Prevalence and risk factors of recurrent aphthous stomatitis among college students at Mangalore, India.

Background: Recurrent aphthous stomatitis (RAS) is one of the most common oral mucosal diseases affecting an approximate 25% of the world's population. Some common etiological factors are genetics, nutritional deficiencies, stress and immune dysfunction. There is currently no specific medication to treat the condition but RAS tends to heal by itself within a week or two. We aimed to explore about the prevalence and related risk factors of recurrent aphthous ulcers among college students aged 18-30 years who had been affected within the preceding six months prior to the study duration. Methods: A questionnaire survey was conducted among 681 students from four colleges in Mangalore, Karnataka, India after obtaining the approval for the same from the respective colleges. Consenting participants returned a survey containing various questions. The collected data was then analyzed using descriptive statistics. The study was approved by the Institutional Ethics Committee. Results: Of the 681 participants, 322 (47.2%) were affected with RAS in the past six months which included 131 (40.6%) males and 191 (59.3%) females. Single mouth ulcers were the most common presentation seen among the study participants (74.2%). Factors showing statistically significant association were: family history of RAS (P < 0.001), known diabetics (P < 0.001), history of smoking (P < 0.001), oral trauma (P < 0.001), history of wearing braces/dentures (P < 0.001) as well as those using toothpastes containing sodium lauryl sulphate (P < 0.001), stress and lack of sleep (P < 0.001). The most common form of medication used were topical agents (43.1%) (P < 0.001). Conclusions: There was a statistically significant association between the occurrence of RAS and family history of RAS, diabetes, smoking, history of braces/dentures, oral trauma, sodium lauryl sulphate toothpastes, lack of sleep, stress, menstruation, consumption of particular foods and beverages. Further research is needed in this field to truly understand the prevalence and risk factors of RAS and to help in discovering a treatment modality for this condition.

Overweight and Obese Status Is Not Associated With Disease Activity for Children and Adolescents With Newly Diagnosed Inflammatory Bowel Disease.

INTRODUCTION: Despite the high prevalence of pediatric obesity, its impact on Crohn's disease (CD) and ulcerative colitis (UC) activity remains poorly characterized. The aim of this study was to evaluate disease-related outcomes in overweight and obese children with CD and UC. METHODS: We conducted a retrospective cohort study using the ImproveCareNow Network, a multicenter registry of children with inflammatory bowel disease. We included children with newly diagnosed CD and UC enrolled in ImproveCareNow Network from September 2006 to December 2018 who had at least 1 follow-up visit 12-18 months after diagnosis. Patients were stratified into normal weight, overweight, or obese categories. Primary outcome was remission at 1 year based on physician's global assessment (PGA); key secondary outcomes included short pediatric CD activity index and pediatric UC activity index. RESULTS: There were 4,972 children included (70% CD). Compared with normal weight, obese and overweight children with CD did not have worse disease activity at 1 year based on PGA. However, obese children did have modestly worse disease activity based on short pediatric CD activity index (inactive 43% vs 58%, mild 48% vs 36%, and moderate-severe 9% vs 7% for obese vs normal weight, P < 0.01). For children with UC, there were no differences in disease activity at 1 year based on PGA or pediatric UC activity index. Logistic regression mirrored these findings. DISCUSSION: Obese and overweight children with newly diagnosed inflammatory bowel disease do not seem to have worsened disease activity at 1 year after diagnosis compared with normal weight children.

Single-Cell Analysis Reveals Unexpected Cellular Changes and Transposon Expression Signatures in the Colonic Epithelium of Treatment-Naïve Adult Crohn's Disease Patients.

BACKGROUND & AIMS: The intestinal barrier comprises a monolayer of specialized intestinal epithelial cells (IECs) that are critical in maintaining mucosal homeostasis. Dysfunction within various IEC fractions can alter intestinal permeability in a genetically susceptible host, resulting in a chronic and debilitating condition known as Crohn's disease (CD). Defining the molecular changes in each IEC type in CD will contribute to an improved understanding of the pathogenic processes and the identification of cell type-specific therapeutic targets. We performed, at single-cell resolution, a direct comparison of the colonic epithelial cellular and molecular landscape between treatment-naïve adult CD and non-inflammatory bowel disease control patients. METHODS: Colonic epithelial-enriched, single-cell sequencing from treatment-naïve adult CD and non-inflammatory bowel disease patients was investigated to identify disease-induced differences in IEC types. RESULTS: Our analysis showed that in CD patients there is a significant skew in the colonic epithelial cellular distribution away from canonical LGR5+ stem cells, located at the crypt bottom, and toward one specific subtype of mature colonocytes, located at the crypt top. Further analysis showed unique changes to gene expression programs in every major cell type, including a previously undescribed suppression in CD of most enteroendocrine driver genes as well as L-cell markers including GCG. We also dissect an incompletely understood SPIB+ cell cluster, revealing at least 4 subclusters that likely represent different stages of a maturational trajectory. One of these SPIB+ subclusters expresses crypt-top colonocyte markers and is up-regulated significantly in CD, whereas another subcluster strongly expresses and stains positive for lysozyme (albeit no other canonical Paneth cell marker), which surprisingly is greatly reduced in expression in CD. In addition, we also discovered transposable element markers of colonic epithelial cell types as well as transposable element families that are altered significantly in CD in a cell type-specific manner. Finally, through integration with data from genome-wide association studies, we show that genes implicated in CD risk show heretofore unknown cell type-specific patterns of aberrant expression in CD, providing unprecedented insight into the potential biological functions of these genes. CONCLUSIONS: Single-cell analysis shows a number of unexpected cellular and molecular features, including transposable element expression signatures, in the colonic epithelium of treatment-naïve adult CD.

Health Maintenance Consensus for Adults With Inflammatory Bowel Disease.

BACKGROUND: With the management of inflammatory bowel disease (IBD) becoming increasingly complex, incorporating preventive care health maintenance measures can be challenging. The aim of developing these updated recommendations is to provide more specific details to facilitate their use into a busy clinical practice setting. METHOD: Fifteen statements were formulated with recommendations regarding the target, timing, and frequency of the health maintenance interventions in patients with IBD. We used a modified Delphi method and a literature review to establish a consensus among the panel of experts. The appropriateness of each health maintenance statement was rated on a scale of 1 to 5 (1-2 as inappropriate, and 4-5 as appropriate) by each panelist. Interventions were considered appropriate, and statements were accepted if ≥80% of the panelists agreed with a score ≥4. RESULTS: The panel approved 15 health maintenance recommendations for adults with IBD based on the current literature and expert opinion. These recommendations include explicit details regarding specific screening tools, timing of screening, and vaccinations for adults with IBD. CONCLUSIONS: Patients with IBD are at an increased risk for infections, malignancies, and other comorbidities. Given the complexity of caring for patients with IBD, this focused list of recommendations can be easily incorporated in to clinical care to help eliminate the gap in preventative care for patients with IBD.

Increased colonic expression of ACE2 associates with poor prognosis in Crohn's disease.

The host receptor for SARS-CoV-2, angiotensin-converting enzyme 2 (ACE2), is highly expressed in small intestine. Our aim was to study colonic ACE2 expression in Crohn's disease (CD) and non-inflammatory bowel disease (non-IBD) controls. We hypothesized that the colonic expression levels of ACE2 impacts CD course. We examined the expression of colonic ACE2 in 67 adult CD and 14 NIBD control patients using RNA-seq and quantitative (q) RT-PCR. We validated ACE2 protein expression and localization in formalin-fixed, paraffin-embedded matched colon and ileal tissues using immunohistochemistry. The impact of increased ACE2 expression in CD for the risk of surgery was evaluated by a multivariate regression analysis and a Kaplan-Meier estimator. To provide critical support for the generality of our findings, we analyzed previously published RNA-seq data from two large independent cohorts of CD patients. Colonic ACE2 expression was significantly higher in a subset of adult CD patients which was defined as the ACE2-high CD subset. IHC in a sampling of ACE2-high CD patients confirmed high ACE2 protein expression in the colon and ileum compared to ACE2-low CD and NIBD patients. Notably, we found that ACE2-high CD patients are significantly more likely to undergo surgery within 5 years of CD diagnosis, and a Cox regression analysis found that high ACE2 levels is an independent risk factor for surgery (OR 2.17; 95% CI, 1.10-4.26; p = 0.025). Increased intestinal expression of ACE2 is associated with deteriorated clinical outcomes in CD patients. These data point to the need for molecular stratification that can impact CD disease-related outcomes.

Increased Colonic Expression of ACE2 Associates with Poor Prognosis in Crohn's disease.

BACKGROUND AND AIMS: The host receptor for SARS-CoV-2, angiotensin-converting enzyme 2 (ACE2), is highly expressed in small intestine. Our aim was to study colonic ACE2 expression in Crohn's disease (CD) and non-inflammatory bowel disease (non-IBD) controls. We hypothesized that the colonic expression levels of ACE2 impacts CD course. METHODS: We examined the expression of colon ACE2 using RNA-seq and quantitative (q) RT-PCR from 69 adult CD and 14 NIBD control patients. In a subset of this cohort we validated ACE2 protein expression and localization in formalin-fixed, paraffin-embedded matched colon and ileal tissues using immunohistochemistry. The impact of increased ACE2 expression in CD for the risk of surgery was evaluated by a multivariate regression analysis and a Kaplan-Meier estimator. To provide critical support for the generality of our findings, we analyzed previously published RNA-seq data from two large independent cohorts of CD patients. RESULTS: Colonic ACE2 expression was significantly higher in a subset of adult CD patients (ACE2-high CD). IHC in a sampling of ACE2-high CD patients confirmed high ACE2 protein expression in the colon and ileum compared to ACE2-low CD and NIBD patients. Notably, we found that ACE2-high CD patients are significantly more likely to undergo surgery within 5 years of diagnosis, with a Cox regression analysis finding that high ACE2 levels is an independent risk factor (OR 2.18; 95%CI, 1.05-4.55; p=0.037). CONCLUSION: Increased intestinal expression of ACE2 is associated with deteriorated clinical outcomes in CD patients. These data point to the need for molecular stratification that may impact CD disease-related outcomes.

Decreased Colonic Activin Receptor-Like Kinase 1 Disrupts Epithelial Barrier Integrity in Patients With Crohn's Disease.

BACKGROUND & AIMS: Intestinal epithelial cell (IEC) barrier dysfunction is critical to the development of Crohn's disease (CD). However, the mechanism is understudied. We recently reported increased microRNA-31-5p (miR-31-5p) expression in colonic IECs of CD patients, but downstream targets and functional consequences are unknown. METHODS: microRNA-31-5p target genes were identified by integrative analysis of RNA- and small RNA-sequencing data from colonic mucosa and confirmed by quantitative polymerase chain reaction in colonic IECs. Functional characterization of activin receptor-like kinase 1 (ACVRL1 or ALK1) in IECs was performed ex vivo using 2-dimensional cultured human primary colonic IECs. The impact of altered colonic ALK1 signaling in CD for the risk of surgery and endoscopic relapse was evaluated by a multivariate regression analysis and a Kaplan-Meier estimator. RESULTS: ALK1 was identified as a target of miR-31-5p in colonic IECs of CD patients and confirmed using a 3'-untranslated region reporter assay. Activation of ALK1 restricted the proliferation of colonic IECs in a 5-ethynyl-2-deoxyuridine proliferation assay and down-regulated the expression of stemness-related genes. Activated ALK1 signaling increased colonic IEC differentiation toward colonocytes. Down-regulated ALK1 signaling was associated with increased stemness and decreased colonocyte-specific marker expression in colonic IECs of CD patients compared with healthy controls. Activation of ALK1 enhanced epithelial barrier integrity in a transepithelial electrical resistance permeability assay. Lower colonic ALK1 expression was identified as an independent risk factor for surgery and was associated with a higher risk of endoscopic relapse in CD patients. CONCLUSIONS: Decreased colonic ALK1 disrupted colonic IEC barrier integrity and was associated with poor clinical outcomes in CD patients.

Identifying IBD Providers' Knowledge Gaps Using a Prospective Web-based Survey.

BACKGROUND: As treatments, management strategies, and the role of advanced practice providers (APPs) have evolved in recent years, the Crohn's & Colitis Foundation sought to understand the educational and resource needs of clinicians caring for patients with inflammatory bowel diseases (IBDs). The aim of this study was to describe the self-identified IBD knowledge and resource gaps of clinicians to inform the development of future programming. METHODS: A survey containing 19 questions created by the foundation's Professional Education Committee, a subset of its National Scientific Advisory Committee, was conducted from September 7, 2018 to October 15, 2018. Responses were included from providers if they were currently seeing any IBD patients in a clinical setting. The foundation distributed the survey by email and various social media channels to encourage a diverse response. The survey included questions on comfort levels around diagnosis, treatment, and management of patients with IBD, in addition to preferences and utilization of educational resources. The × 2 test was used to evaluate significant differences among respondents in the various domains surveyed. RESULTS: There were 197 eligible responses, of which 75% were from MD/Dos, followed by 25% APN/PA/RN/MSN/PhD/other; and 70% of respondents provide care for adult patients. The amount of time in practice was divided evenly among respondents. Fifty-seven percent of respondents practice in an academic/university setting, and approximately 75% indicated that ≥21% of their practice consisted of patients with IBD. Forty-four percent and 46% of respondents reported access to IBD based mental health providers and social workers in their practice, respectively. Seventy-two percent reported access to radiologists, 69% had access to dietitians, and 62% had access to advance practice providers. The areas of greatest educational need were prescribing medical cannabis (if approved locally) for pain management (62%); caring for patients with prior malignancy (35%); caring for pregnant patients and family planning (33%); caring for elderly patients (30%); and therapy decisions, including use of JAK inhibitors (29%), drug holidays (25%), and use of biosimilars (24%). More than 50% of respondents stated they do not participate in shared decision-making, citing time as the most common limiting factor. The majority of providers cited live education as their preferred learning format, and they wish to earn continuing medical education (CME) hours. CONCLUSION: This survey helped identify current IBD educational needs in our professional community. With a rapidly changing treatment landscape and an increase in the diversity of providers delivering care, additional opportunities to keep abreast of practice changes are critical to providing comprehensive, quality care in IBD. Our survey demonstrated that shared decision-making is underutilized in practice due to a need for resources that aid in its efficient integration into practice. Based on our results, a focus on creating live learning opportunities that offer CME are needed in the areas of therapeutic decision-making and treating IBD in special subsets (eg, prior malignancy, pregnancy, elderly).

Chronic Antibiotic Dependent Pouchitis Is Associated With Older Age at the Time of Ileal Pouch Anal Anastomosis (J-pouch) Surgery.

BACKGROUND: Risk factors for the development of chronic antibiotic dependent pouchitis (CADP) are not well understood. METHODS: Using multivariable logistic regression, we compared clinical factors between 194 patients with acute antibiotic responsive pouchitis or CADP. RESULTS: Individuals with CADP were significantly older (40.9 vs 30.8 years, P < 0.001) and demonstrated a longer disease duration before IPAA (10.3 vs 7.0 years, P = 0.004). Age ≥55 years at the time of IPAA was significantly associated with CADP (adjusted odds ratio = 4.35, 95% confidence interval = 1.01-18.7). CONCLUSIONS: Although older age should not represent a barrier to IPAA, further studies evaluating etiologies of this association are warranted.

Bariatric Surgery Is a Safe and Effective Option for Patients with Inflammatory Bowel Diseases: A Case Series and Systematic Review of the Literature.

BACKGROUND: Questions remain regarding both the safety and efficacy of bariatric surgery in patients with inflammatory bowel diseases (IBD), including the effects of bariatric surgery on the course of disease. We report a case series from a tertiary care IBD referral center and review the existing literature regarding the safety and efficacy of bariatric surgery in IBD patients. OBJECTIVES: Examine the safety and efficacy of bariatric surgery in IBD patients. Explore possible effects of weight loss on postoperative IBD course. METHOD: We performed a retrospective review of patients at our center undergoing bariatric surgery with a concurrent IBD diagnosis, collecting baseline characteristics, surgery type, and postoperative course (including IBD outcomes and weight loss). Data from these patients were combined with available data from the existing literature to calculate standardized means with standard error, variance, and confidence intervals (CI). RESULTS: Data from 13 patients who had undergone bariatric surgery at our facility were combined with data from 8 other studies to create a study population of 101 patients. Of these, 61 had Crohn's disease, 37 ulcerative colitis, and 3 IBD-unspecified, with a mean preoperative BMI of 44.2 (95% CI 42.9-45.7). Following surgery, a mean excess weight loss of 68.4% was demonstrated (95% CI, 65.7-71.2). Of the 101 patients, 22 experienced early and 20 experienced late postoperative complications. Postoperatively, 10 patients experienced a flare of IBD, 20 remained in remission, and 7 patients were able to discontinue immunosuppressive therapy. CONCLUSIONS: Based on available studies, bariatric surgery appears to be both an effective and safe option for weight loss in patients with IBD.

Obesity Does Not Affect Early Outcomes in Children With Newly Diagnosed Crohn Disease.

The impact of obesity on pediatric Crohn disease (CD) remains poorly characterized. We aimed to evaluate disease-related outcomes in overweight and obese children with CD, compared to normal-weight children. We conducted a retrospective cohort study of children with newly diagnosed CD enrolled in the ImproveCareNow Network. Patients were stratified into normal weight, overweight, and obese groups using standardized weight percentiles. A total of 898 children were included, with 87 children (10%) being overweight and 43 children (5%) being obese; baseline characteristics were similar between groups. There was no significant difference in number of visits in remission during 1 year between normal weight, overweight, and obese children. At 1-year follow-up, nutritional status, growth status, or medication use also did not differ between groups. Hence, obesity does not appear to adversely affect CD outcomes in children with newly diagnosed CD in the first year after diagnosis.

Colonic ulcerations may predict steroid-refractory course in patients with ipilimumab-mediated enterocolitis.

AIM: To investigate management of patients who develop ipilimumab-mediated enterocolitis, including association of endoscopic findings with steroid-refractory symptoms and utility of infliximab as second-line therapy. METHODS: We retrospectively reviewed all patients at our center with metastatic melanoma who were treated with ipilimumab between March 2011 and May 2014. All patients received a standard regimen of intravenous ipilimumab 3 mg/kg every 3 wk for four doses or until therapy was stopped due to toxicity or disease progression. Basic demographic and clinical data were collected on all patients. For patients who developed grade 2 or worse diarrhea (increase of 4 bowel movements per day), additional data were collected regarding details of gastrointestinal symptoms, endoscopic findings and treatment course. Descriptive statistics were used. RESULTS: A total of 114 patients were treated with ipilimumab during the study period and all were included. Sixteen patients (14%) developed ≥ grade 2 diarrhea. All patients were treated with high-dose corticosteroids (1-2 mg/kg prednisone daily or equivalent). Nine of 16 patients (56%) had ongoing diarrhea despite high-dose steroids. Steroid-refractory patients received one dose of intravenous infliximab at 5 mg/kg, and all but one had brisk resolution of diarrhea. Fourteen of the patients underwent either colonoscopy or sigmoidoscopy with variable endoscopic findings, ranging from mild erythema to colonic ulcers. Among 8 patients with ulcers demonstrated by sigmoidoscopy or colonoscopy, 7 patients (88%) developed steroid-refractory symptoms requiring infliximab. With a median follow-up of 264 d, no major adverse events associated with prednisone or infliximab were reported. CONCLUSION: In patients with ipilimumab-mediated enterocolitis, the presence of colonic ulcers on endoscopy was associated with a steroid-refractory course.

Safety and efficacy of laser lithotripsy for complicated biliary stones using direct choledochoscopy.

BACKGROUND: The first-line therapy for choledocholithiasis is endoscopic retrograde cholangiopancreatography (ERCP) with stone extraction, which is successful in over 90% of cases. However, large biliary stones often require extracorporeal shockwave lithotripsy, electrohydraulic lithotripsy (EHL), or laser lithotripsy. The objective of our study was to assess the safety and efficacy of laser lithotripsy with choledochoscopy guidance. METHODS: Between March 2001 and November 2009, laser lithotripsy with a holmium laser was used for complicated bile stones in 20 patients. All patients included had failed standard stone extraction techniques after a mean of 2.1 ± 1.1 ERCP sessions. Main outcome measures included complete stone clearance and complications post-procedure. RESULTS: Twenty patients (mean age 61.0 ± 22.3 years, six men) underwent laser lithotripsy with a mean stone size was 2.2 cm (range 1.1-3.5 cm) and a mean number of stones of 2.2 (range 1-6). A mean of 0.25 ± 0.20 kJ was applied during laser lithotripsy sessions with a mean procedure time of 85.3 ± 23.0 min. The majority (18/20, 90%) achieved final clearance after a mean of 1.4 ± 0.8 (29 total) laser sessions and a mean of 1.9 ± 0.8 (38 total) ERCP sessions. Five complications occurred: two patients required post-procedure admission for pain and three patients had bile leaks. All bile leaks were minor and resolved after biliary stenting. CONCLUSIONS: Laser lithotripsy using the holmium laser is safe and effective with direct cholangioscopic guidance. Further prospective studies are warranted.

Mortality in patients undergoing covered self-expandable metal stent revisions in malignant biliary stricture: does pathology matter?

BACKGROUND AND AIMS: Partially covered metal stents have been extensively used for palliation of obstructive jaundice in malignant distal biliary strictures and can be removed in cases of malfunction or need for tissue diagnosis. We investigated independent predictors of mortality in patients undergoing partially covered metal stents revision (i.e., removal and replacement). METHODS: Patients with a distal malignant biliary obstruction palliated with a partially covered metal stent were followed-up prospectively over 5 years until malfunction or death. All patients who required removal of their partially covered metal stents were captured in a specific database. Multivariate analysis was performed on non-surgical patients to assess for independent predictors of death using known risk factors including type of malignancy (adenocarcinoma versus all others), age greater than 55, gender, and exposure to adjuvant chemotherapy and/or radiotherapy. RESULTS: Forty-two patients (28 men, mean age of 62±12 years) underwent partially covered metal stents removal. Of these, biliary drainage was achieved in 38 patients by placement of a new partially covered metal stent (n=32) or plastic stent (n=6). The remaining 4 patients did not undergo stent replacement because of refusal (2), resolution of obstruction (1) and unrelated death (1). Long-term follow-up post removal in patients who were not surgical candidates (n=31) was 35 weeks (95% CI 28-40), with a survival rate of 29% at 10 months. Logistic regression analysis in the 31 patients with unresectable disease showed that a histologic diagnosis of adenocarcinoma was associated with increased mortality post partially covered metal stents revision. CONCLUSIONS: Partially covered metal stents revision should be undertaken especially when dealing with a non-adenocarcinoma type cancer.

Management of complications associated with partially covered biliary metal stents.

BACKGROUND: Partially covered metal stents (PCMS) have been increasingly used for both malignant and benign biliary indications. This study reports their complications and subsequent management. METHODS: Over 5 years, all patients receiving biliary PCMS were followed prospectively until stent-related dysfunction or death. Data were analyzed for the following variables: primary disease, time until revision, and type and reason for revision. RESULTS: PCMS were placed in 396 patients (247 with malignant biliary strictures and 149 with benign biliary disease). Complications were observed in 70 patients (18%), occurring a mean time following placement of 159 days. Duodenal migration occurred in 27 cases (6.8%), while proximal migration occurred in 9 cases (2.3%). Cholecystitis was documented in 13 cases (3.3%). There were six cases of stent occlusion due to debris or sludge (1.6%), four cases of pancreatitis (1%), four cases of tumor overgrowth (1%), three cases of benign stenosis in the uncovered portion of the PCMS (0.8%), two cases of abdominal pain (0.5%), one case of an infected biloma (0.3%), and one case of a liver abscess (0.3%). CONCLUSIONS: Major complications associated with PCMS placement include migration and cholecystitis. Their management includes endoscopic revision, cholecystectomy, and gallbladder drainage. Further improvements in the structure and composition of PCMS may prevent these complications.