bluuebunny/crossref_metadata_2025_split huggingface dataset:
A NEWLY DISCOVERED REGULATORY CD8 T CELL NETWORK HAS THE POTENTIAL TO REGULATE AND ELIMINATE PATHOGENIC CD4 T CELLS IN AUTOIMMUNE MEDIATED DISEASE OF THE GUT
Authors: Crane Courtney , Bowser Justin , Fasnacht Rachael , Gardell Jennifer , Maurer Meghan , Julien Susan , Templeton Megan , Therriault Jon Henry , Swiderek Kristine 
Published: January 2022

Abstract

INTRODUCTION
Several groups have described a subset of CD8 T cells with immunosuppressive characteristics in inflammatory disease settings. The increased prevalence of a defined subset of CD8 T cells and correlation to disease has been reported in mouse and human autoimmune diseases, suggesting a protective role for select CD8 T cells in autoimmunity. We hypothesized that a dysregulated regulatory CD8 T cell (CD8 Treg) network was similarly involved in the pathology of autoimmune diseases of the gut, including Celiac disease, Crohn’s, and Ulcerative Colitis. Recently, investigators have described CD8 Treg activation through a canonical T cell receptor that results in oligoclonal expansion and perforin dependent elimination of pathogenic CD4 T cells in animal models. Here, we have demonstrated the presence of this CD8 Treg cell network in Celiac patients and its potential to regulate and eliminate pathogenic CD4 T cells.

METHODS
Using antigen induced animal models of autoimmunity, as well as PBMCs and tissues derived from patients with Celiac disease, we have developed assays to evaluate CD8 Tregs. Our approach integrates imaging, gene expression, flow cytometry, and quantification of soluble analytes following gluten exposure. This platform may be extended to evaluate the CD8 Treg network following exposure to an antigenic trigger resulting in disease flare, including in diseases with poorly defined antigenic triggers, such as Crohn’s and colitis.

RESULTS
We have characterized a surface and functional phenotype associated with CD8 Treg prevalence and activation via agonism of a native TCR. Using this phenotype, we then confirmed the presence and prevalence in Celiac patient PBMCs and duodenal tissues and distinct from CD8 T cells (Figure 1). Activation resulted in a rapid and specific cytolytic mechanism of action in mouse and human CD8 Treg cells. CD8 Treg in Celiac patients are not inherently dysfunctional, as activation of celiac patient CD8 Tregs resulted in the elimination of pathogenic CD4 T cells, which are responsible for the initiation and perpetuation of tissue destructive inflammation in Celiac disease and IBD. Using Celiac disease as platform to introduce a known antigenic trigger for autoimmunity, we have established a panel of phenotypic and functional markers to define CD8 Tregs and their activity in patients with other autoimmune diseases, including Crohn’s disease and Ulcerative Colitis.

CONCLUSION
We postulate the importance of a newly described regulatory network in autoimmune mediated gut disorders and other inflammatory disease. This network can potentially be targeted by immune-modulating biologics, to suppress pathogenic T cells, reduce disease severity & onset, as well as mitigate flare severity & frequency.
TNFAIP3 DRIVES COLITIS THROUGH DEATH CELL AND TNFα PRODUCTION
Authors: Huerta Alvaro Torres , Ruley-Haase Katelyn , Boger-May Antonia , Boone David 
Published: January 2022

Abstract
IBD is characterized by inflammation involving a complex interplay between innate and adaptive immunity, non-immune cells, and intestinal microbes. To understand the contributions of innate immunity to inflammation during colitis we have developed a chronic model of innate immune-mediated colitis wherein RAG1-/- mice are crossed with mice expressing TNFAIP3 in intestinal epithelial cells (villin-TNFAIP3 mice). These villin-TNFAIP3 x RAG1-/- (TRAG) mice develop early onset, 100% penetrant, chronic colitis driven by gut microbes. To understand the inflammatory signals that lead to innate colitis in this model, we crossed TRAG mice with TNFα-/- mice (FRAG mice) and compared the severity of colitis in TRAG vs. FRAG mice. In addition, we characterized TNFα-producing myeloid populations from the lamina propria of TRAG mice. Finally, we assessed the expression and localization of proteins involved in cell death pathways, to unravel the mechanisms driving innate-immune mediated colitis. Our results show that, compared to RAG1-/- mice, TRAG mice have significantly increased numbers of lamina propria leukocytes, including increased numbers of neutrophils, inflammatory monocytes, macrophages, dendritic cells, and innate lymphoid cells. TRAG mice lacking TNFα (FRAG mice) had significantly lower numbers of all these leukocyte subsets. Consistent with this, FRAG mice had significantly lower histological colitis scores, compared to TRAG mice. Inflammatory monocytes, monocytes, macrophages, and neutrophils were found to be the main sources of TNFα production, while TNFα production was null or minimal in dendritic cells, natural killer cells, ILC1, ILC3 and IC2. Macrophages and inflammatory monocytes in TRAG mice were characterized by the expression of iNOS, whereas macrophages and monocytes of FRAG and RAG1-/- mice were notably marked by Arginase1 expression. Localization of active caspase3, phosphor-MLKL and TUNEL positive cells indicated extensive epithelial crypt cell death in TRAG mice that was markedly suppressed in FRAG mice. Together our results show that TNFα drives innate immune mediated colitis, potentially through induction of IEC necroptosis. TNFAIP3 is well known as a negative regulator of receptor-mediated NFκB and MAPK activation and therefore attempts to increase TNFAIP3 expression are considered promising avenues for prevention of inflammation. The present study, indicating that intestinal epithelial cell expression of TNFAIP3 drives TNFα-induced IEC death and innate colitis, highlights potential tissue-specific roles for TNFAIP3 that should be considered in the paradigm of TNFAIP3 as a target for prevention of inflammation.
ACTIVATION OF MK2 IN CROHN’S DISEASE-ASSOCIATED FIBROSIS: NEW TARGET FOR ANTI-FIBROTIC THERAPY
Authors: Chulkina Marina , McAninch Steven , Ehudin Melanie , Cohen Claire , Dovat Sinisa , Koltun Walter , Yochum Gregory , Pinchuk Irina , Beswick Ellen 
Published: January 2022

Abstract

INTRODUCTION
Fibrosis is the major aggressive complication of Crohn’s disease (CD), causing intestinal obstruction. No targeted therapies are currently available to revert CD-associated fibrosis. While inflammatory mechanisms in CD have been extensively investigated, understanding the pathogenesis of fibrosis is relatively limited. Mesenchymal cells are believed to be the major effectors in profibrotic processes in CD. There is a dramatic increase in α-SMA expressing subsets of mesenchymal cells, also known as myofibroblasts (MF), and this is considered to be among the main hallmarks of profibrotic changes in CD. Thus, targeting the profibrotic reprogramming/increase of α-SMA+ MFs and/or fibrosis-driving signaling could lead to the development of novel anti-fibrotic approaches in CD. Mitogen-activated protein kinase-activated protein kinase 2 (MK2) is a downstream substrate of p38 and is known to regulate pro-inflammatory cytokines. Moreover, MK2 is a regulator of downstream signaling in the profibrotic non-canonical TGF-β1/p38 pathway. However, the role of MK2 in CD-associated fibrosis and profibrotic reprogramming of MFs is not known. We hypothesize that hyperactivation of MK2 is critical to the profibrotic reprogramming of MF in CD and has potential as an anti-fibrotic therapeutic target.

METHODS
Human normal- and CD-derived MFs were analyzed using RNAseq, cytokine/chemokine multiplex array, FACS, and confocal microscopy. Chronic IL-10 KO colitis murine models relevant to CD were used in this study.

RESULTS
Increased expression of MK2 within α-SMA+ mesenchymal cells was observed in stricturing CD. Ex vivo treatment of the CD tissues with MK2 inhibitor PF-3644022 (10 μM) abrogated MK2 activity and decreased expression of fibrosis-related genes. An increase in MK2 activity within intestinal MFs was observed in vivo in IL-10KO murine colitis. Therapeutic use of the MK2 inhibitor PF-3644022 (0.2 mg/kg, daily for 10 days) in vivo significantly decreased the degree of intestinal fibrosis as measured by collagen deposition and reduced the expression of fibrosis-related genes. When compared to the WT murine-derived MFs, MK2-/- MFs showed low basal and TGF-β1 induced levels of pro-fibrotic genes expression in vitro. Using primary human MFs, we found that MK2 activity was associated with hallmark profibrotic genes in CD-MFs. Inhibition of MK2 activity with PF-3644022 reduced TGF-β1-induced overexpression of Col1α2, α-SMA, TNC, Fn1, and TGF-β1 genes. Profibrotic responses in MFs through SMAD2/3 and p38, but not MAPK signaling were mediated by MK2.

CONCLUSIONS
Our data provide evidence that activation of MK2 drives profibrotic reprogramming of mesenchymal cells in CD and it may be an attractive therapeutic target for the development of novel targeted strategies against CD-associated fibrosis.
ENHANCED RECOVERY PROGRAMS: HOW ARE WE BENEFITTING PATIENTS WITH IBD?
Authors: Shao Connie , McLeod Marshall , Gleason Lauren , Marques Isabel , Smith Burke , Chu Daniel 
Published: January 2022

Abstract

BACKGROUND
Enhanced Recovery Programs (ERPs) improve postoperative outcomes in colorectal surgery. Patients with IBD have been shown to benefit from use of ERP, but are immunosuppressed and chronically ill. We aimed to determine how patient outcomes under an ERP are affected by IBD.

METHODS
Patients undergoing colorectal surgery for IBD under an ERP from Oct 2015-May 2021 at a single institution were abstracted using ACS-NSQIP data, which was cross referenced with an internal health literacy database (BRIEF, 4-20). Adherence was defined as the sum of adherence to six components: pre-admission counseling, pre-op VTE prophylaxis, clear liquid diet pre-op, regional anesthesia, anti-emetic prophylaxis, and multi-modal pain management. Chi-square and two-sample t-test were used to compare patients with and without IBD. Multivariable linear and logistic regression were used to determine factors associated with IBD, SSI, and 30-day readmission.

RESULTS
Overall, patients (n=2,221) were 54% female, 76% White, 26% privately insured, 78% ASA Class 3, with mean age 57 yr, BMI 28.8 (SD=7.4). BRIEF scores were available for 644 patients, with a mean of 18.1. There were 308 patients (13.9%) undergoing surgery for IBD. Surgeries were 99.5% inpatient, 81.6% elective and 60% were laparoscopic. Procedure types included partial colectomy (69%), proctectomy (21%), total colectomy (6%), and total colectomy with proctectomy (4%). Overall ERP adherence was 59% (3.52 out of 6 components). Mean pLOS was 6.9 days (SD=7.7), SSI rate was 12.6%, readmission rate was 13.2%
On univariate analysis, patients with IBD were younger (41 vs 60 yr, p&lt;0.001), healthier at the time of surgery (ASA2: 23% vs 12%, ASA3: 73% vs 79%, p&lt;0.001), and more male (53% vs 45%, p=0.02), White (82% vs 75%, p=0.004), and privately insured (42% vs 23%, p&lt;0.001). IBD patients had lower BMI (27.4 vs 29, p&lt;0.001) and more frequently underwent total colectomy (16% vs 5%) and total colectomy with proctectomy (14% vs 2%, p&lt;0.001), as well as laparoscopic surgery (65% vs 59%, p=0.04). Despite similar ERP adherence (60% vs 59%, p=0.6), patients with IBD had higher rates of SSI (17% vs 12%, p=0.008) and readmission (20.6% vs 12%, p&lt;0.001).
On multivariable analysis, patients who were older (OR 0.92), Black (OR 0.25) or publicly insured (Medicaid OR 0.28, Medicare OR 0.53) we’re less like to have IBD. Those with IBD had greater health literacy scores (OR 1.11). Controlling for patient- and provider-level factors, patients with IBD were more likely to have post-operative SSI (OR 2.7) and readmission (OR 1.8).

CONCLUSION
Within an ERP, IBD is independently associated with greater rates of SSI and readmission despite factors associated with improved post-operative outcomes: younger age, private insurance, and greater health literacy. Additional research is needed to better adapt ERPs to the needs of patients with IBD.
EVALUATING THE IMPACT OF THE COVID-19 PANDEMIC ON URGENT MEDICAL ACCESS FOR PATIENTS WITH INFLAMMATORY BOWEL DISEASE AT A PRIVATE COMMUNITY GASTROENTEROLOGY PRACTICE
Authors: Kwon Michelle , Tse Chung Sang , van Deen Welmoed , Danielewicz Michael , Ward Christopher , Kogan Lawrence , Saeed Firrah , Shah Samir 
Published: January 2022

Abstract

BACKGROUND
Patients with inflammatory bowel disease (IBD) are subject to frequent emergency department (ED) visits. In order to decrease unnecessary ED utilization, we established an urgent care hotline (IBD URGENT) at a private community gastroenterology practice to triage pressing concerns from our patients with IBD. However, at the beginning of the Coronavirus disease 2019 (COVID-19) pandemic in Mar 2020, in-person visits were converted to telehealth visits, which could have adversly impacted patient care. Therefore, we examined the impact of the COVID-19 pandemic on the access and utilization of urgent healthcare by patients with IBD.

METHODS
In Jun 2018 we implemented a triage system involving gastroenterologists, nurses, and support staff to enable patients to contact our practice for urgent IBD issues with the goal of providing a plan of action from a provider within 4 hours of the call. Incoming patient calls were flagged with a red exclamation mark and labeled as “IBD URGENT” in our electronic medical record (eClinicalWorks) if they met any of the following criteria: new, severe abdominal pain; new, severe anal pain; fever greater than 101F; refractory emesis; or anything otherwise deemed urgent by the clinic nurses. Patients were then either advised to present to the ED for immediate evaluation, scheduled for same-day/next-day medical appointment +/- urgent labs, or received medical advice such as medication changes. The number (two-sample t-test) and triage (two-sample Z-test) of IBD URGENT calls were compared between pre-COVID (Jun 2018-Feb 2020) and post-COVID (Mar 2020-Sep 2021).

RESULTS
A total of 366 IBD URGENT calls were received and 91% had a response from a provider within 4 hours (Figure 1). The average number of IBD URGENT calls received per month were comparable pre- and post-COVID (10 vs 9, p=0.32). From Mar 2020 onwards, 40% of IBD URGENT calls were managed by urgent appointments, 51% medical advice, and only 9% ED visits, which was comparable to pre-COVID (Table 1).

CONCLUSION
It is reassuring that the COVID-19 pandemic did not cause any significant changes to the utilization and triage outcomes of the urgent IBD hotline system in our practice. Timely clinical operational changes to meet the needs of patients with the onset of the pandemic has allowed our proportion of ED visits to remain comparable to pre-COVID despite the decrease in in-person visits. As we return to normal operations, we plan to sustain our urgent hotline service by educating new staff and by reminding our patients of the IBD URGENT service. We believe this service improves quality of care for patients with IBD by avoiding unnecessary ED visits that often include overuse of Computer Tomography (CT) scans and prescription of steroids and narcotics—all associated with significant risks and financial costs.
LOCAL IBD-EXPERTS DISSATISFACTION WITH BIOLOGIC MEDICATION AUTHORIZATION DENIALS - A SURVEY OF SPECIFIC CLINICAL SCENARIOS
Authors: DeCoste Leah , Pellish Randall 
Published: January 2022

Abstract

BACKGROUND
Treatment with biologic medications for patients with inflammatory bowel disease (IBD) requires authorization by insurers. Insurance authorization denials are often a major obstacle in many clinical scenarios to use biologics, including specific denials of escalated dosing regimens directed by appropriate clinical indications. The objective of this study is to assess IBD-focused gastroenterologists’ (GIs) views and experiences on specific clinical scenarios resulting in biologic authorization denials.

METHODS
The survey was distributed by email to adult and pediatric IBD-focused GIs with 24 specific clinical scenarios, assessing experience and opinions on each authorization denial scenario. Survey data was recorded using REDCap software.

RESULTS
The survey was completed by 22 GIs including 17 adult GIs (81%), 4 pediatric GIs (19%), and one undisclosed provider. 70% or greater of participants disagreed with denials for (1) infliximab (IFX) dose-escalation, (2) Remicade in place of biosimilar, (3) facility-based IFX induction, (4) vedolizumab (VDZ) dose-escalation, (5) facility-based VDZ induction, (6) first-line ustekinumab (UST) therapy, (7) UST dose-escalation or re-induction, (8) UST maintenance after induction approval, (9) tofacitinib after mechanistic biologic failures, (10) VDZ or UST first-line in elderly or co-morbid patients, (11) facility-based biologic infusion for patients with prior acute infusion reactions. Variable experience was reported across the clinical scenarios ranging from 18.2% to 100%. In addition, variable experience was reported with the scenarios on whether specific denials were increasing in the past year, ranging from 16.7% to 90%.

CONCLUSION
This data portrays the collective experience of authorization denials as obstacles to using biologic medications, including escalated dosing, in multiple specific clinical scenarios. Many of these denial scenarios contradict treatment strategies that are utilized for optimal care of complex IBD patients. The data indicates many authorization denials reflect significant discrepancies between GIs and insurers on the clinical appropriateness of multiple different biologic treatment strategies. Broader survey data could better elucidate further experience with biologic treatment strategies that are being denied IBD patients, the nature of the obstacles created by insurers, and guide collaboration between physicians and insurers on best practices in the treatment of complex IBD patients.
MEDICAL DECISION-MAKING AND EDUCATION RELATED TO OSTOMY SURGERY IN PEDIATRIC PATIENTS WITH IBD: QUALITATIVE THEMES FROM MULTIDISCIPLINARY PROVIDER FOCUS GROUPS
Authors: David Jennie , Dotson Jennifer , Mackner Laura 
Published: January 2022

Abstract

INTRODUCTION
Pediatric patients with Inflammatory Bowel Disease (IBD) may undergo ostomy surgery, which surgically diverts stool to be collected in a bag worn on the abdomen. In addition to medical decision-making about ostomy surgery being innately complex and necessary to take a developmental approach, the medical decision also intersects with multiple disciplines and arguably requires nuanced coordination and collaboration for optimal medical decision-making and educational support.

METHODS
Multidisciplinary providers at a large, urban pediatric institution were recruited to participate in semi-scripted focus groups on medical decision-making and education related to ostomy surgery in pediatric patients with IBD. Focus groups occurred virtually and were recorded and transcribed for qualitative analysis of focus group content, with iterative analysis to generate qualitative themes.

RESULTS
Three focus groups were held, with a total of n=12 providers across all focus groups. Participants included pediatric GI providers (n=6), surgeons (n=2), GI nurse practitioner (n=1), GI social worker (n=1), and ostomy nurses (n=2). Participants reported providing care to patients at the institution for an average of 10 years (SD=9.7), and all worked with pediatric IBD patients. Focus group themes included 1) Ostomy surgery as a later treatment option for IBD patients, 2) Perception of “Defeat”/“failure,” 3) Differences between IBD patients (e.g., Crohn’s Disease versus ulcerative colitis), 4) Patients feeling unwell medically pre-operatively plays a role, 5) Psychosocial needs/support of patients, 6) Professional role issues/Provider Role considerations, 7) Provider perceptions of ostomies, 8) Provider Concerns/Needs, 10) Timing Considerations/Concerns, 11) Family Considerations/Challenges, and 12) Coordination/collaboration challenges.

CONCLUSIONS
The decision to consider ostomy surgery in pediatric IBD is often a complex decision that requires nuanced medical decision-making conversations and education for the patient and the parent/family. Further, this medical decision-making process often involves coordination and collaboration with multidisciplinary providers and often occurs over a period of time. This work assessed multidisciplinary providers’ perception of coordination and collaboration across specialties in supporting young people with IBD considering ostomy surgery. Qualitative themes identified psychosocial needs of patients and families throughout the process, various roles of multidisciplinary providers in the ostomy surgery decision, and logistical timing and coordination concerns during this medical decision. This work highlights the developmental and psychosocial considerations in supporting patients and parents through a complex medical decision.
INCREASED PREVALENCE OF ANXIETY IN HOSPITALIZED CROHN’S DISEASE PATIENTS IN THE UNITED STATES: INSIGHTS FROM NATIONAL INPATIENT DATABASE FROM 2009 TO 2018
Authors: Bhurwal Abhishek , Mutneja Hemant , Pimpinelli Sophia , Pimpinelli Marcella , Seril Darren 
Published: January 2022

Abstract

BACKGROUND
Patients with Crohn’s disease (CD) are at increased risk of developing anxiety and depression, and there is growing evidence that these patients would benefit from mental health screening. This study aimed to examine the temporal trends of anxiety and depression diagnoses in hospitalized CD patients in the United States.

METHODS
Using the National Inpatient Database (NIS) for the years 2009 to 2018, we analyzed all admissions for CD-related discharges using ICD 9 and ICD 10 CM codes. Besides the primary discharge diagnosis of CD, we also included discharges with a primary complication of CD or with a secondary diagnosis of CD. ICD CM codes were also utilized to identify associated comorbidities of depression and anxiety. Subsequently, we analyzed (1) the overall prevalence of depression and anxiety for CD related admissions, and (2) national temporal trends for depression and anxiety in hospitalized CD patients, from 2009 to 2018. All statistical analyses were performed using STATA software.

RESULTS
Using the NIS cohort for the years 2009 to 2018, a total of 585,867 CD-related discharges were identified. Overall, the prevalence of anxiety amongst CD-related admissions was 15.3%, and the prevalence of depression was 16.5%. The prevalence rate of anxiety increased from 7.7% in 2009 to 22.21% in 2018 (p&lt;0.001). The prevalence of depression increased from 14.8% in 2009 to 17.3% in 2018 (p=0.15) (see Figure 1).

CONCLUSION
These results obtained utilizing the NIS indicate that the prevalence of psychiatric diagnosis, particularly anxiety, increased in hospitalized CD patients over time. The diagnosis of anxiety increased 3-fold during the time period studied. The prevalence of anxiety and depression have been reported to be higher in CD patients than in the general population. This study highlights the importance of incorporating psychological screening and mental health services in the management CD patients in both the outpatient and inpatient settings. Further studies are needed to examine the cause of the increased anxiety and depression rates observed in this patient population.