The Xenobiotic Transporter Mdr1 Enforces T Cell Homeostasis in the Presence of Intestinal Bile Acids.

CD4+ T cells are tightly regulated by microbiota in the intestine, but whether intestinal T cells interface with host-derived metabolites is less clear. Here, we show that CD4+ T effector (Teff) cells upregulated the xenobiotic transporter, Mdr1, in the ileum to maintain homeostasis in the presence of bile acids. Whereas wild-type Teff cells upregulated Mdr1 in the ileum, those lacking Mdr1 displayed mucosal dysfunction and induced Crohn's disease-like ileitis following transfer into Rag1-/- hosts. Mdr1 mitigated oxidative stress and enforced homeostasis in Teff cells exposed to conjugated bile acids (CBAs), a class of liver-derived emulsifying agents that actively circulate through the ileal mucosa. Blocking ileal CBA reabsorption in transferred Rag1-/- mice restored Mdr1-deficient Teff cell homeostasis and attenuated ileitis. Further, a subset of ileal Crohn's disease patients displayed MDR1 loss of function. Together, these results suggest that coordinated interaction between mucosal Teff cells and CBAs in the ileum regulate intestinal immune homeostasis.

Autotaxin loss accelerates intestinal inflammation by suppressing TLR4-mediated immune responses.

Autotaxin (ATX) converts lysophosphatidylcholine and sphingosyl-phosphorylcholine into lysophosphatidic acid and sphingosine 1-phosphate, respectively. Despite the pivotal function of ATX in lipid metabolism, mechanisms by which ATX regulates immune and inflammatory disorders remain elusive. Here, using myeloid cell lineage-restricted Atx knockout mice, we show that Atx deficiency disrupts membrane microdomains and lipid rafts, resulting in the inhibition of Toll-like receptor 4 (TLR4) complex formation and the suppression of adaptor recruitment, thereby inhibiting TLR4-mediated responses in macrophages. Accordingly, TLR4-induced innate immune functions, including phagocytosis and iNOS expression, are attenuated in Atx-deficient macrophages. Consequently, Atx-/- mice exhibit a higher bacterial prevalence in the intestinal mucosa compared to controls. When combined with global Il10-/- mice, which show spontaneous colitis due to the translocation of luminal commensal microbes into the mucosa, myeloid cell lineage-restricted Atx knockout accelerates colitis development compared to control littermates. Collectively, our data reveal that Atx deficiency compromises innate immune responses, thereby promoting microbe-associated gut inflammation.

Artificial Intelligence for Inflammatory Bowel Diseases (IBD); Accurately Predicting Adverse Outcomes Using Machine Learning.

BACKGROUND: Inflammatory Bowel Diseases with its complexity and heterogeneity could benefit from the increased application of Artificial Intelligence in clinical management. AIM: To accurately predict adverse outcomes in patients with IBD using advanced computational models in a nationally representative dataset for potential use in clinical practice. METHODS: We built a training model cohort and validated our result in a separate cohort. We used LASSO and Ridge regressions, Support Vector Machines, Random Forests and Neural Networks to balance between complexity and interpretability and analyzed their relative performances and reported the strongest predictors to the respective models. The participants in our study were patients with IBD selected from The OptumLabs® Data Warehouse (OLDW), a longitudinal, real-world data asset with de-identified administrative claims and electronic health record (EHR) data. RESULTS: We included 72,178 and 69,165 patients in the training and validation set, respectively. In total, 4.1% of patients in the validation set were hospitalized, 2.9% needed IBD-related surgeries, 17% used long-term steroids and 13% of patients were initiated with biological therapy. Of the AI models we tested, the Random Forest and LASSO resulted in high accuracies (AUCs 0.70-0.92). Our artificial neural network performed similarly well in most of the models (AUCs 0.61-0.90). CONCLUSIONS: This study demonstrates feasibility of accurately predicting adverse outcomes using complex and novel AI models on large longitudinal data sets of patients with IBD. These models could be applied for risk stratification and implementation of preemptive measures to avoid adverse outcomes in a clinical setting.

The effects of inflammatory bowel disease on caregivers: significant burden and loss of productivity.

BACKGROUND: Caregiver burden is the emotional, physical, practical, and/or financial burden associated with taking care of a patient with a chronic condition. Limited literature on caregiver burden in Inflammatory Bowel Diseases (IBD) has accounted for some predictors, but its effect on work productivity (absenteeism and presenteeism) is unknown. METHODS: In a prospective study, patients and their respective caregivers were surveyed from November 2015 until July 2017. Data on demographics, work productivity, quality of life, disease activity, caregiver burden and productivity were collected. The burden on caregivers was assessed and associations between caregiver productivity and caregiver burden were analyzed. Additionally, predictors for caregiver burden were identified. RESULTS: One hundred two IBD patients and their respective caregiver were included. In total, 39% of IBD caregivers experienced burden. Caregivers with burden experienced significantly more absenteeism and presenteeism (65 and 85% respectively). Furthermore, 51% of caregivers felt that they should be doing more for their care recipient and felt they could do a better job at caregiving. Predictors of burden included race/ethnicity, history of fistulas, diagnosis of ulcerative colitis, higher caregiver education, and hours spent caregiving. CONCLUSION: Caregivers with burden had significantly more productivity decrease compared to those without burden. Additionally, the majority of caregivers feel they should be providing more and better care for their recipients. The development of strategies to address caregiver's distress and perceived burden when caring for IBD patients is warranted.

An Exploration Into the Use of a Chatbot for Patients With Inflammatory Bowel Diseases: Retrospective Cohort Study.

BACKGROUND: The emergence of chatbots in health care is fast approaching. Data on the feasibility of chatbots for chronic disease management are scarce. OBJECTIVE: This study aimed to explore the feasibility of utilizing natural language processing (NLP) for the categorization of electronic dialog data of patients with inflammatory bowel diseases (IBD) for use in the development of a chatbot. METHODS: Electronic dialog data collected between 2013 and 2018 from a care management platform (UCLA eIBD) at a tertiary referral center for IBD at the University of California, Los Angeles, were used. Part of the data was manually reviewed, and an algorithm for categorization was created. The algorithm categorized all relevant dialogs into a set number of categories using NLP. In addition, 3 independent physicians evaluated the appropriateness of the categorization. RESULTS: A total of 16,453 lines of dialog were collected and analyzed. We categorized 8324 messages from 424 patients into seven categories. As there was an overlap in these categories, their frequencies were measured independently as symptoms (2033/6193, 32.83%), medications (2397/6193, 38.70%), appointments (1518/6193, 24.51%), laboratory investigations (2106/6193, 34.01%), finance or insurance (447/6193, 7.22%), communications (2161/6193, 34.89%), procedures (617/6193, 9.96%), and miscellaneous (624/6193, 10.08%). Furthermore, in 95.0% (285/300) of cases, there were minor or no differences in categorization between the algorithm and the three independent physicians. CONCLUSIONS: With increased adaptation of electronic health technologies, chatbots could have great potential in interacting with patients, collecting data, and increasing efficiency. Our categorization showcases the feasibility of using NLP in large amounts of electronic dialog for the development of a chatbot algorithm. Chatbots could allow for the monitoring of patients beyond consultations and potentially empower and educate patients and improve clinical outcomes.

Patient Experiences and Outcomes of a Telehealth Clinical Care Pathway for Postoperative Inflammatory Bowel Disease Patients.

Background:Despite advancements in treatment for inflammatory bowel disease (IBD), surgery remains inevitable for patients and IBD management is costly.Introduction:Frequent postoperative monitoring is needed for early detection of both short-term complications and long-term disease recurrence. We developed a care pathway for postoperative home monitoring of IBD patients using telehealth applications.Materials and Methods:We performed a retrospective cohort study with a matched control group to assess the efficacy of the Tight Control Surgery Scenario (TCSS), a 4-week postoperative care pathway. IBD patients aged 18 or older who underwent an IBD-related intestinal operation between October 2013 and December 2015 were eligible. Enrolled participants submitted postsurgical questionnaires and wound photos through e-mail. We measured patient satisfaction with the care pathway and assessed its impact on 30-day postoperative hospital readmission rates, emergency department (ED) visits, and gastroenterologist (GI)-related office visits.Results:Sixty-four (n) cases were enrolled in TCSS and matched to 64 historic controls. Patients who completed the additional evaluation survey expressed overall satisfaction. Readmissions, 30-day ED rates, and GI visits were numerically higher in cases compared with controls, but this difference was not statistically significant.Discussion:TCSS demonstrates the feasibility of implementing a telehealth care coordination platform for postsurgery IBD management. Patients with more complications may have sent in more photos due to greater concern for maintaining their health.Conclusions:Implementation of TCSS for easy home monitoring is feasible. While we did not see reductions in ED visits, GI follow-up visits, or readmissions, patient satisfaction was high, thus demonstrating its feasibility for telehealth applications.

Effect of tight control management on Crohn's disease (CALM): a multicentre, randomised, controlled phase 3 trial.

BACKGROUND: Biomarkers of intestinal inflammation, such as faecal calprotectin and C-reactive protein, have been recommended for monitoring patients with Crohn's disease, but whether their use in treatment decisions improves outcomes is unknown. We aimed to compare endoscopic and clinical outcomes in patients with moderate to severe Crohn's disease who were managed with a tight control algorithm, using clinical symptoms and biomarkers, versus patients managed with a clinical management algorithm. METHODS: CALM was an open-label, randomised, controlled phase 3 study, done in 22 countries at 74 hospitals and outpatient centres, which evaluated adult patients (aged 18-75 years) with active endoscopic Crohn's disease (Crohn's Disease Endoscopic Index of Severity [CDEIS] >6; sum of CDEIS subscores of >6 in one or more segments with ulcers), a Crohn's Disease Activity Index (CDAI) of 150-450 depending on dose of prednisone at baseline, and no previous use of immunomodulators or biologics. Patients were randomly assigned at a 1:1 ratio to tight control or clinical management groups, stratified by smoking status (yes or no), weight (<70 kg or ≥70 kg), and disease duration (≤2 years or >2 years) after 8 weeks of prednisone induction therapy, or earlier if they had active disease. In both groups, treatment was escalated in a stepwise manner, from no treatment, to adalimumab induction followed by adalimumab every other week, adalimumab every week, and lastly to both weekly adalimumab and daily azathioprine. This escalation was based on meeting treatment failure criteria, which differed between groups (tight control group before and after random assignment: faecal calprotectin ≥250 µg/g, C-reactive protein ≥5mg/L, CDAI ≥150, or prednisone use in the previous week; clinical management group before random assignment: CDAI decrease of <70 points compared with baseline or CDAI >200; clinical management group after random assignment: CDAI decrease of <100 points compared with baseline or CDAI ≥200, or prednisone use in the previous week). De-escalation was possible for patients receiving weekly adalimumab and azathioprine or weekly adalimumab alone if failure criteria were not met. The primary endpoint was mucosal healing (CDEIS <4) with absence of deep ulcers 48 weeks after randomisation. Primary and safety analyses were done in the intention-to-treat population. This trial has been completed, and is registered with ClinicalTrials.gov, number NCT01235689. FINDINGS: Between Feb 11, 2011, and Nov 3, 2016, 244 patients (mean disease duration: clinical management group, 0·9 years [SD 1·7]; tight control group, 1·0 year [2·3]) were randomly assigned to monitoring groups (n=122 per group). 29 (24%) patients in the clinical management group and 32 (26%) patients in the tight control group discontinued the study, mostly because of adverse events. A significantly higher proportion of patients in the tight control group achieved the primary endpoint at week 48 (56 [46%] of 122 patients) than in the clinical management group (37 [30%] of 122 patients), with a Cochran-Mantel-Haenszel test-adjusted risk difference of 16·1% (95% CI 3·9-28·3; p=0·010). 105 (86%) of 122 patients in the tight control group and 100 (82%) of 122 patients in the clinical management group reported treatment-emergent adverse events; no treatment-related deaths occurred. The most common adverse events were nausea (21 [17%] of 122 patients), nasopharyngitis (18 [15%]), and headache (18 [15%]) in the tight control group, and worsening Crohn's disease (35 [29%] of 122 patients), arthralgia (19 [16%]), and nasopharyngitis (18 [15%]) in the clinical management group. INTERPRETATION: CALM is the first study to show that timely escalation with an anti-tumour necrosis factor therapy on the basis of clinical symptoms combined with biomarkers in patients with early Crohn's disease results in better clinical and endoscopic outcomes than symptom-driven decisions alone. Future studies should assess the effects of such a strategy on long-term outcomes such as bowel damage, surgeries, hospital admissions, and disability. FUNDING: AbbVie.

Is Stem Cell Therapy Ready for Prime Time in Treatment of Inflammatory Bowel Diseases?

Autologous hematopoietic stem cell transplantation (HSCT) and mesenchymal stromal cell therapy have been proposed for patients with refractory Crohn's disease (CD) and fistulizing CD, respectively. Will these highly advanced techniques be available only for select patients, at specialized centers, or is further clinical development justified, with the aim of offering widespread, more definitive therapeutic options for often very difficult to treat disease? Patients with CD who are eligible for HSCT have typically been failed by most approved therapies, have undergone multiple surgeries, and have coped with years of disease activity and poor quality of life. The objective of HSCT is to immediately shut down the immune response and allow the transplanted stem cells to develop into self-tolerant lymphocytes. For patients with fistulizing CD, mesenchymal stromal cell therapy deposits MSCs locally, into fistulizing tracts, to down-regulate the local immune response and induce wound healing. Recent trials have produced promising results for HSCT and mesenchymal stromal cell therapy as alternatives to systemic therapies and antibiotics for patients with inflammatory bowel diseases, but are these immunotherapies ready for prime time?

Using insurance claims to predict and improve hospitalizations and biologics use in members with inflammatory bowel diseases.

OBJECTIVE: Inflammatory Bowel Disease (IBD) is an inflammatory disorder of the gastrointestinal tract that can necessitate hospitalization and the use of expensive biologics. Models predicting these interventions may improve patient quality of life and reduce expenditures. MATERIALS AND METHODS: We used insurance claims from 2011 to 2013 to predict IBD-related hospitalizations and the initiation of biologics. We derived and optimized our model from a 2011 training set of 7771 members, predicting their outcomes the following year. The best-performing model was then applied to a 2012 validation set of 7450 members to predict their outcomes in 2013. RESULTS: Our models predicted both IBD-related hospitalizations and the initiation of biologics, with average positive predictive values of 17% and 11%, respectively - each a 200% improvement over chance. Further, when we used topic modeling to identify four member subpopulations, the positive predictive value of predicting hospitalization increased to 20%. DISCUSSION: We show that our hospitalization model, in concert with a mildly-effective interventional treatment plan for members identified as high-risk, may both improve patient outcomes and reduce insurance expenditures. CONCLUSION: The success of our approach provides a roadmap for how claims data can complement traditional medical decision making with personalized, data-driven predictive medicine.

Quality Improvement in Gastroenterology: A Systematic Review of Practical Interventions for Clinicians.

BACKGROUND: Quality improvement (QI) identifies practical methods to improve patient care; however, it is not always widely known which QI methods are successful. We sought to create a primer of QI in gastroenterology for the practicing clinician. METHODS: We performed a systematic review of QI literature in gastroenterology. We included search terms for inflammatory bowel disease, irritable bowel syndrome, celiac disease, gastroesophageal reflux disease, pancreatitis, liver disease, colorectal cancer screening, endoscopy, and gastrointestinal bleeding. We used general search terms for QI as well as specific terms to capture established quality metrics for each GI disease area. RESULTS: We found 33 studies that met our definitions for QI. There were 17 studies of endoscopy including screening colonoscopy, six on liver disease, four on IBD, two on GERD, three on GI bleeding, and one on celiac disease. Education was the most common intervention, although most successful studies combined education with another intervention. Other effective interventions included retraining sessions to reach ADR goals in colonoscopy, nursing protocols to increase HCC screening, and EMR decision support tools to prompt reassessment of PPI therapy. Many studies showed improved compliance to metrics, but few were able to show differences in length of stay, readmissions, or mortality. CONCLUSIONS: Our review of quality improvement literature in gastroenterology revealed common themes of successful programs: Education was frequently used but often insufficient, the EMR may be underutilized in guiding decision making, and patient-reported outcomes were infrequently assessed. Further research may be needed to compare QI strategies directly.

NK cells are biologic and biochemical targets of 6-mercaptopurine in Crohn's disease patients.

NK cells, which contribute to immune defense against certain viral infections and neoplasia, are emerging as modifiers of chronic immunologic diseases including transplant rejection and autoimmune diseases. Immunobiology and genetic studies have implicated NK cells as a modifier of Crohn's disease, a condition often treated with thiopurine agents such as 6-mercaptopurine (6-MP). Here, we demonstrate that thiopurines mediate NK cell apoptosis via a caspase 3 and 9 inclusive pathway, and that this process is triggered by thiopurine-mediated inhibition of Rac1. We also show that CD patients in clinical remission maintained on 6-MP have decreased NK cell Rac1 activity, and decreased NK cell numbers in their intestinal biopsies. These observations suggest that thiopurine targeting of NK cells may be a previously unappreciated therapeutic action of these agents in IBD.

Circulating cathelicidin levels correlate with mucosal disease activity in ulcerative colitis, risk of intestinal stricture in Crohn's disease, and clinical prognosis in inflammatory bowel disease.

BACKGROUND: Cathelicidin (LL-37) is an antimicrobial peptide known to be associated with various autoimmune diseases. We attempt to determine if cathelicidin can accurately reflect IBD disease activity. We hypothesize that serum cathelicidin correlates with mucosal disease activity, stricture, and clinical prognosis of IBD patients. METHODS: Serum samples were collected from two separate cohorts of patients at the University of California, Los Angeles. Cohort 1 consisted of 50 control, 23 UC, and 28 CD patients. Cohort 2 consisted of 20 control, 57 UC, and 67 CD patients. LL-37 levels were determined by ELISA. Data from both cohorts were combined for calculation of accuracies in indicating mucosal disease activity, relative risks of stricture, and odds ratios of predicting disease development. RESULTS: Serum cathelicidin levels were inversely correlated with Partial Mayo Scores of UC patients and Harvey-Bradshaw Indices of CD patients. Among IBD patients with moderate or severe initial disease activity, the patients with high initial LL-37 levels had significantly better recovery than the patients with low initial LL-37 levels after 6-18 months, suggesting that high LL-37 levels correlate with good prognosis. Co-evaluation of LL-37 and CRP levels was more accurate than CRP alone or LL-37 alone in the correlation with Mayo Endoscopic Score of UC patients. Low LL-37 levels indicated a significantly elevated risk of intestinal stricture in CD patients. CONCLUSION: Co-evaluation of LL-37 and CRP can indicate mucosal disease activity in UC patients. LL-37 can predict future clinical activity in IBD patients and indicate risk of intestinal stricture in CD patients.

Value redefined for inflammatory bowel disease patients: a choice-based conjoint analysis of patients' preferences.

PURPOSE: Value-based healthcare is an upcoming field. The core idea is to evaluate care based on achieved outcomes divided by the costs. Unfortunately, the optimal way to evaluate outcomes is ill-defined. In this study, we aim to develop a single, preference based, outcome metric, which can be used to quantify overall health value in inflammatory bowel disease (IBD). METHODS: IBD patients filled out a choice-based conjoint (CBC) questionnaire in which patients chose preferable outcome scenarios with different levels of disease control (DC), quality of life (QoL), and productivity (Pr). A CBC analysis was performed to estimate the relative value of DC, QoL, and Pr. A patient-centered composite score was developed which was weighted based on the stated preferences. RESULTS: We included 210 IBD patients. Large differences in stated preferences were observed. Increases from low to intermediate outcome levels were valued more than increases from intermediate to high outcome levels. Overall, QoL was more important to patients than DC or Pr. Individual outcome scores were calculated based on the stated preferences. This score was significantly different from a score not weighted based on patient preferences in patients with active disease. CONCLUSIONS: We showed the feasibility of creating a single outcome metric in IBD which incorporates patients' values using a CBC. Because this metric changes significantly when weighted according to patients' values, we propose that success in healthcare should be measured accordingly.

Sex disparity in colonic adenomagenesis involves promotion by male hormones, not protection by female hormones.

It recently has been recognized that men develop colonic adenomas and carcinomas at an earlier age and at a higher rate than women. In the Apc(Pirc/+) (Pirc) rat model of early colonic cancer, this sex susceptibility was recapitulated, with male Pirc rats developing twice as many adenomas as females. Analysis of large datasets revealed that the Apc(Min/+) mouse also shows enhanced male susceptibility to adenomagenesis, but only in the colon. In addition, WT mice treated with injections of the carcinogen azoxymethane (AOM) showed increased numbers of colonic adenomas in males. The mechanism underlying these observations was investigated by manipulation of hormonal status. The preponderance of colonic adenomas in the Pirc rat model allowed a statistically significant investigation in vivo of the mechanism of sex hormone action on the development of colonic adenomas. Females depleted of endogenous hormones by ovariectomy did not exhibit a change in prevalence of adenomas, nor was any effect observed with replacement of one or a combination of female hormones. In contrast, depletion of male hormones by orchidectomy (castration) markedly protected the Pirc rat from adenoma development, whereas supplementation with testosterone reversed that effect. These observations were recapitulated in the AOM mouse model. Androgen receptor was undetectable in the colon or adenomas, making it likely that testosterone acts indirectly on the tumor lineage. Our findings suggest that indirect tumor-promoting effects of testosterone likely explain the disparity between the sexes in the development of colonic adenomas.

Development and Validation of an Inflammatory Bowel Diseases Monitoring Index for Use With Mobile Health Technologies.

BACKGROUND & AIMS: Mobile health technologies are advancing rapidly as smartphone use increases. Patients with inflammatory bowel disease (IBD) might be managed remotely through smartphone applications, but no tools are yet available. We tested the ability of an IBD monitoring tool, which can be used with mobile technologies, to assess disease activity in patients with Crohn's disease (CD) or ulcerative colitis (UC). METHODS: We performed a prospective observational study to develop and validate a mobile health index for CD and UC, which monitors IBD disease activity using patient-reported outcomes. We collected data from disease-specific questionnaires completed by 110 patients with CD and 109 with UC who visited the University of California, Los Angeles, Center for IBD from May 2013 through January 2014. Patient-reported outcomes were compared with clinical disease activity index scores to identify factors associated with disease activity. Index scores were validated in 301 patients with CD and 265 with UC who visited 3 tertiary IBD referral centers (in California or Europe) from April 2014 through March 2015. RESULTS: We assessed activity of CD based on liquid stool frequency, abdominal pain, patient well-being, and patient-assessed disease control, and activity of UC based on stool frequency, abdominal pain, rectal bleeding, and patient-assessed disease control. The indices identified clinical disease activity with area under the receiver operating characteristic curve values of 0.90 in patients with CD and 0.91 in patients with UC. They identified endoscopic activity with area under the receiver operating characteristic values of 0.63 in patients with CD and 0.82 in patients with UC. Both scoring systems responded to changes in disease activity (P < .003). The intraclass correlation coefficient for test-retest reliability was 0.94 for CD and for UC. CONCLUSIONS: We developed and validated a scoring system to monitor disease activity in patients with CD and UC that can be used with mobile technologies. The indices identified clinical disease activity with area under the receiver operating characteristic curve values of 0.9 or higher in patients with CD or UC, and endoscopic activity in patients with UC but not CD.

MicroRNA214 Is Associated With Progression of Ulcerative Colitis, and Inhibition Reduces Development of Colitis and Colitis-Associated Cancer in Mice.

BACKGROUND & AIMS: Persistent activation of the inflammatory response contributes to the development of inflammatory bowel diseases, which increase the risk of colorectal cancer. We aimed to identify microRNAs that regulate inflammation during the development of ulcerative colitis (UC) and progression to colitis-associated colon cancer (CAC). METHODS: We performed a quantitative polymerase chain reaction analysis to measure microRNAs in 401 colon specimens from patients with UC, Crohn's disease, irritable bowel syndrome, sporadic colorectal cancer, or CAC, as well as subjects without these disorders (controls); levels were correlated with clinical features and disease activity of patients. Colitis was induced in mice by administration of dextran sodium sulfate (DSS), and carcinogenesis was induced by addition of azoxymethane; some mice also were given an inhibitor of microRNA214 (miR214). RESULTS: A high-throughput functional screen of the human microRNAome found that miR214 regulated the activity of nuclear factor-κB. Higher levels of miR214 were detected in colon tissues from patients with active UC or CAC than from patients with other disorders or controls and correlated with disease progression. Bioinformatic and genome-wide profile analyses showed that miR214 activates an inflammatory response and is amplified through a feedback loop circuit mediated by phosphatase and tensin homolog (PTEN) and PDZ and LIM domain 2 (PDLIM2). Interleukin-6 induced signal transducer and activator of transcription 3 (STAT3)-mediated transcription of miR214. A miR214 chemical inhibitor blocked this circuit and reduced the severity of DSS-induced colitis in mice, as well as the number and size of tumors that formed in mice given azoxymethane and DSS. In fresh colonic biopsy specimens from patients with active UC, the miR214 inhibitor reduced inflammation by increasing levels of PDLIM2 and PTEN. CONCLUSIONS: Interleukin-6 up-regulates STAT3-mediated transcription of miR214 in colon tissues, which reduces levels of PDLIM2 and PTEN, increases phosphorylation of AKT, and activates nuclear factor-κB. The activity of this circuit correlates with disease activity in patients with UC and progression to colorectal cancer.

Allogeneic Bone Marrow-Derived Mesenchymal Stromal Cells Promote Healing of Refractory Perianal Fistulas in Patients With Crohn's Disease.

BACKGROUND & AIMS: Patients with perianal fistulizing Crohn's disease have a poor prognosis because these lesions do not heal well. We evaluated the effects of local administration of bone marrow-derived mesenchymal stromal cells (MSCs) to these patients from healthy donors in a double-blind, placebo-controlled study. METHODS: Twenty-one patients with refractory perianal fistulizing Crohn's disease were randomly assigned to groups given injections of 1 × 10(7) (n = 5, group 1), 3 × 10(7) (n = 5, group 2), or 9 × 10(7) (n = 5, group 3) MSCs, or placebo (solution with no cells, n = 6), into the wall of curettaged fistula, around the trimmed and closed internal opening. The primary outcome, fistula healing, was determined by physical examination 6, 12, and 24 weeks later; healing was defined as absence of discharge and <2 cm of fluid collection-the latter determined by magnetic resonance imaging at week 12. All procedures were performed at Leiden University Medical Center, The Netherlands, from June 2012 through July 2014. RESULTS: No adverse events were associated with local injection of any dose of MSCs. Healing at week 6 was observed in 3 patients in group 1 (60.0%), 4 patients in group 2 (80.0%), and 1 patient in group 3 (20.0%), vs 1 patient in the placebo group (16.7%) (P = .08 for group 2 vs placebo). At week 12, healing was observed in 2 patients in group 1 (40.0%), 4 patients in group 2 (80.0%), and 1 patient in group 3 (20.0%), vs 2 patients in the placebo group (33.3%); these effects were maintained until week 24 and even increased to 4 (80.0%) in group 1. At week six, 4 of 9 individual fistulas had healed in group 1 (44.4%), 6 of 7 had healed in group 2 (85.7%), and 2 of 7 had healed in group 3 (28.6%) vs 2 of 9 (22.2%) in the placebo group (P = .04 for group 2 vs placebo). At week twelve, 3 of 9 individual fistulas had healed in group 1 (33.3%), 6 of 7 had healed in group 2 (85.7%), 2 of 7 had healed in group 3 (28.6%), and 3 of 9 had healed in the placebo group (33.3%). These effects were stable through week 24 and even increased to 6 of 9 (66.7%) in group 1 (P = .06 group 2 vs placebo, weeks 12 and 24). CONCLUSIONS: Local administration of allogeneic MSCs was not associated with severe adverse events in patients with perianal fistulizing Crohn's disease. Injection of 3 × 10(7) MSCs appeared to promote healing of perianal fistulas. ClinicalTrials.gov ID NCT01144962.

Defining a Patient Population With Cirrhosis: An Automated Algorithm With Natural Language Processing.

OBJECTIVES: The objective of this study was to use natural language processing (NLP) as a supplement to International Classification of Diseases, Ninth Revision (ICD-9) and laboratory values in an automated algorithm to better define and risk-stratify patients with cirrhosis. BACKGROUND: Identification of patients with cirrhosis by manual data collection is time-intensive and laborious, whereas using ICD-9 codes can be inaccurate. NLP, a novel computerized approach to analyzing electronic free text, has been used to automatically identify patient cohorts with gastrointestinal pathologies such as inflammatory bowel disease. This methodology has not yet been used in cirrhosis. STUDY DESIGN: This retrospective cohort study was conducted at the University of California, Los Angeles Health, an academic medical center. A total of 5343 University of California, Los Angeles primary care patients with ICD-9 codes for chronic liver disease were identified during March 2013 to January 2015. An algorithm incorporating NLP of radiology reports, ICD-9 codes, and laboratory data determined whether these patients had cirrhosis. Of the 5343 patients, 168 patient charts were manually reviewed at random as a gold standard comparison. Positive predictive value (PPV), negative predictive value (NPV), sensitivity, and specificity of the algorithm and each of its steps were calculated. RESULTS: The algorithm's PPV, NPV, sensitivity, and specificity were 91.78%, 96.84%, 95.71%, and 93.88%, respectively. The NLP portion was the most important component of the algorithm with PPV, NPV, sensitivity, and specificity of 98.44%, 93.27%, 90.00%, and 98.98%, respectively. CONCLUSIONS: NLP is a powerful tool that can be combined with administrative and laboratory data to identify patients with cirrhosis within a population.