bluuebunny/crossref_metadata_2025_split huggingface dataset:
IDENTIFYING INADEQUATE RESPONSE AMONG ULCERATIVE COLITIS PATIENTS ON AN ADVANCED THERAPY IN A REAL-WORLD ADMINISTRATIVE CLAIMS DATABASE
Authors: Naegeli April , Hunter Theresa , Grabner Michael , Isenberg Keith , Shan Mingyang , Teng Chia-Chen 
Published: January 2021

Abstract

Objectives
The purpose of this analysis was to assess the frequency of inadequate response (IR) over 1 year from advanced therapy (AT) initiation among ulcerative colitis (UC) patients in the United States using a claims-based algorithm. Baseline factors associated with IR to an AT were also analyzed.

Methods
This was a retrospective cohort study using claims data from the HealthCore Integrated Research Database (HIRD®). Adult patients with UC who initiated an AT (TNFi: adalimumab, golimumab, infliximab; non-TNFi: vedolizumab; other agent: tofacitinib) from 7/1/2016 to 8/31/2018 and had continuous enrollment ≥6 months before and ≥12 months after index date (date of first AT claim) were included. The index AT was defined as the first AT prescribed during the study time period. The claims-based algorithm used in this study to identify IR was originally developed and validated in rheumatoid arthritis1, and was modified for UC patients. Patients were identified as having IR to their index AT if during the 12 months after index date they had one or more of the following: low adherence (defined as proportion of days covered (PDC)&lt;80%), switched/added new AT, added a new conventional therapy, increased dose/frequency of AT, addition or dose increase of oral glucocorticoids, used a new pain medication, or had surgery for UC. Baseline patient characteristics were compared between responders and IRs using chi-square tests for categorical variables and t-tests for continuous variables. A multivariable logistic regression model was constructed to identify baseline characteristics associated with IR to the index AT.

Results
A total of 1,692 UC patients were included in this analysis. Mean age was 42 years, 52% were male, 78% initiated a TNFi, and 22% initiated a non-TNFi as their index AT (Table 1). Over the 1-year follow-up period, 63% of UC patients had an IR to their AT: 42% of patients had low adherence, 24% switched/added a new AT, 18% added a new conventional therapy, 13% had a dose/frequency increase of their index AT, 14% had an addition/dose increase of oral glucocorticoids, 8% used a new pain medication, and 2% had surgery.
Inadequate responders were more likely to be prescribed a TNFi (odds ratio (OR)=2.76; p&lt;0.001), and have a higher baseline Quan-Charlson Comorbidity Index (OR=1.15; p=0.015); while patients with baseline use of azathioprine were more likely to be responders (OR=0.72; p=0.025) (Table 2).
UNDERSTANDING REAL-WORLD BIOLOGIC MAINTENANCE DOSING PATTERNS AMONG PEDIATRIC ULCERATIVE COLITIS AND CROHN’S DISEASE PATIENTS
Authors: Crandall Wallace , Colletti Richard , Komocsar Wendy , Liu Chunyan , Dotson Jennifer , Benkov Keith , Steiner Steven , Zhang Nanhua , Hunter Theresa 
Published: January 2021

Abstract

Objectives
To assess the initial and long-term maintenance dosing of biologic medications in pediatric UC and CD patients, using data in the ICN registry.

Methods
Pediatric patients (2–17 years) in the US who were diagnosed with UC or CD between June 1, 2013 and December 31, 2019, who, after enrollment in the ICN registry, initiated a biologic (adalimumab, infliximab, certolizumab, golimumab, ustekinumab, vedolizumab, and natalizumab) and were actively followed for at least 12 months after first maintenance dose were included in this study. Descriptive statistics of baseline patient demographics were summarized for the overall Inflammatory Bowel Disease (IBD) patient population and separately for UC and CD. Biologic maintenance dosage was calculated for UC and CD patients who had data for both dose and weight for each biologic at the baseline visit (first maintenance dose), 1-year and 3-year time points.

Results
A total of 1,887 pediatric IBD patients (UC=350; CD=1,537) were included in this study. Patients had a mean age at diagnosis of 12.9 years (UC=13.1; CD=12.9), 57.1% were male (UC=48.9%; CD=59.0%), and 80.6% were White (UC=79.8%; CD=80.8%) (Table 1). Infliximab (77.0%) was the most commonly prescribed biologic for UC, followed by adalimumab (12.4%), vedolizumab (10.1%), certolizumab (0.3%), and ustekinumab (0.3%). Similarly, infliximab (80.6%) was the most commonly prescribed biologic for CD, followed by adalimumab (16.5%), vedolizumab (1.6%), ustekinumab (1.2%), and certolizumab (0.1%) (Table 2).
At first maintenance dose, UC patients on infliximab were receiving a mean dose of 10.5mg/kg/8wk, patients on adalimumab (weight &lt;40kg) were receiving a mean dose of 1.3mg/kg/2wk, patients on adalimumab (weight≥40kg) were receiving a mean dose of 0.8mg/kg/2wk, and patients on vedolizumab were receiving a mean dose of 6.9mg/kg/8wks. Mean dose of infliximab among UC patients increased from 10.5mg/kg/8wk at first maintenance dose to 11.8mg/kg/8wk at 1-year from first maintenance dose.
At the first maintenance dose, CD patients on infliximab were receiving a mean dose of 8.1mg/kg/8wk, patients on adalimumab (weight &lt;40kg) were receiving a mean dose of 1.1mg/kg/2wk, patients on adalimumab (weight ≥40kg) were receiving a mean dose of 0.8mg/kg/2wk, patients receiving vedolizumab were receiving a mean dose of 10.5mg/kg/8wks. Mean dose of infliximab among CD patients increased from 8.1mg/kg/8wk at first maintenance dose to 9.6mg/kg/8wk at 1-year from first maintenance dose.

Conclusion
These results highlight the biologic maintenance dose changes among pediatric UC and CD patients. TNF inhibitors remain the most commonly used class of biologic, but the doses being used are double the standard dosing guidelines. There is little evidence of dose reduction over time among pediatric UC and CD patients in the ICN registry.
ADENOSINE A3 RECEPTOR INTERACTS WITH GASDERMIN D TO MODULATE INTESTINAL EPITHELIAL CELL PYROPTOSIS IN ULCERATIVE COLITIS
Authors: Xiao Peng , Lv Minmin , Chen Wenke , Tian Ting , Ren Tianhua 
Published: January 2021

Abstract

Background
Adenosine A3 receptor (A3AR) plays a role in intestinal inflammation, but little is known about its mechnisms in intestinal inflammation such as ulcerative colitis (UC). Pyroptosis, characterized by Gasdermin D (GSDMD) activation, is implicated in the pathogenesis of UC. We investigated the role of A3AR in GSDMD-mediated pyroptosis in UC and its underlying molecular mechanisms.

Methods
The expression of A3AR in colonic mucosa of patients with UC were examined. A3AR agonist was used to study the role of A3AR in ex vivo colonic explants of UC patients. In addition, human intestinal epithelial cells Caco-2 were used to further verify the effect of A3AR on pyroptosis induced by LPS+ATP. RT-qPCR and western blotting were used to detect the expression levels of pyroptosis-associated factors including NLRP3, caspase-1, gasdermin-D N-terminal domain (GSDMD-NT), IL-1β and IL-18 in colonic tissues and Caco-2 cells. Immunofluorescence was used to detect the protein expression in tissues and cells. Enzyme-linked immunosorbent assay was used to determine the levels of IL-1β and IL-18 in tissue and cell culture supernatants. Lactate dehydrogenase (LDH) release assay and propidium iodide (PI) staining were used to measure cell pyroptosis. Molecular interactions beween A3AR and GSDMD were investigated using Co-IP and GST pull-down assays.

Results
A3AR expression was significantly reduced in colonic mucosa of patients with active UC, and colonic epithelial cells were the main cell subpopulation with down-regulated A3AR expression. Pyroptosis-associated factors, including Caspase-1, NLRP3, and GSDMD-NT, were upregulated in UC colonic tissues. The expression of A3AR and GSDMD-NT was negatively correlated. A3AR agonist reduced the production of cytokines (IL-1β and IL-18) and attenuates the expression levels of NLRP3 and GSDMD-NT in the colonic tissues of patients with UC. Furthermore, A3AR overexpression alleviated pyroptosis with reduced LDH release, PI-stained cell number and decreased expressions of GSDMD-NT, NLRP3, caspase-1, IL-1β, and IL-18 in the LPS+ATP-stimulated Caco-2 cells, whereas the opposite occurred in cells treated with small interfeing RNA (siRNA) targeting A3AR. Knockdown of GSDMD in Caco-2 cells significantly blocked the effects of A3AR overexpression or down-regulation on pyroptosis, suggesting that A3AR acts through the GSDMD-mediated pyroptosis pathway. Co-IP and GST pull-down assays showed that A3AR interacted with GSDMD.

Conclusion
A3AR modulates intestinal inflammation in UC through GSDMD-mediated intestinal epithelial cell pyroptosis. We propose a novel mechanism by which A3AR-GSDMD interaction affects UC through pyroptosis, suggesting that A3AR is a potential target for the treatment of UC.
NOVEL GENETIC SUSCEPTIBILITY CANDIDATES IN GRANULOMATOUS AND NON-GRANULOMATOUS PEDIATRIC CROHN’S DISEASE
Authors: Hodgkins Allyson , Harris R Alan , Qian Justin , Kellermayer Richard 
Published: January 2021

Abstract

Background
Non-caseating granulomas are a hallmark histopathological finding of Crohn’s disease (CD). Studies have suggested that the presence of granulomas may indicate a more aggressive CD phenotype associated with a complicated clinical course, including stricturing and/or penetrating disease, need for biologic therapy, and need for surgery. As such, identification of genetic associations of granulomatous CD (GCD) may help elucidate disease pathogenesis, which in turn may optimize treatments and guide novel therapeutics to combat CD complications. There is relatively sparse genetic information known about CD subtypes, especially GCD. The aim of this study was to determine the extent of genetic variation between pediatric CD patients with and without a pathognomonic sub-mucosal granuloma detected at the time of diagnosis.

Methods
Whole-exome next-generation sequencing (WES) was performed on peripheral blood derived DNA from patients with GCD and non-GCD (NGCD). PLINK analysis was used to identify single nucleotide polymorphisms (SNPs) that were overrepresented in comparisons between groups, and subgroup allele frequencies were also compared to publically available, large population-based genomic data in gnomAD. The potential deleteriousness of single nucleotide variants was determined by the CADD scoring tool.

Results
WES was completed for 17 patients with GCD and 19 with NGCD. There were no significant differences in baseline clinical characteristics, treatments, nor 1-year outcomes between the groups. Overlap analyses between PLINK- and gnomAD-generated SNPs revealed significant enrichment in those associated with HLA-DQA1, LILRA1, SAA2, PCDHB, HLA-B, NOD2, and IGH shared by GCD and NGCD groups. In the meantime, GCD-specific (top candidates linked with HLA-B and MUC4) and NGCD-specific (top candidates linked with HLA-B and ACOT9) SNPs were sparse.

Conclusions
We are the first to examine WES-based genetic variation between treatment-naïve pediatric CD patients purely separated by the presence of a sub-mucosal epithelioid granuloma. While there were very few SNPs consistently differentiating between GCD and NGCD patients in our cohort using two distinct methodologies, we were able to identify several novel SNPs that were significantly enriched in pediatric CD patients compared to the control human genome. Our findings will require subsequent confirmation in larger but similarly scrutinized cohorts of patients.
GPR120 MAINTAINS INTESTINAL HOMEOSTASIS THROUGH REGULATION OF CD4+ T CELL IL-10 PRODUCTION
Authors: Yang Wenjing , Yao Suxia , Dann Sara , Cong Yingzi 
Published: January 2021

Abstract
Irregular CD4+ effector T cell responses play an essential role in the intestinal inflammation, while IL-10 produced by effector T cells limits their pathogenesis to maintain the intestinal homeostasis. Dietary free fatty acids are actively involved in regulating immune responses, and mammalian G protein-coupled receptor (GPR) 120, a receptor for long-chain fatty acids, has been implicated in metabolic syndrome. However, the effect of GPR120 on intestinal homeostasis is still unknown. Here, we showed that deficiency of GPR120 resulted in more severe colitis in mice induced by dextran sodium sulfate (DSS) and Citrobacter Rodentium. Interestingly, CD4+ T cells expressed a high level of GPR120, and mice specifically lacking GPR120 in CD4+ T cells were more susceptible to DSS-induced colitis. Besides, GPR120-deficient CD45Rbhi CD4+ cells are more colitogenic in Rag-/- mice, in which IL-17 and IFNg producing CD4+ T cells were increased but IL-10 production by CD4+ T cells was reduced. Furthermore, CpdA, the GPR120 agonist, promoted CD4+ T effector cell production of IL-10 through upregulating Blimp1 and inducing glycolysis, which were regulated by mTOR pathway. Besides, docosahexaenoic acid, a dietary long-chain fatty acid, also upregulated the IL-10 production in CD4+ T cells. Additionally, GPR120 agonist-treated Th1 effector cells induced less severe colitis, whereas this protection was absent in Blimp1-deficient Th1 cells. Importantly, oral administration of CpdA protected mice against intestinal inflammation. Thus, our findings demonstrate the roles of dietary fatty acids receptor GPR120 in regulating intestinal CD4+ T cell production of IL-10 and intestinal homeostasis.
PHENOTYPIC ALTERATIONS OF MACROPHAGE CONTRIBUTES TO EXTRACELLULAR MATRIX DEPOSITION IN CULTURED MACROPHAGE RAW 264.7
Authors: Li Chao , Kuemmerle John 
Published: January 2021

Abstract
Macrophages are essential immune cells for the maintenance of tissue homeostasis in the intestinal mucosa barrier. They are also involved in dysregulated process of wound healing, particularly in the context of intestinal damage and tissue repair in inflammatory bowel diseases. Phenotypic plasticity of macrophages from classical M1 to alternative M2 is regulated by a variety of inflammatory cytokines including IFN-γ and IL-4. The IL-4-derived M2 can further differentiate into myofibroblasts. Activated alpha-smooth muscle actin (α-SMA) positive-myofibroblasts are central to the wound healing process and in patients with fibrostenotic Crohn’s disease. They contribute to fibrosis by excessive production of extracellular matrix (ECM) proteins. Despite rapid advances in our understanding of how macrophages help maintain intestinal homeostasis following inflammation, the role of macrophages during the development of intestinal fibrosis in patients with Crohn’s disease is poorly studied. We have previously reported that increased endoplasmic reticulum (ER) stress contributed to the development of TGF-β1-induced intestinal fibrosis. We recently observed that epigallocatechin-3-gallate (EGCG), blocked macrophage polarization from M1 to M2 in bone marrow-derived macrophages from TNBS colitis mice. Here we hypothesized that ER stress regulates the phenotypic change of macrophages and ECM deposition. This notion was examined in RAW 264.7 murine macrophage cells, which were labeled with markers of phenotype: M1-CD38, M2-CD163 after incubation with IFN-γ and IL-4, respectively. Macrophage to myofibroblast transition and evaluation of ECM production were further determined by using myofibroblast marker: α-SMA and ECM markers: collagen 1α1 and periostin. Cells were treated with EGCG to determine whether inhibition of ER stress would block macrophage-to-myofibroblast transition and ECM production. The CD38+M1 increased by 43±2.1% and α-SMA expression increased by 15±1.2% in IFN-γ-induced macrophages compared to untreated control. Correspondingly, collagen 1α1 and periostin also increased by 81± 4.3% and 75±3.7% respectively in CD38+M1. The CD163+M2 increased by 21±1.2% in macrophages treated with IL-4 compared to untreated control. Collagen 1α1 and periostin also increased by 45± 2.3% and 38±1.8% respectively in CD163+M2. ER stress marker, GRP78, increased by 15±0.8% in CD38+ M1 compared to the 5±0.3% increase in CD163+M2. Treatment with EGCG decreased GRP78 by 15±0.8%, collagen 1α1 by 60±3%, and periostin by 63.5±2.1% in CD38+M1 compared to the same markers that decreased by 3±0.2%, 25±1.3%, and 35±1.8% in CD163+M2, respectively. Together, our data suggest that macrophage polarization from M1 to M2 plays a role in macrophage-to-myofibroblast transition, ECM deposition, and increase in ER stress response, which can be blocked by Inhibition of ER stress with EGCG.
RISK FACTORS FOR OUTCOMES OF PATIENTS WITH HISTOLOGICALLY PROVEN CHECKPOINT-INHIBITOR COLITIS
Authors: Voth Elida , Saha Srishti , Raffals Laura , Pardi Darrell , Khanna Sahil 
Published: January 2021

Abstract

Background
Immune checkpoint inhibitor (ICPI)-mediated diarrhea and colitis is the leading cause of discontinuation of ICPI therapy in patients with malignancy. Existing literature on predictors of adverse outcomes is limited. We evaluated the association between risk factors, concomitant Clostridioides difficile infection (CDI), and abdominal CT scan findings of colitis on outcomes in patients with ICPI-related diarrhea and colitis.

Methods
A retrospective study was conducted for patients who received an ICPI for treatment of malignancy and developed diarrhea or colitis, with endoscopic findings consistent with ICPI colitis. Variables including smoking history, proton pump inhibitor (PPI) use, non-steroidal anti-inflammatory (NSAID) use, concomitant CDI, and abdominal CT scan findings were extracted. The Common Terminology Criteria for Adverse Events (CTCAE) criteria was used to determine diarrhea and colitis severity. We analyzed the effect on risk factors on outcomes including hospitalization rates, diarrhea and colitis severity, and mortality at 1 year. Statistical analysis comprised of descriptive statistics and univariate and multivariate logistic regression analyses.

Results
There were 33 patients with histologically proven ICPI-related colitis with median age 70 years (28–92). Seventeen patients (52%) had melanoma and 24 patients (73%) had metastatic disease (Table 1). There was no association between age, gender, smoking history, PPI use, NSAID use on rates of hospitalization, toxicity severity, or mortality related to ICPI-related diarrhea or colitis (p&gt;0.05) on univariate analysis. CDI at diagnosis was associated with a higher grade of toxicity (p=0.04) and higher rate of mortality at 1-year follow-up (p=0.03) compared to patients with a negative GI pathogen panel; however, this effect was not seen on multivariate analysis controlling for age and cancer stage (p&gt;0.05). In patients with metastatic malignancy, there were significant higher rates of hospitalization for ICPI-colitis compared to those without metastatic disease on multivariate analysis controlling for age (OR, 4.53 [95% CI, 1.11–35.99]). In patients with CT scan findings consistent with colitis, there was a significantly higher rate of hospitalization compared to patients without these imaging findings on multivariate analysis controlling for age and cancer stage (OR, 2.99 [95% CI, 1.22–6.64]).

Conclusions
Patients with metastatic malignancy or CT scan findings consistent with colitis had a significantly higher rate of hospitalization for ICPI colitis compared to patients with non-metastatic disease or without radiographic features of colitis. CDI at diagnosis was associated with mortality and higher grade of toxicity. Further investigation is needed to examine predictors of adverse outcomes with use of ICPI to reduce morbidity and mortality in this patient population.
A NEW BACTERIAL TRANSFER THERAPY FOR IBD: ENDOSCOPIC BIFIDOBACTERIUM AND XYLOGLUCAN ADMINISTRATION
Authors: Bozkurt Hüseyin 
Published: January 2021

Abstract
Ulcerative colitis (UC) pathogenesis includes the altered gut microbiota, environmental factors, and human immune and genetic predisposition. Recently, its association with reduced bifidobacteria quantity in the microbiota is reported.Xyloglucan, a plant based prebiotic oligosaccharide, causes increase in bifidobacteria quantity.
In this article we share the results of our UC cases treated by intracolonic single dose administration of Bifidobacterium animalis subsp. Lactis and xyloglucan combination. Intracolonic single dose administration of 200 billion CFUs of Bifidobacterium animalis subsp. lactis and 4 gr of xyloglucan combination was administrated to ten severe UC patients, who were either unresponsive or had inadequate response to treatment. All patients continued treatment after the procedure. Treatment responses were evaluated by colonoscopic, laboratory and clinical examination after 6 weeks. Intracolonic single dose administration of Bifidobacterium animalis subsp. lactis and xyloglucan was found effective in the mucosal healing and resolution of colonic symptoms in ulcerative colitis patients. Intracolonic administration of Bifidobacterium animalis subsp. lactis and xyloglucan in UC is a new single strain and strain specific prebiotic combination method. It is easy to apply and has no observable side effect. Its effectiveness on mucosal healing could be attributed to the enhancement of non-stimulatory status and biodiversity in colonic mucosa. Nonetheless, it is still necessary to develop diagnostic strategies to determine the patients to whom this method would be the most applicable.
COMMON FOOD ADDITIVES ACCELERATE ONSET OF INFLAMMATORY BOWEL DISEASE IN MICE BY ALTERING MICROBIOME COMPOSITION AND HOST-MICROBE INTERACTION
Authors: Zangara Megan , Sangwan Naseer , McDonald Christine 
Published: January 2021

Abstract
Multiple factors contribute to inflammatory bowel disease (IBD) pathogenesis, including diet. Although correlations exist between the introduction of processed foods and a rise in IBD prevalence, it is not understood what components of processed foods drive disease pathogenesis or how. Despite a FDA classification of Generally Regarded As Safe (GRAS), food additives significantly impact microbe communities and phenotypes. We hypothesized that common food additives, such as maltodextrin (MDX) and carboxymethyl cellulose (CMC), alter intestinal microbes and increase the onset and progression of IBD. We tested this hypothesis using the interleukin-10 deficient (IL10KO) mouse model of spontaneous colitis. To standardize disease onset, IL10KO mice were pre-conditioned with fecal material from nucleotide-binding oligomerization domain 2 deficient mice (NOD2KO) to promote intestinal inflammation. Pre-conditioned IL10KO mice were randomized to chow diets containing either 1% MDX, 1% CMC, or a control diet. MDX and CMC accelerated the onset of colitis compared to the control diet. This was accompanied by elevated fecal lipocalin-2 (p&lt;0.05) and serum amyloid A (p&lt;0.01), intestinal infiltration of CD3+ cells, and intestinal pathology consistent with chronic inflammation (p&lt;0.05). Although both dietary additives promote disease in this model, the molecular mechanisms involved appear to be distinct. Intestinal mucus modulates interactions of the microbiome and the host. Strikingly, goblet cells in MDX fed mice had reduced mucin granule content (~50% of control diet) as assessed by Muc2 and Periodic Acid Schiff staining. This mucin depletion did not correlate with degree of disease activity, suggesting this deficiency is not a result of inflammation in MDX fed mice and was not observed in CMC fed mice or control diet mice. Food additives also altered the intestinal microbiome, with MDX fed mice demonstrating a significant decrease in microbiome alpha diversity (p&lt;0.05, ANOVA), and both food additives resulting in a significant shift in beta diversity (R2=0.40, p=0.002, PERMANOVA) as compared to the control diet. Flagella expression by microbes was slightly elevated in CMC-fed mice, but not in MDX-fed mice, suggesting that these food additives have distinct actions on microbes. Magnitude of genus-level changes in microbial abundance correlated with disease severity as assessed by serum amyloid A levels. This data indicates that common food additives are not biologically inert substances, and may drive the progression of inflammatory bowel disease through additive-specific alterations of the microbiome and host-microbe interactions.