bluuebunny/crossref_metadata_2025_split huggingface dataset:
CRYPTOGENIC MULTIFOCAL ULCEROUS STENOSING ENTERITIS (CMUSE): A 20-YEAR SINGLE CENTER CLINICAL AND RADIOLOGIC EXPERIENCE
Authors: Ramos Guilherme Piovezani , Bartlett David , Bledsoe Adam , Bruining David , Fidler Jeff , Sheedy Shannon , Murray Joseph 
Published: January 2021

Abstract

Background
Cryptogenic multifocal ulcerous stenosing enteritis (CMUSE) is a rare illness characterized by multiple strictures and shallow ulcers of the small bowel. Even though diagnostic criteria have been described, further ellucidation is needed on therapeutic interventions and potential discriminating factors between CMUSE and other more common causes of intestinal ulcerations, including Crohn’s disease.

Aim
The purpose of this article is to report the clinical, CT, and MR enterography characteristics of confirmed cases of CMUSE.

Materials and Methods
Retrospective review of electronic medical records identified 33 patients considered for a diagnosis CMUSE. Diagnosis was confirmed if all requirements of the previously published diagnostic criteria for CMUSE were met. Patients were excluded if they had less than one year follow-up or incomplete clinical data. Two GI radiologists reviewed all CT and MR enterography (CTE/MRE) exams in consensus of confirmed patients to characterize the cross sectional imaging features.

Results
CMUSE was confirmed in 9 patients (27%) and 24 patients (73%) had a confirmed alternative diagnosis. Crohn’s disease (CD) (30%, n=7) and drug-induced enteropathy (30%, n=7) were the most frequent alternative. Male gender (66.7% vs. 25%, p=0.04) and clinical manifestation of anemia at presentation were more commonly observed on CMUSE-confirmed cases (66.7% vs. 4.2%, p=0.005) when compared to patients with non-CMUSE diagnosis, in which abdominal pain was the most common presenting symptom (44.5% vs 87.5%, p=0.02). Multiple (100%) and circumferential (75%) ulcers with restricted mucosal involvement (55.6%) were major features at endoscopy and pathology. Most common treatments were corticosteroids (78%) or surgical resection (55.6%), with 33% receiving biologics. Disease recurrence after first treatment occurred in the majority (88.9%) after a median time of 6 months (Table 1).
9 CTE and 1 MRE of 8 confirmed cases images were analyzed (Table 2). Major imaging features included multiple (≥ 5; 88%; 7/8), short (&lt; 2 cm; 100%; 8/8) circumferential (100%;8/8) strictures with moderate wall thickening (6–9 cm), and stratified hyper enhancement (100%; 8/8) located in the ileum (100%; 8/8). Median proximal small bowel dilation was 2.95 cm (2.5–4.1 cm). Less common findings included: mesenteric adenopathy (50%; 4/8), increased mesenteric edema/ascites (38%; 3/8), mesenteric vascularity (25%; 2/8), colon inflammation (13%; 1/8), and decreased small bowel fold pattern (13%; 1/8). No patients with confirmed CMUSE cases demonstrated penetrating disease (e.g., abscess, fistula).

Conclusion
CMUSE is rare cause of small bowel strictures with overlapping clinical and imaging features of more common etiologies such as Crohn’s Disease and NSAID enteropathy that need to be excluded through a multidisciplinary approach to confirm the diagnosis.
ULTRASOUND - FIRST-LINE IMAGING MODALITY IN EVALUATION OF THE INFLAMMATORY BOWEL LESIONS IN CHILDREN
Authors: Grzegorczyk Magdalena , Kuczynska Maryla , Siejka Karolina , Zbroja Monika , Cyranka Weronika , Piekarska Monika , Nowakowska Malgorzata , Wozniak Magdalena Maria , Brodzisz Agnieszka 
Published: January 2021

Abstract

Introduction
Crohn’s disease is classified as chronic inflammatory bowel disease. The incidence in Europe ranges from 1 to almost 11.4 per 100,000 population per year. Ultrasound examination plays an important role in imaging diagnostics of inflammatory bowel lesions. It allows for assessing response to therapy as well as recognizing possible penetrating complications of the disease, i.e. fistula or abscess.

Materials and Methods
36 children were included in the study: 16 boys and 20 girls with an active phase of Crohn’s disease. Each patient underwent intestinal ultrasound examination with a high frequency 7–12 Mhz linear probe.

Results
In all patients US examination depicted thickened, hypoechoic ileal wall showing patterns of vascularization. In 8 patients Bauhin’ valve edema was visible. In 16 children, inflammatory infiltration of the periintestinal fat around the affected segment of the intestine was found. In addition, all patients presented mesenteric lymphadenopathy with short-axis diameter of 10–15 mm. 8 patients had penetrating complications of Crohn’s disease: 4 small intestine fistulas and 4 abscesses.

Conclusion
Given its safety profile and diagnostic efficacy, US examination should be considered as the first-line imaging modality for assessing inflammatory bowel disease in children. US proved to be a reliable and easily accessible tool in the diagnosis of enteric inflammatory lesions, evaluating CD activity and assessing potential penetrating complications of the disease.
WEARABLE SWEAT SENSING DEVICE FOR DETECTION OF IBD BIOMARKERS
Authors: Jagannath Badrinath , Muthukumar Sriram , Prasad Shalini 
Published: January 2021

Abstract

Introduction
Inflammatory Bowel Disease affects 1.2 million in the United States. Flare-up of the disease occurs in a random way and current testing methods lack ability for real-time prediction of a flare up. The levels of cytokines elevate during a flareup. Therefore, we hypothesize that real-time monitoring of cytokine biomarkers can be useful for early detection of flare-ups and provide better patient management. In this context, sweat-based diagnostics can be promising for real-time tracking of IBD biomarkers.

Materials and Methods
A wearable SWEATSENSER was developed by functionalization of specific affinity capture probes (IL-1β, CRP antibodies) on metal/semiconducting interface deposited on a porous patch substrate. Electrochemical impedance spectroscopy technique was used to detect the interaction between the specific antibody and target analyte. The developed SWEATSENSER was tested on 20 healthy human subjects in compliance with an approved IRB at UT Dallas. Continuous on-body measurements were recorded to report IL-1β, CRP levels in sweat in real-time.

Results
In this work, a wearable multiplexed sweat sensor for detection of IL-1β, CRP in sweat has been demonstrated. The sensor demonstrates a limit of detection of 1 pg/mL with a dynamic range from 1 pg/mL- 512 pg/mL for both the biomarkers in sweat. The sweat sensor demonstrated excellent correlation with reference ELISA method (Pearson’s r ≥0.95). On-body monitoring using sweat sensor from passively perspired human sweat demonstrated a mean concentration of 28 pg/mL for IL-1β in healthy cohort.

Conclusion
A wearable sweat sensor was developed to monitor potential IBD markers in sweat. The developed device can be useful in better management of IBD patients.
RESULTS FROM A NATIONAL CROSS-SECTIONAL STUDY OF DISEASE BURDEN IN CROHN’S DISEASE
Authors: Seabury Jamison , Zizzi Christine , Weinstein Jennifer , Wagner Ellen , Rosero Spencer , Dilek Nuran , Kaat Aaron , McDermott Michael , Saubermann Lawrence , Temple Larissa , Rogoff Scott , Heatwole Chad 
Published: January 2021

Abstract

Background
Patients with Crohn’s disease experience a wide variety of clinical symptoms that affect how they feel and function. As therapeutic trials are planned for patients with Crohn’s disease, it is important to better understand the symptoms that have the greatest impact on Crohn’s disease patient’s lives.

Objective
To identify the most common and important disease manifestations in Crohn’s disease in a large population of patients. To determine the modifying factors that are associated with these symptoms.

Methods
We conducted a national cross-sectional study of 415 patients from the IBD Partners patient registry sponsored by the Crohn’s & Colitis Foundation to identify the prevalence and relative importance of 148 individual symptoms across 17 unique symptomatic themes. These themes were previously identified through 16 semi-structured qualitative interviews with Crohn’s patients.

Results
Crohn’s disease participants provided over 55,000 symptom rating responses. The symptomatic themes with the highest prevalence in Crohn’s disease were gastrointestinal issues (93.0%), fatigue (86.4%), dietary restrictions (77.9%), impaired sleep or daytime sleepiness (75.6%), and inability to do activities (72.3%). Symptomatic theme prevalence was widely associated with having above the median number of stools per day, having above the median number of bowel movements per day, having perianal disease, having to miss work, and unemployment.
Discussion/Conclusion: Crohn’s disease symptoms, some under-recognized, vary based on disease characteristics and demographic features. These symptoms represent targets for future therapeutic interventions and are potential areas of interest for an upcoming disease-specific patient-reported outcome measure for this population.

Acknowledgements
Funding for this project was provided by UR Ventures. Research activities were conducted in collaboration with the Crohn’s & Colitis Foundation.
IDENTIFYING INADEQUATE RESPONSE AMONG CROHN’S DISEASE PATIENTS ON A BIOLOGIC IN A REAL-WORLD ADMINISTRATIVE CLAIMS DATABASE
Authors: Hunter Theresa , Naegeli April , 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 biologic initiation among Crohn’s disease (CD) patients in the United States using a claims-based algorithm. Baseline factors associated with IR to a biologic were also analyzed.

Methods
This was a retrospective cohort study using claims data from the HealthCore Integrated Research Database. Adult patients with CD who initiated a biologic (TNFi: adalimumab, certolizumab, infliximab; non-TNFi: natalizumab, ustekinumab, and vedolizumab) from 7/1/2016 to 8/31/2018 and had continuous enrollment ≥6 months before and ≥12 months after index date (date of first biologic claim) were included. The index biologic was defined as the first biologic prescribed during the study time period. The claims-based algorithm used in this study to identify IR was originally developed and validated in rheumatoid arthritis and was modified for CD patients. Patients were identified as having IR to their index biologic 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 biologic, added a new conventional therapy, increased dose/frequency of biologic, addition or dose increase of oral glucocorticoids, used a new pain medication, or had surgery for CD. 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 biologic.

Results
A total of 2,437 CD patients were included in this analysis. Mean age was 41 years, 53% were female, 81% initiated a TNFi, and 19% initiated a non-TNFi as their index biologic (Table 1). Over the 1-year follow-up period, 62% of CD patients had an IR to their biologic: 41% of patients had low adherence, 14% switched/added a new biologic, 13% added a new conventional therapy, 12% had a dose/frequency increase of their index biologic, 12% had an addition/dose increase of oral glucocorticoids, 8% used a new pain medication, and 5% had surgery. Inadequate responders were more likely to be female (odds ratio (OR)=1.36; p&lt;0.001), have historical use of TNFi (OR=1.94; p&lt;0.001), and be on a consumer-driven health plan (OR=1.28; p&lt;0.001); while patients with baseline use of conventional therapy were more likely to be responders (OR=0.72; p&lt;0.001) (Table 2).

Conclusion
Over 62% of CD patients had an inadequate response to their index biologic within 1 year after initiation, mostly driven by low adherence. This modified claims-based algorithm for CD appears useful to classify inadequate responders in health plan claims data. Additional research is needed to further validate this algorithm in a clinical setting.
PAIN MEDICATION USE AMONG CROHN’S DISEASE AND ULCERATIVE COLITIS PATIENTS BEFORE AND AFTER INITIATION OF BIOLOGIC THERAPY
Authors: Hunter Theresa , Naegeli April , Nguyen Chi , Shan Mingyang , Smith Joseph , Tan Hiangkiat , Gottlieb Klaus , Isenberg Keith 
Published: January 2021

Abstract

Objective
The purpose of this analysis was to describe pain medication utilization of newly diagnosed patients with Crohn’s disease (CD) and ulcerative colitis (UC) over 12-months before and after initiation of a biologic.

Methods
This is a retrospective study using administrative claims from the HealthCore Integrated Research Database. Patients newly diagnosed with CD or UC who initiated a biologic from 1/1/2014 to 7/31/2017 were included. Medications that could be used for pain control were assessed 12-months prior and 12-months after biologic initiation. Demographics, baseline clinical characteristics, and pain medication use were described using descriptive statistics. Frequencies and percentages were provided for categorical variables and means, standard deviations, and medians were presented for continuous measures. The differences in pain medication use 12 months prior and 12 months after biologic initiation were assessed using McNemar’s Test for categorical variables and Wilcoxon signed-rank test for continuous variables..

Results
540 CD patients and 373 UC patients were included in this analysis. CD patients had a mean age of 36.8 years, 50.0% were female, and the mean time from diagnosis to biologic initiation was 7.1 months. UC patients had a mean age of 39.9 years, 44.0% were female, and the mean time from diagnosis to biologic initiation was 10.9 months. Prior to biologic initiation, 23.1% of CD patients were prescribed NSAIDs, 78.1% glucocorticoids, 49.4% opioids, and 29.3% neuromodulators. Similarly, prior to biologic initiation, 20.9% of UC patients were receiving NSAIDs, 91.4% glucocorticoids, 40.8% opioids, and 29.5% neuromodulators.
Twelve months after biologic initiation, use of NSAIDs (CD: 23.1% vs. 15.0%; UC: 20.9% vs. 15.8%) and glucocorticoids (CD: 78.1% vs. 58.9%; UC: 91.4% vs. 74.3%) significantly decreased among CD and UC patients. Opioid use decreased among UC and CD patients; however this decrease was only statistically significant for CD patients (CD: 49.4% vs. 41.5%; UC: 40.8% vs. 36.5%). Use of neuromodulators significantly increased during 12-months after biologic initiation compared to 12 months prior to initiation among CD (29.3% vs. 33.7%) and UC (29.5% vs. 35.7%) patients.

Conclusion
Use of pain medications such as NSAIDs, glucocorticoids, opioids, and neuromodulators were common among CD and UC patients. Though rates of NSAIDs and glucocorticoids decreased after the initiation of biologics, 59% of CD and 74% of UC patients were still receiving glucocorticoids, and 15% of CD and 16% of UC patients were still receiving NSAIDs 12-months after initiation of a biologic. In addition, 42% of CD and 37% UC patients were still receiving opioids 12-months after initiation of a biologic. The results suggested that CD and UC patients are still receiving pain medication even after initiating biologics.
AN AUTOPHAGY PROTEIN ATG16L1 PREVENTS NECROPTOSIS BY REGULATING INTERFERON SIGNALING IN THE INTESTINAL EPITHELIUM
Authors: Matsuzawa Yu , Cadwell Ken 
Published: January 2021

Abstract

Introduction
ATG16L1, an essential component of autophagy, is one of the susceptibility genes of Crohn’s disease. We previously showed mice with decreased expression of Atg16L1 and Crohn’s disease patients homozygous for ATG16L1T300A risk alleles develop Paneth cell abnormalities in the intestinal epithelium. Moreover, the abnormalities were dependent on murine norovirus (MNV) infection in mice. Most recently, we reported mice with deletion of ATG16L1 in the intestinal epithelial cells (Atg16L1ΔIEC) are more susceptible to disease following intestinal injury than wild type mice when they are infected with MNV. Also, we revealed intestinal organoids derived from Atg16L1ΔIEC mouse are susceptible to TNFa-induced necroptosis. However, how ATG16L1 protects IECs against TNFa, and whether the susceptibility is preserved in human IECs harboring ATG16L1T300A risk alleles remains unclear.

Aims
In this study, we first examined the mechanism by which ATG16L1-deficiency renders IECs susceptible to necroptosis. Next, we investigated whether a specific ISG might be involved in the increased susceptibility. Finally, we tested whether human intestinal organoids harboring ATG16L1T300A risk alleles are susceptible to TNFa-induced necroptosis.

Methods & Results
We performed RNA-Seq analysis using small intestinal organoids derived from Atg16L1ΔIEC and control mouse, and found 49 genes were upregulated in naïve Atg16L1ΔIEC organoids (Figure 1). Interestingly, most of them were the genes known as interferon-stimulated genes (ISGs) representing a type I IFN (IFN-I) signature. Importantly, we found Atg16L1ΔIEC organoids pretreated with JAK-STAT inhibitor Ruxolitinib displayed better viability and decreased level of necroptosis-related proteins when they were stimulated with TNFa. Moreover, we found protein kinase R (PKR) was increased in naïve Atg16L1ΔIEC organoids, and inhibition of PKR significantly protected Atg16L1ΔIEC organoids from TNFa. Finally, we generated human intestinal organoids using biopsy specimens mostly collected from Crohn’s disease patients. We compared the viability between individuals with 2 copies vs 0 or 1 copy of ATG16L1T300A risk allele, and found organoids derived from ATG16L1T300A homozygous individuals exhibited heightened susceptibility to TNFa (Figure 2 A and B). Moreover, we tested the effect of Ruxolitinib as well as multiple necroptosis inhibitors on human organoids, and found all the inhibitors successfully protected ATG16L1T300A homozygous organoids from TNFa-induced cell death.

Conclusion
Our data indicate ATG16L1 prevents necroptosis by regulating interferon signaling in both mouse and human IECs, and suggest inhibition of JAK-STAT as well as necroptosis pathway could be promising therapeutic options for Crohn’s disease patients with ATG16L1T300A risk alleles.
FK506 BINDING PROTEIN 8 (FKBP8) INTERACTIONS WITH MYOSIN LIGHT CHAIN KINASE 1 ARE REQUIRED FOR TNF-INDUCED TIGHT JUNCTION BARRIER LOSS
Authors: Zuo Li , Cao Feng , Kuo Wei-Ting , Turner Jerrold 
Published: January 2021

Abstract

Background
Tumor necrosis factor (TNF) regulates intestinal epithelial tight junction permeability by activating myosin light chain kinase 1 (MLCK1) expression and enzymatic activity. MLCK1 recruitment to the apical perijunctional actomyosin ring (PAMR) is, however, required for barrier regulation; Divertin, a small molecule drug that blocks this recruitment, prevents barrier loss and attenuates both acute and chronic experimental diarrheal disease. We therefore hypothesized that MLCK1 recruitment to the PAMR requires interactions with as yet unidentified chaperone protein(s).

Objective
To identify binding partners and define the mechanisms by which they activate MLCK1 recruitment to the PAMR.

Results
We performed a yeast-2-hybrid (Y2H) screen using the MLCK1 domains required for PAMR recruitment as bait. FKBP8, which encodes a peptidyl-prolyl cis-trans isomerase (PPI), was recovered, and direct binding to the MLCK1 domains (Kd=~5mM) was confirmed using microscale thermophoresis (MST). This binding interaction required the FK506-binding PPI domain and was specifically inhibited by FK506 (tacrolimus). Immunofluorescent microscopy demonstrated partial colocalization of MLCK1 and FKBP8 within intestinal epithelial monolayers; TNF caused both to concentrate around the PAMR. To further characterize this interaction, we performed proximity ligation assays (PLA) and found that TNF increased interaction between MLCK1 and FKBP8 &gt; 2-fold. FK506 prevented TNF-induced increases in PLA signal. FK506 was also able to reverse TNF-induced increases in myosin light chain (MLC) phosphorylation and tight junction permeability. In Caco-2 monolayers, FKBP8 knockout blocked TNF-induced MLCK1 recruitment, MLC phosphorylation, and tight junction barrier loss; all of which were restored by FKBP8 re-expression. In mice, MLC phosphorylation and intestinal barrier loss triggered by acute, anti-CD3-induced, T cell activation were blocked by luminal FK506. Importantly, this local FK506 treatment did not prevent anti-CD3-induced increases in mucosal TNF, IL-1b, and IFNg. Immunostains of biopsies from IBD patients documented increased PAMR MLC phosphorylation, MLCK1 recruitment, FKBP8 recruitment, and MLCK1-FKBP8 PLA signal relative to control subjects.

Conclusions
FKBP8 is a chaperone protein required for TNF-induced MLCK1 recruitment and barrier loss. This requires direct interaction between MLCK1 and the PPI domain of FKBP8. FK506 binding to the PPI domain displaces MLCK1 thereby preventing recruitment to the PAMR and barrier loss. These activities are separate from the immunosuppressive effects of FK506. We speculate that molecular blockade of the FKBP8-MLCK1 interaction may be a novel approach to barrier restoration and therapy of diseases associated with intestinal barrier dysfunction.

Support
NIH (DK068271, DK061931) and the NNSF of China (81800464, 82070548).
METHYLTRANSFERASE SMYD5 EXAGGERATES INFLAMMATORY BOWEL DISEASE BY REGULATING PPAR-γ COACTIVATOR 1-α STABILITY
Authors: Hou Yuning , Sun Xiaonan , Gheinani Pooneh , Guan Xiaoqing , Sharma Shaligram , Zhou Yu , Jin Chengliu , Yang Zhe , Naren Anjaparavand , Yin Jun , Denning Timothy , Gewirtz Andrew , Xie Zhonglin , Li Chunying 
Published: January 2021

Abstract

Background and Aims
The expression and role of methyltransferase SET and MYND domain-containing protein 5 (SMYD5) in inflammatory bowel diseases (IBD) is completely unknown. Here, we investigated the role and the underlying mechanism of epithelial SMYD5 in IBD pathogenesis and progression.

Methods
The expression and subcellular localization of SMYD5 and peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) were examined by Western blot analysis, immunofluorescence staining, and immunohistochemistry in intestinal epithelial cells (IECs) and in colon tissues from human IBD patients and mice with experimental colitis. Mice with Smyd5 conditional knockout in IECs and littermate controls were subjected to DSS-induced experimental colitis and the disease severity and inflammation were assessed. SMYD5-regulated mitochondrial biogenesis was examined by RT-qPCR and transmission electron microscopy and mitochondrial oxygen consumption rate was measured in a Seahorse Analyzer system. The interaction between SMYD5 and PGC-1α was determined by co-immunoprecipitation assay. PGC-1α degradation and turnover (half-life) were analyzed by cycloheximide chase assay. SMYD5-mediated PGC-1α methylation was measured via in vitro methylation followed by mass spectrometry to identify the specific lysine residues that were methylated.

Results
Up-regulated SMYD5 and down-regulated PGC-1α were observed in IECs from IBD patients and mice with experimental colitis. However, Smyd5 depletion in IECs protected mice from DSS-induced colitis. SMYD5 was critically involved in regulating mitochondrial biology such as mitochondrial biogenesis, respiration, and apoptosis. Mechanistically, SMYD5 regulated mitochondrial functions in a PGC-1α dependent manner. Further, SMYD5 mediated lysine methylation of PGC-1α and facilitated its ubiquitination and proteasomal degradation.

Conclusion
SMYD5 attenuates mitochondrial functions in IECs and promotes IBD progression by enhancing the proteasome-mediated degradation of PGC-1α protein in a methylation-dependent manner. Strategies to decrease SMYD5 expression and/or increase PGC-1α expression in IECs might be a promising therapeutic approach to treat patients with IBD.