bluuebunny/crossref_metadata_2025_split huggingface dataset:
P131 NATIONAL TRENDS IN HOSPITALIZATION, SURGICAL RESECTION, AND COMORBIDITIES IN PEDIATRIC INFLAMMATORY BOWEL DISEASES
Authors: Ihekweazu Faith , Dongarwar Deepa , Salihu Hamisu , Kellermayer Richard 
Published: January 2020

Abstract

Background
Therapeutic options for pediatric inflammatory bowel disease (PIBD) have dramatically changed over the last decades with the widespread use of biologic medications. However, the overall impact of biologic therapy on PIBD outcomes (specifically hospitalizations, comorbidities, surgical rates, and postoperative complications) remains unclear. We aimed to fill this gap in the literature by using a large, validated, national database, to study the change in outcomes over the last decade. We hypothesized that morbidity in pediatric IBD has decreased over time with the increased use of biologic therapy.

Methods
The National Inpatient Sample (NIS) Database and ICD-9-CM codes were utilized to identify inpatient admissions with a primary or secondary diagnosis of pediatric Crohn’s disease (CD) or ulcerative colitis (UC) from 2002–2015. Trends in hospitalizations, comorbidities (including malnutrition and weight loss), surgical procedures, and post-operative complications were examined using joinpoint regression analysis.

Results
There were 119,282 admissions for PIBD during the study period. The annual incidence of hospitalization increased significantly over time for both CD (average annual percent change [AAPC] 6.0%, 95%confidence interval [CI] 4.7, 7.2) and UC (AAPC 7.2%, 95% CI 6.2, 8.1). The rate of intestinal resection decreased in CD patients (AAPC -6.4%, 95%CI, -8.7, -4.1) while postoperative complications remained unchanged. However, comorbidities increased significantly in CD patients (AAPC 6.8%, 95%CI, 4.6, 9.0). For pediatric UC patients, postoperative complications (AAPC 6.7%, 95%CI, 1.2, 12.4), and comorbidities (AAPC 10.2%, 95%CI, 8.8–11.6) increased significantly over time while intestinal resection rates remained stable.

Conclusions
Intestinal resection rate in pediatric CD has decreased over time, but not in pediatric UC. Annual incidence of hospitalization and comorbidities continue to increase in PIBD despite the increased availability and use of biologic medications. Our findings emphasize the critical need for prevention and novel therapeutic options for this vulnerable patient population.
P132 OUTCOMES AND REASONS FOR ADMISSION IN CROHN’S DISEASE. AN ANALYSIS OF NATIONWIDE INPATIENT SAMPLE 2016
Authors: Vohra Ishaan , Katiyar Vatsala , Sharma Sachit , Attar Bashar 
Published: January 2020

Abstract

Objective
Recent research suggests increasing nationwide admission for Crohn’s disease (CD), but the most common reasons for admission are not well known. We sought to enumerate the most common presentations of Crohn’s disease requiring admission in Nationwide Inpatient Sample (NIS) 2016 using ICD-10 codes.

Methods
We identified all adults aged greater than or equal to 18 years with a primary diagnosis of CD, using ICD 10 in Nationwide inpatient database. We analyzed inpatient demographics via chi-square. Inpatient mortality,Length of stay (LOS) and Total Charge (TOTCHG) was calculated using univariate and multivariable linear models.

Results
60,244 patients with CD required inpatient admission. Majority of patients were females (53%), white (69%), with private insurance (46%) admitted to large bed sized (53.3%) teaching hospitals (68%). The common reasons for admission in CD patients included bowel obstruction at 24.6% (14,850) of which 57.8% (8,590) presented with small bowel obstruction (SBO). 42.1% (6260) were admitted with both SBO and LBO. Other reasons for admission were GI bleeding (6.5%) and fistulizing CD (2.4%). The inpatient mortality was 0.5%. Age was an independent predictor of mortality in these patients. (aOR 1.08, 95% CI 1.04–1.12; p=0.000). Protein energy malnutrition (PEM) (aOR 2.45, p=0.348), patients requiring pressor support (aOR 4.2, p=1.06) and those with bowel obstruction (aOR 1.1.9 p=0.84) had higher odds of mortality on multivariate analysis model, but couldn’t reach statistical significance. The mean LOS was 4.9 days and patients admitted over weekend had a longer LOS (coeff 0.22, 95% CI 0.08–0.37, p=0.002) as compared to weekdays on multivariate linear regression. The total cost attributable to Crohn’s disease was 706$ million. Independent predictors of increased total charge were Large bed sized hospitals, African-American, protein energy malnutrition, patients requiring pressor support and bowel obstruction in multivariate linear analysis.

Conclusions
The common reasons for inpatient admission in patients with CD include bowel obstruction, GI bleeding and fistulizing CD. Age was an independent predictor of mortality. The economic burden was highest amongst African-Americans, malnourished, patients requiring pressor support and those with bowel obstruction.
P133 PRESCRIPTION OPIOID USE AMONG VETERANS WITH INFLAMMATORY BOWEL DISEASE
Authors: Love Bryan , Finney Christopher , Gaidos Jill 
Published: January 2020

Abstract

Background
Opioids are commonly prescribed to manage pain in patients with IBD despite increasing evidence of harm associated with chronic use. The aim of the current study was to describe trends in opioid use among veterans with IBD.

Methods
This was a retrospective cohort study derived from the Veterans Affairs (VA) Health Care System. A unique patient identifier facilitated longitudinal evaluation of electronic databases that include medical diagnoses, surgical procedures, pharmaceuticals, labs, vital status information, dates of treatment, and radiology findings. Veterans were labeled as having IBD if there were at least 2 outpatient or 1 inpatient health care encounters with an ICD-9/10 diagnostic code consistent with IBD from fiscal years 2002 to 2016. Veterans without a minimum of 2 years of follow-up or who had a cancer diagnosis within 1 year before or after IBD diagnosis were excluded. In order to standardize the quantity of opioid exposure, morphine milligram equivalents (MME) for each prescription was calculated using published conversion factors. Individual prescriptions with missing quantity or day’s supply and prescriptions exceeding 1000 MME/day were excluded. Opioid exposure during the first year following the initial diagnosis date was determined as the average MME/day for those with at least one opioid prescription. Annual opioid prescribing rates per 100 IBD patients were calculated. Comorbidities were assessed using a modified Charlson Comorbidity Index (CCI), excluding cancer from the calculation.

Results
During the study period, 65,817 veterans with IBD were identified. The majority were males (92.1%), Caucasian (78.2%), and had a mean age of 58.2 years. In total, 1,471,019 individual opioid prescriptions were evaluated. The quantity and rate of opioid prescriptions peaked in 2012, with 115,774 unique prescriptions and 698.5 opioid prescriptions per 100 IBD patients, respectively. Twenty-seven percent (n=17,844) of IBD patients had at least one opioid prescription within the initial year of diagnosis. Mean opioid exposure during the initial year of diagnosis averaged 33.2 MME/day, and 12.2% had mean opioid exposure greater than 50 MME/day. Opioid exposure peaked in 2005 at 37.4 MME/day and consistently declined to 29.3 MME/day in 2016.

Conclusion
There has been a significant decline in opioid prescriptions, prescribing rate, and mean opioid exposure since peaking in 2012. These trends are similar to those seen in the non-veteran US population.
P146 OXPHOS INDUCTION IN HEALING: A CRITICAL MISSING STEP IN INFLAMMATORY BOWEL DISEASE?
Authors: Kapur Neeraj , Bradford Emily , Thomas Justin , Perry Courtney , Barrett Terrence 
Published: January 2020

Abstract

Background
In Inflammatory Bowel Disease (IBD), mucosal healing represents a key outcome in clinical remission. Mitochondrial dysfunction is one of the major features of IBD, which is hallmarked by increased oxidative stress and impaired ATP production. However, partial wound healing continues even with repressed mitochondrial respiration in an inflammatory environment. In this study, we demonstrate that intestinal epithelial cells (IEC) responding to colitis produce a gene signature with downregulated mitochondrial expression associated with oxidative phosphorylation (OxPHOS) and upregulate epithelial-to-mesenchymal transition (EMT). These data were consistent with the notion that EMT induced in IEC is fueled by glycolysis (repressed OxPHOS). We also wish to determine if this OxPHOS repression is present in normal healing.

Methods
We are actively enrolling patients with Ulcerative Colitis (UC) and normal patients into a prospective study evaluating biopsy site healing. Biopsy samples from UC patients were collected in Allprotect® or PBS. Biopsy samples collected in PBS were processed for IEC isolation using enzymatic digestion followed by flow sorting of EpCAM+ cells. To investigate the healing process in colitis and normal patients, the sigmoid colon is tattooed at initial endoscopy and 10–12 biopsies are collected in Allprotect®. Patients are brought back a week later for a flexible sigmoidoscopy. The tattooed area is examined, and biopsies are obtained from the previous biopsy sites (“biopsy of the biopsy”) and collected in Allprotect®. RNA is extracted from Allprotect® preserved tissue or isolated IECs and analyzed with RT-PCR.

Results
Genes corresponding to subunits of NADH dehydrogenase (Ubiquinone) of complex I (ND1, ND2, ND3, ND4, ND5 and ND6) were consistently downregulated in ulcer sites of colitis patients as compared to “biopsy of the biopsy” sites near the tattoo in normal patients. As expected, samples from colitis patients exhibited significant upregulation of inflammatory markers (iNOS, NLRP3, CCL2, RANTES, TGF-b1, CCL20 and CXCL10) compared to “biopsy of the biopsy” sites in normal patients undergoing healing. Intriguingly, epithelial marker E-cadherin was noted to be decreased in samples obtained from colitis patients with concomitant increase in mesenchymal markers (Vimentin, Snail, Twist-1 and Zeb-1) compared to previously biopsied normal controls.

Discussion
Our data suggests that repressed OxPHOS observed in inflamed IEC from colitis patients may serves as an inducer of EMT governing delayed but partial healing in IBD. We found this to be in stark opposition to healing in normal patients, who exhibit enhanced OxPHOS associated with rapid healing. These important findings indicate OxPHOS metabolism may be an important target for therapeutic agents to improve healing in refractory colitis.
P147 PATIENT DERIVED INTESTINAL ORGANOIDS REPRESENT AN EPITHELIAL MODEL TO STUDY PEDIATRIC CROHNS DISEASE
Authors: Niklinska-Schirtz Barbara , Matthews Jason , Dodd Anne , Prince Jarod , Biliya Shweta , Venkateswaran Suresh , Kugathasan Subra 
Published: January 2020

Abstract

Background
Although therapeutics in Crohn’s disease (CD) have dramatically improved, current approaches targeting the immune system have limited success at a population level. Thus, there is a need for future therapeutics to target different pathways/cell types. Recently, patient derived stem cells have shown promise in helping to better understand the molecular basis of disease. We used patient derived organoids (PDOs), produced from both CD and healthy patients’ pinch biopsies, to determine the ability of PDOs to functionally represent the human intestinal epithelium, and to better understand the role of the epithelium in CD.

Methods
Mucosal biopsies from the terminal ileum were obtained from pediatric subjects (CD = 16, healthy controls = 13) by colonoscopy. We performed bulk RNA-seq on the freshly isolated ileal crypts (IC), and on the corresponding PDOs grown from the IC stem cells. The sequencing was performed on an Illumina HiSeq system in a single batch. The raw FastQ files were aligned with reference genome Hg38 using STAR package. Differential expression analysis was performed on the read counts using DEseq package. We compared the organoid gene expression to that of the IC for each patient, along with the differential analysis between groups.

Results
On average, 7.5M read counts were obtained for each IC and organoid sample. Of the 19,900 genes tested against Hg38, we found 15,554 genes expressed in either IC or organoids. Of those, 14,149 (91%) were expressed in both IC and organoids, 1,091 (7%) were expressed only in IC, and 314 (2%) expressed only in organoids. We compared PDOs from healthy controls to CD cases and the differentially expressed genes were identified using cutoff of log2FC &gt; ±1.2 and statistically significant threshold p &lt; 0.05. Compared to healthy controls, CCL5 and CXCL5 genes were up-regulated in CD, whereas PDGFB, IL-33 and ILDR2 genes were down-regulated.

Conclusion
We demonstrate that PDOs are 91% similar in gene expression to in vivo epithelium and thus are an excellent patient-specific in vitro epithelial model system. We have further used this model to show the CD specific transcriptional defects in the epithelium. Our data suggests that the epithelium is responsible, in part, in promoting neutrophil recruitment and inflammation through increases in CCL5 and CXCL5 expression, and changes in the Th1/Th2 profile through downregulation of IL-33 expression. Dysregulation of the cytoskeleton and barrier formation are both likely affected by down regulation of PDGFB and ILDR2, respectively, resulting in a negative effect on intestinal barrier function and restitution.
P138
SCGN DEFICIENCY RESULTS IN COLITIS SUSCEPTIBILITY
Authors: Sifuentes-Dominguez Luis , Li Haying , Llano Ernesto , Liu Zhe , Singla Amika , Patel Ashish , Kathania Mahesh , Khoury Areen , Norris Nicholas , Rios Jonathan , Starokadomskyy Petro , Park Jason , Gopal Purva , Liu Qi , Tan Shuai , Chan Lillienne , Ross Theodora , Harrison Steven , Venuprasad K , Baker Linda , Jia Da , Burstein Ezra 
Published: January 2020

Abstract
Inflammatory bowel disease (IBD) affects 1.5–3.0 million people in the United States. IBD is genetically determined and many common risk alleles have been identified. Yet, a large proportion of genetic predisposition remains unexplained. In this study we report the identification of an ultrarare missense variant (NM_006998.3:c.230G&gt;A;p.Arg77His) in the SCGN gene causing Mendelian early-onset ulcerative colitis. SCGN encodes a calcium sensor that is exclusively expressed in neuroendocrine lineages, including enteroendocrine cells and gut neurons. SCGN interacts with the SNARE complex, which is required for vesicle fusion with the plasma membrane. We show that the SCGN mutation identified impacted the localization of the SNARE complex partner, SNAP25, leading to impaired hormone release. Finally, we show that mouse models of Scgn deficiency recapitulate impaired hormone release and susceptibility to DSS-induced colitis. Altogether, these studies demonstrate that functional deficiency in SCGN can result in intestinal inflammation and implicates the neuroendocrine cellular compartment in IBD.
P160 γδ T CELLS, IL-22, THE PROBIOTIC, LACTOBACILLUS DELBRUECKII, AND THE ROLE THEY PLAY IN ATTENUATION OF ALCOHOL INDUCED EXACERBATION OF DSS-COLITIS
Authors: Cannon Abigail , Shim Esther , Kuprys Paulius , Choudhry Mashkoor 
Published: January 2020

Abstract
Ulcerative colitis is characterized by cycles of active disease flare and inactive disease remission. During UC remission, IL-22 expression can be upregulated, acting as a hallmark of entrance into a UC remission period. Recently, we found that in our mouse model of binge alcohol consumption after DSS-induced colitis, alcohol increases severity of UC flare symptoms. In this study, we assessed whether alcohol influenced IL-22 expression and thereby perpetuates UC flare. Male C57BL/6 mice received 2% DSS or water ad libitum for 5 days. On day 5, DSS was removed to mimic entrance into remission. Additionally on day 5, DSS and Sham mice were subdivided into mice gavaged with ethanol (∼3g/kg) or with water on days 5, 6, and 7. Three hours after the last gavage on day 7, mice were humanely euthanized. Large intestine lamina propria (LP) cells were isolated. The percentage of total IL-22+ LP cells was significantly decreased (p&lt;0.05) in DSS Ethanol compared to DSS Vehicle. No differences in IL-22+ T cells, Innate Lymphoid Cells Type 3, or neutrophils were observed. Examination of I γδ T cells revealed DSS Vehicle treated mice had a significantly increased percentage of IL-22+ γδ T cells, while DSS Ethanol treated mice were unable to mount this response. Therefore, we hypothesized that by re-establishing IL-22, through either rIL-22 or a probiotic, we could alleviate the alcohol-induced exacerbation of UC. Firstly, rIL-22 administration substantially restored weight loss of DSS Ethanol treated mice back to that of DSS Vehicle (∼12.5% back to ∼6% on day 7). Increased colonic shortening (p&lt;0.001) and increased Enterobacteriaceae copy number were also attenuated following binge alcohol and colitis with IL-22 treatment. Knockout of STAT3 in IECs resulted in loss of IL-22 protection, demonstrating STAT3 is required for protection. Secondly, we utilized Lactobacillus delbrueckii, a common probiotic known to play a role in IL-22 release. Treatment with Lacto attenuated both weight loss and colon length in DSS Ethanol mice back to levels of DSS alone (p&lt;0.01 and p&lt;0.001, respectively). Additionally, Lacto treatment mitigated increases in Enterobacteriaceae copy number seen in DSS Ethanol mice and trended towards an increase in IL-22 in DSS Ethanol + Lacto mice. Levels of pSTAT3 were decreased in DSS Ethanol treated mice compared to DSS Vehicle, but administration of Lacto in DSS Ethanol mice increased levels of pSTAT3 back to that of the DSS Vehicle group. Treatment with Lacto supernatant alone was not sufficient to mitigate the exacerbation of UC following ethanol. Our findings suggest that both rIL-22 and Lactobacillus delbrueckii utilize the IL-22/pSTAT3 signaling pathway to attenuate alcohol-induced increases in ulcerative colitis symptoms. (R21AA022324, R21AA025806, T32AA013527, F30AA027442, F31AA025536)
P140 3D BIOENGINEERED TISSUE MODEL OF THE LARGE INTESTINE TO STUDY INFLAMMATORY BOWEL DISEASE
Authors: Roh Terrence , Chen Ying , Paul Harry , Guo Chengchen , Kaplan David 
Published: January 2020

Abstract
An in vitro model of intestine epithelium with an immune compartment was bioengineered to mimic immunologic responses seen in inflammatory bowel disease [1]. While aspects of intestinal immunity can be modeled in transwells and 2D culture systems, 3D tissue models improve physiological relevance by providing a 3D substrate which enable migration of macrophages towards the epithelium. An intestinal epithelium comprised of non-transformed human colon organoid cells and a subepithelial layer laden with monocyte-derived macrophages was bioengineered to mimic native intestinal mucosa cell organization using spongy silk scaffolds. Confluent epithelial monolayers with microvilli, a mucus layer, and infiltration of macrophages to the basal side of the epithelium were observed. Inflammation, induced by E. coli O111:B4 lipopolysaccharide and interferon γ resulted in morphology changes to the epithelium, resulting in ball-like structures, decreased epithelial coverage, and migration of macrophages to the epithelium. Analysis of cytokines present in the inflamed tissue model demonstrated significantly upregulated secretion of pro-inflammatory cytokines associated with active inflammatory bowel disease, including CXCL10, IL-1β, IL-6, MCP-2, and MIP-1β. The macrophage layer enhanced epithelial and biochemical responses to inflammatory stimuli, and this new tissue system may be useful to study and develop potential therapies for inflammatory bowel disease.
References: 6 Roh, T.T., et al., 3D bioengineered tissue model of the large intestine to study inflammatory bowel disease. Biomaterials, 2019: p. 119517.
7 In, J., et al., Enterohemorrhagic Escherichia coli reduce mucus and intermicrovillar bridges in human stem cell-derived colonoids. Cellular and molecular gastroenterology and hepatology, 2015. 2(1): p. 48–62.e3.
8 Chen, Y., et al., In vitro enteroid-derived three-dimensional tissue model of human small intestinal epithelium with innate immune responses. PLoS ONE, 2017. 12(11): p. e0187880.
Colonoid and macrophage cultivation scheme in the 3D bilayer system. (A) Human monocytes were isolated from whole blood and human colonoids from large intestine biopsies were cultured according to established protocols [2]. (B) Cell suspensions of colonoids were seeded on the film surface on the inner silk scaffold and monocyte-derived macrophages were seeded throughout the porous outer silk scaffold using established protocols [3]. (C) The model is cultured for 3 weeks total with 2 weeks in High WNT media and 1 week in differentiation media based on established protocol. Colonoids are present in the model throughout the 3 week culture time. 2 sets of macrophages are added with the first set added after the first week of culture and the second set replacing the first set after the second week.
P073 DIET AS A MICROBIOME-CENTERED THERAPY FOR IBD
Authors: Olednzki Barbara , Bucci Vanni , Cawley Caitlin , McCormick Beth , Ward Doyle , Maldonado-Contreras Ana 
Published: January 2020

Abstract
Your food is your best medicine. Nowhere else is this more real than for those suffering from inflammatory bowel disease (IBD). Thus, we developed the IBD-Anti-Inflammatory Diet (IBD-AID™) to relieve IBD symptoms while providing nutrient adequacy. The IBD-AID™ was designed to increase the diversity of bacteria that produce short-chain fatty acids (SCFAs) to modulate the local immune response. After 4 weeks on the IBD-AID™, patients have reported a reduction of symptoms and medication.
Our goal is to define diet-microbiome-inflammation interactions that promote health while consuming the IBD-AID™. We posit that IBD-AID™ favors SCFA-producing bacteria resulting in dampening of inflammation and assisting patient’s remission. We recruited 19 patients with mild to severe CD or UC, to determine diet-dependent changes in the microbiota that could support the hypothesis. The study design was a single-arm, prospective, pre-post intervention trial. After a ‘baseline’ period of 4 weeks, the dietary ‘Intervention’ phase started and continued for 8–10 weeks (Fig 1).
We performed metagenomic sequencing of 400+ fecal samples and analyzed 300+ food frequency questionnaires. Most (88.2%) patients achieved ≥50% diet compliance. The IBD-AID™ significantly promoted microbiota signatures that have been associated with colonic health. We found that increased intakes of prebiotics foods correlated with the abundance of SCFAs-producing members of the Bacteroides and Parabacteroides. Similarly, increase intakes of probiotics foods during intervention correlated with the abundance of Clostridium bolteae, a bacterium known to play a critical role in the induction of regulatory T cells. We found that vegetable and nuts intake -encouraged in IBD-AID™, correlated with the abundance of butyrate-producing Roseburia hominis, Eubacterium rectale, and Faecalibacterium prausnitzii. The increased abundance of those SCFAs-producing bacteria after the intervention was accompanied by declines in putative pathogenic strains, such as Escherichia sp., Alistipes sp., and Eggerthella sp. The majority (61.3%) of patients treated for at least 8 weeks, who achieved as minimum as 50% dietary compliance reported a dramatic decrease in disease severity.
To examine the role of those diet-dependent microbiome signatures in inflammation, we use P-glycoprotein (P-gp) expression as a biomarker. P-gp is an ABC transporter in epithelial cells implicated in the development and persistence of chronic intestinal inflammation in IBD. We found that fecal supernatants from IBD patients adopting the IBD-AID™ induced P-gp expression. Altogether, these results uncover a novel molecular mechanism of the diet-microbiome-immune interaction allowing us to customize dietary guidelines to emphasize foods with known effect on microbiome signatures associated with health.

Fig 1. Schematic representation of the study design and sampling schedule.