bluuebunny/crossref_metadata_2025_split huggingface dataset:
AUPHOS, A “FIRST-IN CLASS“ ORAL AGENT FOR CORRECTING METABOLIC DYSFUNCTION IN IBD
Authors: Wempe Lesley , Mohamed Rana , Warinner James , Goretsky Tatiana , Avdiushko Margarita , Kim Jong , Abomhya Ahmed , Lee Goo , Awuah Samuel , Barrett Terrence , Kapur Neeraj 
Published: January 2022

Abstract

BACKGROUND
Mucosal repair is the goal of medical therapy in IBD. Prospective inception cohort pediatric studies suggest that suppression of mitochondrial genes lead to unfavorable clinical outcomes in ulcerative colitis (UC) and Crohn’s disease (CD). We posit that the inability to restore epithelial mitochondrial respiration impairs ulcer healing in IBD. In the current study, we tested whether a novel compound (AuPhos) that improves mitochondrial function promotes ulcer healing in IBD.

METHODS
Biodistribution and pharmacokinectic (PK) studies were performed (6h, 12h, 24h) after single oral dose (25mg/kg) of AuPhos using C57/BL/6 (WT) mice. Mitochondrial uptake of AuPhos was determined by measuring gold content in normal colonocytes (NCM460) using graphite furnace atomic absorption spectroscopy. Oxygen consumption rate (OCR) in isolated crypt-IECs from AuPhos-fed WT mice were examined using high-resolution respirometry. The effect of AuPhos in colitis was tested in DSS (2%; 7d) WT (B6) mice. Disease activity index (DAI) (weight loss, diarrhea, and hematochezia), intestinal permeability (FITC-dextran), histological scoring and the frequency of fissioning crypts were determined throughout the 21d time course. Tissue mRNA levels for mitochondrial enzyme, cytokine, chemokine and intestinal stem cell (ISC) marker genes were assessed by RT-qPCR.

RESULTS
Biodistribution and PK studies revealed that higher levels of orally administered AuPhos in small intestine and colon tissue, with limited systemic absorption. AuPhos displayed a dose-dependent mitochondrial uptake in IEC where respirometry showed &gt;30% increase in OCR after oral dosing in vivo. AuPhos treatment decreased DAI (**; p&lt;0.01), histologic colitis scores D11-15 (*; p&lt;0.05) and FITC-dextran permeability in DSS colitis mice. Notably, AuPhos increased fissioning crypt numbers near healing ulcers in DSS-colitis mice (**; p&lt;0.01) while it reduced mRNA for pro-inflammatory cytokines/chemokines (IL-1β, IL-6, IFN-γ, IP10). AuPhos induced mRNA for ISC markers [Lgr4 (*; p&lt;0.05), Lgr5, Lrig1 (***; p&lt;0.001)] and mitochondrial complexes [mtCO1 (**; p&lt;0.01) and COX2 (***; p&lt;0.001)]. These findings suggest that AuPhos-induced mitochondrial respiration drives transcriptomic regulation of IEC genes involved in colitis ulcer healing.

CONCLUSION
Our data suggests that AuPhos compound improves ulcer healing under acute colitis conditions by increasing mucosal OxPHOS metabolism. Specifically, we find that AuPhos increases mitochondrial respiration-induced crypt fissioning and ulcer healing associated with reduced mucosal inflammation and increased barrier integrity. Overall, AuPhos may be an important “first-in class” oral therapeutic for correcting the metabolic dysfunction central to IBD pathogenesis.
INTERLEUKIN-17 RECEPTOR SIGNALING TO PANETH CELLS HELPS MAINTAIN INTESTINAL INTEGRITY AFTER GAMMA RADIATION INDUCED INJURY
Authors: Kempen Cody , Gaudino Stephen , Bahadur Tej , Singh Ankita , Kumar Pawan 
Published: January 2022

Abstract

BACKGROUND
IL-17A/F signaling through the IL-17RA/RC receptor complex plays a vital role in immunity and inflammation. The expression of IL-17RA/RC by diverse intestinal epithelial cell types including Paneth cells and the observation that therapies neutralizing IL-17A or IL-17RA in Crohn’s disease (CD) patients induce adverse events suggest essential homeostatic functions of this cytokine. Paneth cells and their antimicrobial products (a-defensins, lysozyme etc.) play a critical role in mediating small intestinal host defense under homeostatic conditions as well as after injury or infection, and their dysregulation constitutes a pathogenic factor for CD. The specific role of intestinal IL-17A signaling in Paneth cells to regulate host defense at steady state or after intestinal inflammation remains poorly understood. Thus, we hypothesize that intestinal IL-17A signaling, specifically in Paneth cells, plays an important role in regulating microbiota colonization as well as maintaining intestinal integrity after gamma radiation induced injury.

METHODS
To examine the importance of IL-17RA signaling to Paneth cells, we utilized total, entire gut epithelium (Il17rafl/fl;villin-cre) and Paneth cell-specific IL-17RA knockout mice (Il17rafl/fl;Defa6-cre+). We subjected these mice with gamma irradiation (1200 cGy) to study intestinal injury and regenerative responses. Mice were sacrificed 3/5 days post irradiation. Terminal ilium was collected from naïve or irradiated mice for immunofluorescence imaging, RT-PCR, RNA sequencing, and enteroid cultures.

RESULTS
Our preliminary data from irradiated Il17ra-/- and Il17rafl/fl;villin-cre mice suggest that IL-17A signaling is important in maintaining intestinal barrier integrity. Specifically, these mice revealed increased microbial dissemination to liver and spleen compared to their respective control mice. Reduced expression of Lyz1 3 days post radiation in the terminal ileum of Il17ra-/- mice suggest impaired Paneth cell function. Cessation of Paneth cell specific IL-17RA signaling, also resulted in systemic bacterial dissemination 5 days post radiation. We also observed increased level of fecal Lcn2 in irradiated Il17rafl/fl;Defa6-cre+ mice. To understand Paneth cell-specific IL-17RA functions, we performed 16S microbial and RNA sequencing from ileum luminal contents and terminal ilea of naïve Il17rafl/fl;Defa6-cre+/- mice, respectively. While microbial 16s sequencing revealed no change to the overall microbial community, specific changes were observed at a select family level. Specifically, the level of Streptococcaceae was increased. RNA sequencing data showed no difference in Paneth cell antimicrobial peptides but did show reduced Caspase 4 expression in Il17rafl/fl;Defa6-cre+ mice. Collectively, our data revealed an important role of IL-17RA signaling in Paneth cell function at steady state and after injury.
THE ASSESSMENT OF MRE FINDINGS ACCORDING TO CDAI SCORE IN PATIENTS WITH CROHN’S DISEASE
Authors: Zbroja Monika , Kuczynska Maryla , Cyranka Weronika , Nowakowska Malgorzata , Grzegorczyk Magdalena , Siejka Karolina , Piekarska Monika 
Published: January 2022

Abstract

INTRODUCTION
Crohn’s disease (CD) is a chronic inflammatory bowel disease of the gastrointestinal tract. One of the diagnostic steps is to perform a magnetic resonance enterography (MRE). The purpose of the study was to compare MRE findings with clinical index of the disease activity - CDAI score, in order to verify the usefullness of magnetic resonance enterography.

SUBJECTS/METHODS
The study included 46 patients who underwent MRE according to a standard protocol, with dynamic contrast-enhanced sequences. All studies were performed in prone position, using mannitol as a positive oral contrast agent. The MRE severity grading was performed according to the consensus recommendations. CDAI score was assessed prior to examination by a specialist.

RESULTS
32 patients had multifocal lesions, 14 presented with unilocular lesions and 14 had a history of previous bowel resection. Penetrating disease was diagnosed in 15 subjects. The results indicate for good correlation between MRE and CDAI assessment in groups of patients with moderate and severe clinical symptoms. However, there is a significant discrepancy in MRE findings in the group of patients with mild disease activity according to CDAI. Out of 23 patients with clinically mild symptoms, 1 exhibited MRE characteristics of severe, 9 of moderate and 7 of mild inflammatory intestinal lesions.

CONCLUSION
There is good accordance between MRE and clinical findings in patients with prominent disease symptoms, indicating that MR enterography might be a promising modality in terms of lesion activity grading. Nonetheless, there exist a significant group of patients with mild disease symptoms, in whom MRE tends to show full spectrum of disease severity.
EFFECTIVENESS OF CROHN’S DISEASE EXCLUSION DIET FOR INDUCTION OF REMISSION IN CROHN’S DISEASE ADULT PATIENTS
Authors: Szczubelek Martyna , Pomorska Karolina , Korólczyk-Kowalczyk Monika , Lewandowski Konrad , Kaniewska Magdalena , Rydzewska Grazyna 
Published: January 2022

Abstract

INTRODUCTION
The Crohn’s disease exclusion diet (CDED) has a well-documented effectiveness in inducing remission in active Crohn’s disease (CD) in children. However, the data for adult population are limited. The aim of the study was to evaluate the effectiveness of the CDED with a supply of liquid formula Modulen (Nestlé) in inducing remission in CD adult patients.

MATERIALS AND METHODS
Between March 2020 and May 2021, an open label, non-randomized, single centre study was conducted in gastroenterology outpatient center. 32 patients with active CD (Crohn’s disease activity index CDAI &gt;150 points) were treated with CDED with a supply of Modulen (Nestlé). The patients were seen at baseline, at week 6 and at week 12 of the study. During the visits anthropometric measurements, laboratory test, CDAI, Inflammatory Bowel Disease Questionnaire (IBDQ) were performed. Data analysis was based on an intention-to-treat approach. Statistical analysis was carried out using R software, version 4.0.5. Normality of the distribution was validated using the Shapiro–Wilk test, skewness and kurtosis values and on visual assessment of histograms. Comparison between three measurements was conducted with ANOVA for repeated measures or a series of Wilcoxon signed-rank tests. The primary endpoint was the achievement of remission at week 12 (CDAI&lt;150 points). The secondary endpoints were the inducement of a clinical response (a reduction in CDAI by 100 points or more), improved quality of life and an improvement in laboratory parameters and BMI.

RESULTS
32 participants were included in the study. The baseline CDAI was 253 points (175.50; 373.00) (from 151 to 562 points). Baseline calprotectin was at a median level of 393 μg/g (58.85; 969.00), ranging from 11.9 to 4 630 μg/g. A statistically significant drop in CDAI was observed after 6 weeks (p &lt;0.001) and after 12 weeks (p &lt;0.001) of dietary intervention as compared to baseline (Figure 1). IBDQ was significantly higher (p &lt;0.001) at the first and second follow-up vs baseline. Calprotecin levels were significantly lower at the second follow-up vs baseline (p =0.021) (Figure 2). A clinical response was observed in 83.3% of the patients (CI95 [65.3%–94.4%]) after 6 weeks of treatment and in 85.7% of cases (CI95 [67.3%–96.0%]) after 12 weeks of treatment. A clinical remission was present after 6 weeks of treatment vs baseline in 76.7% of patients (CI95[57.7%–90.1]) and in 82.1% of participants (CI95[63.1%–93.9]) after 12 weeks of treatment vs baseline.

CONCLUSIONS
The CDED with a supply of liquid formula is an effective therapy for inducing remission in the adult CD population. However, a randomised trial is needed to obtain higher-level evidence.
MY SCD PROTOCOL - AN ONLINE, COMPREHENSIVE, REMOTELY-SUPERVISED PROTOCOL FOR IBD PATIENTS TO IMPLEMENT AN EFFECTIVE DIETARY INTERVENTION
Authors: Arjomand Ali , Caviness Rachelle 
Published: January 2022

Abstract
Many IBD patients are keen to modify their diet to better manage their disease. However, little or no dietary guidance is offered to IBD patients or is not comprehensive and lacks practical resources to implement and sustain the modification. Up to 70% of IBD patients self-prescribe dietary restrictions with demonstrated risk of nutrient deficiencies. There is currently no comprehensive IBD dietary intervention presented in a customizable, easy-to-follow protocol format. To meet this need, we developed and tested a full-featured online version of an effective IBD dietary intervention. METHOD: ‘My SCD Protocol’ is a comprehensive, customizable protocol based on the specific carbohydrate diet (SCD). The online, self-paced protocol provides educational resources, self-assessment tools, and step-by-step instructions to start and advance through SCD. Ingredients are presented in 4 ordered Stages (Elimination, Reintroduction, Maintenance, Expansion) to help methodically expand tolerable ingredients. Stage-specific curated recipes support implementation and offer variety and personalization. Patients self-report symptoms, meals, and progress using a HIPAA-compliant mobile app. Entries are accessible in real-time by the patient’s care team. The protocol currently holds 304 SCD ingredients and 164 recipes. Patients (n=87) referred to Modulla Health IBD Nutrition Clinic, or seeking support directly, implemented My SCD Protocol based on preference and ingredient tolerance. Symptoms were self-reported using the accompanying app. Interim results are reported here. RESULTS: Patients successfully accessed and personalized My SCD Protocol. Table 1 summarizes patient profiles. Table 2 presents self-reported symptom changes, showing improvements in all categories except urgency and appearance of mucus. Additional outcomes, including fecal calprotectin, will be reported. DISCUSSION: SCD has been shown to induce clinical response and biochemical remission in adult and pediatric IBD patients. SCD is either self-implemented by patients using a trial-and-error approach, or is dietitian-supervised, primarily using the ‘legal’ SCD ingredient list and little else. SCD was implemented in a clinical trial setting using a predefined, prescriptive meal model with little room to personalize diet (DINE-CD). My SCD Protocol is the first comprehensive protocol to help implement, personalize, and safely advance through SCD. Patients reliably accessed the educational videos, staged ingredients, matching recipe libraries, and logging tools using mobile and web tools. We show self-reported symptom improvements during the first 21 days of the protocol leading to longer-term adherence to diet modification. Care teams who recommend My SCD Protocol to patients can conveniently and continuously monitor patient progress in real-time and supervise patients throughout the intervention.
VALIDATION OF THE SIMPLIFIED ENDOSCOPIC MUCOSAL ASSESSMENT OF CROHN’S DISEASE (SEMA-CD) A NOVEL ENDPOINT TO ASSESS ENDOSCOPIC IMPROVEMENT WITH REAL WORLD DATA
Authors: Adler Jeremy , Colletti Richard , Noonan Lenore , Conklin Laurie , Lo Kim Hung , Xiao Yongling , Volger Sheri 
Published: January 2022

Abstract

BACKGROUND
To demonstrate treatment efficacy in Crohn’s disease (CD), regulatory authorities require that trials include an endoscopic remission endpoint. However, standardized endoscopic assessment of mucosal improvement, such as the simple endoscopic score of CD (SES-CD), is not typically recorded by clinicians in practice or outside of clinical trials. A previous study demonstrated the Simplified Endoscopic Mucosal Assessment of CD (SEMA-CD) correlates strongly with SES-CD and that SEMA-CD is a score that can be easily used by clinicians in routine practice (Adler et al., 2021). The objective of this current study was to validate the SEMA-CD scored colonoscopy videos in additional populations and to examine the reliability of SEMA-CD over a range of mucosal disease severity in pediatric and adult participants and to evaluate sensitivity to change over time.

METHODS
We compared SEMA-CD and SES-CD scores in 110 patients with existing pre- and post-treatment colonoscopy videos from two ustekinumab clinical trials (UNISTAR, pediatric, n=36; SEAVUE, adult, n=74; Figure 1). Videos were separately scored with the SEMA-CD and SES-CD by different central readers, blinded to each other’s scores and to clinical history. Spearman’s rank correlation coefficient was used to evaluate correlation between scores, under different settings by study population (pediatric, adult), disease severity, and video quality. Inter- and intra-rater reliability were assessed with interclass correlation coefficient (ICC). Readers also rated ease of SEMA-CD scoring on a 7-point Likert scale.

RESULTS
SEMA-CD was highly correlated (rho [95% CI]) with the SES-CD, 0.89 (0.86, 0.92; Figure 2). Pre-to post-treatment changes in SEMA-CD scores compared with SES-CD scores were highly correlated 0.84 (0.77, 0.89). The positive relationship remained strong between scores when comparing total scores in pediatric 0.94 (0.90, 0.96) and adult 0.86 (0.80, 0.89) participants; across SES-CD disease severity categories (inactive, mild, moderate, severe; rho range 0.69-0.85); and in “optimal” 0.90 (0.86, 0.93) and “less than optimal” quality videos 0.88 (0.83, 0.91). Intra- and inter-reader reliability (ICC [95%CI]) were high, 0.93 (0.88, 0.96) and 0.89 (0.85, 0.91), respectively. SEMA-CD was rated as the same as, or easier than SES-CD 99.6% of the time.

CONCLUSION
This study demonstrated the SEMA-CD is feasible, reliable, reproducible, and sensitive to change in both adult and pediatric patients with CD. SEMA-CD should serve as an easy score for clinicians to record mucosal improvement and provide quality real world evidence for research using data from clinical registries.
ENDOSCOPIC STRICTUROTOMY – A NOVEL THERAPEUTIC MODALITY FOR IBD-RELATED STRICTURES: FIRST EUROPEAN EXPERIENCE
Authors: Lukas Martin , Kolar Martin , Vasatko Martin , Lukas Milan 
Published: January 2022

Abstract

INTRODUCTION
Both primary strictures and secondary anastomotic strictures are common complications in patients with inflammatory bowel diseases (IBD), especially Crohn’s disease (CD). Balloon dilation has been the gold standard in the endoscopic treatment of these strictures. Endoscopic stricturotomy (ESt, Figure 1) represents a promising novel approach, however, the data published on this method so far has been limited to a small sample and few sites.

METHODS
All ESts performed in IBD patients between September 2018 and April 2021 in our tertiary IBD center were included. Data on demographics, disease characteristics, procedure details and outcomes were analyzed. Technical success was defined as an ability to pass the scope through the stricture following the procedure. Complications included perforation and immediate or delayed bleeding with the need of intervention or hospitalization.

RESULTS
In total, 92 procedures were performed in 67 patients (60 with Crohn’s disease, CD, and 7 with ulcerative colitis, UC) Among these 46.3% were males. Mean age was 43.9±12.5 years and mean disease duration was 14.6±9.7 years. Single ESt was done in 73.1% (49) of patients, while 26.9% (18) required multiple procedures. Most common location of stricture was surgical anastomosis site (82, 89.1%), while remaining 10 were located at anal canal (de novo stricture). Anastomotic strictures included ileo-colonic (64.1%), colo-colonic (9.8%), ileo-rectal (3.3%), and ileal pouch-anal (12.0%) anastomoses. Previous endoscopic balloon dilation (EBD) was attempted in 53.3% of the procedures, 27.2% of the analyzed procedures were preceded by earlier ESt. Technical success was achieved in 83 ESts (90.2%), complications occurred in four cases (all delayed bleeding, managed conservatively). After the mean follow-up time of 18.1±10.0 months, cumulative probability of reintervention (ESt, EBD or surgery) at 6 months was 30.2% (95% CI 15.6-46.2%), 40.3% (95% CI 25.5-54.6%) at 12 months and 48.8% (95% CI 34,0-62,1%) at 18 months (Figure 2). Time to reintervention was not significantly affected by previous intervention, age of the anastomosis, sex or age of the patients, concurrent therapy and specific ESt technique employed.

CONCLUSION
ESt is a novel endoscopic technique, which is both efficacious and safe to be performed in patients with IBD-related strictures.
NON-IMMUNE MEDIATED MUSCULOSKELETAL DISEASE IN CROHN’S DISEASE PATIENTS BEING EVALUATED FOR INFLAMMATORY SPONDYLOARTHRITIS - A PILOT STUDY
Authors: Schwartzman Monica , Longman Randy , Scherl Ellen , Schwartzman Sergio 
Published: January 2022

Abstract

BACKGROUND
Musculoskeletal (MSK) disease is the most common extra-intestinal manifestation of inflammatory bowel disease (IBD). The emphasis in the published literature has been on the inflammatory arthritis associated with IBD, spondyloarthritis (SpA). There is a lack of data regarding common, non-inflammatory MSK diseases such as osteoarthritis and fibromyalgia. This distinction is important, as these two conditions have different prognoses, require different clinical approaches and management.

OBJECTIVE
To evaluate the prevalence of non-inflammatory MSK disease in a cohort of Crohn’s disease (CD) patients.

METHODS
This was a cross-sectional study of a validated CD cohort from a single center registry in New York City conducted from 9/2019 - 1/2021. Recruitment was limited due to the COVID-19 Pandemic. Patients were sent a four question MSK survey (Figure 1) addressing peripheral joint and back symptoms. Those who answered positively to any question were considered to have MSK symptoms. All patients underwent one study visit with a rheumatologist that included: 66/68 tender/swollen joint count (TJC/SJC), Spondyloarthritis Research Consortium of Canada Enthesitis Index (SPARCC), Bath Ankylosing Spondylitis Metrology Index (BASMI), American College of Rheumatology fibromyalgia criteria, ESR and CRP. Disease activity was measured via a modified Ankylosing Spondylitis Disease Activity Score (ASDAS), Harvey Bradshaw Index (HBI), and Inflammatory Bowel Disease Questionnaire (IBD-Q).

RESULTS
26 CD patients participated. Median age was 45.6±17.7 years, 35% were male, median disease duration was 17.7±14.2 years and 73% were on immunomodulatory agents for CD. Median values (range) for the following physical exam and disease features were: TJC 10.8±13.2 (0-68), SJC 0.9±2.2 (0-66), SPARCC 2.8±3.1 (0-16), BASMI 1.5±1.0 (0-10, higher values: more motion limitation) ASDAS 1.5±0.9 (&lt;1.3: inactive disease, &gt;2.1: high disease activity), HBI 6.8±3.5 and IBD-Q 159±36. Median ESR and CRP were 18.9±22.2 mm/hr (normal 0-22) and 0.6±0.5 mg/dL (normal&lt;0.7), respectively. 16/26 (62%) reported MSK symptoms. 7/16 (43.8%) had features of SpA, while 9/16 (56.3%) did not have evidence by history or exam of SpA and were therefore determined to have non-inflammatory MSK disease. 13/26 (50%) met fibromyalgia diagnostic criteria.

CONCLUSION
MSK conditions were very common in this pilot cohort. Though features of SpA were present in almost half of patients, non-inflammatory MSK disease was present in the majority of those with MSK symptoms. While both rheumatologists and gastroenterologists need to recognize the importance of SpA, it is additionally essential to understand that the most common MSK disease in IBD may be non-inflammatory, which has distinct implications for management. Future studies should examine the prevalence of these conditions in larger cohorts of IBD patients.