoscope reprocessing was the most cost-effective strategy. Both the ERCP with culture and hold ($4,228,170/QALY) and ERCP with EtO sterilization ($50,572,348/QALY) strategies had unacceptable incremental costs per QALY gained. LC with CBDE was dominated, being both more costly and marginally less effective versus the alternatives. In sensitivity analysis, ERCP with culture and hold became the most cost-effective approach when the pretest probability of CRE exceeded 24%.
CONCLUSIONS
In institutions with a low CRE prevalence, ERCP with FDA-recommended reprocessing is the most cost-effective approach for mitigating CRE transmission risk. Only in settings with an extremely high CRE prevalence did ERCP with culture and hold become cost-effective.
doi:10.1038/ajg.2015.358
PMCID: PMC4721926  PMID: 26526083
25.  Adherence to Competing Strategies for Colorectal Cancer Screening Over 3 Years 
Objectives
We have shown that, in a randomized trial comparing adherence to different colorectal cancer (CRC) screening strategies, participants assigned to either fecal occult blood testing (FOBT) or given a choice between FOBT and colonoscopy had significantly higher adherence than those assigned to colonoscopy during the first year. However, how adherence to screening changes over time is unknown.
Methods
In this trial, 997 participants were cluster randomized to one of the three screening strategies: (i) FOBT, (ii) colonoscopy, or (iii) a choice between FOBT and colonoscopy. Research assistants helped participants to complete testing only in the first year. Adherence to screening was defined as completion of three FOBT cards in each of 3 years after enrollment or completion of colonoscopy within the first year of enrollment. The primary outcome was adherence to assigned strategy over 3 years. Additional outcomes included identification of sociodemographic factors associated with adherence.
Results
Participants assigned to annual FOBT completed screening at a significantly lower rate over 3 years (14%) than those assigned to colonoscopy (38%, P<0.001) or choice (42%, P<0.001); however, completion of any screening test fell precipitously, indicating the strong effect of patient navigation. In multivariable logistic regression analysis, being randomized to the choice or colonoscopy group, Chinese language, homosexuality, being married/partnered, and having a non-nurse practitioner primary care provider were independently associated with greater adherence to screening (P<0.01).
Conclusions
In a 3-year follow-up of a randomized trial comparing competing CRC screening strategies, participants offered a choice between FOBT and colonoscopy continued to have relatively high adherence, whereas adherence in the FOBT group fell significantly below that of the choice and colonoscopy groups. Patient navigation is crucial to achieving adherence to CRC screening, and FOBT is especially vulnerable because of the need for annual testing.
doi:10.1038/ajg.2015.367
PMCID: PMC4887132  PMID: 26526080

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