bluuebunny/crossref_metadata_2025_split huggingface dataset:
IDENTIFYING THE ROLE OF ACINETOBACTER CALCOACETICUS IN DRIVING INTESTINAL INFLAMMATION
Authors: Glover Janiece , Sullivan Kaitlan , Browning Brittney , Ticer Taylor , Gutierrez Alyssa , Dooley Sarah , Engevik Amy , Hartman Jessica , Engevik Melinda 
Published: January 2024

Abstract

BACKGROUND
Inflammatory bowel disease (IBD) is a life-long condition characterized by chronic inflammation of the gastrointestinal tract. Among the potential causes of IBD, the gut microbiota has been implicated in perpetuating inflammation. Analysis of the IBD Transcriptome and Metatranscriptome Meta-Analysis (IBD TaMMA) database revealed that Acinetobacter calcoaceticus is one of the top 10 highest elevated bacteria in Crohn’s’ disease patients. Acinetobacter are well-characterized for their antibiotic resistance, but little is known about their interaction with the gut. We hypothesize that A. calcoaceticus colonizes the gut and promotes intestinal inflammation.

MATERIALS & RESULTS
We grew commercially available and clinical isolates of A. calcoaceticus in vitro with stressors found in the gut. All strains grew in a range of pHs (4-7), osmolarity (0.1-1 M NaCl), ethanol (1- 5%) and hydrogen peroxide (0.05-0.1%); indicating that A. calcoaceticus is well-adapted to withstand the harsher conditions of the gastrointestinal tract. To further investigate the ability of A. calcoaceticus to colonize the gut, we utilized Caenorhabditis elegans as a model. All A. calcoaceticus strains colonized the nematode's gut. We likewise found that all A. calcoaceticus strains colonized human stool-based bioreactors; suggesting that A. calcoaceticus can colonize the gastrointestinal tract. To identify whether A. calocaceticus stimulated inflammation, we incubated intestinal organoids and macrophages with live A. calcoaceticus or LPS derived from our A. calcaoceticus strains and found that both conditions stimulated pro-inflammatory cytokines. In order to confirm our in vitro findings, we oral gavaged adult BalbC mice with A. calcoaceticus and examined fecal levels using selective agar and qPCR. Acinetobacter was observed at low levels in the vehicle control mice and at high levels in our mice gavaged with A. calcoaceticus (average 9.9x 107 CFU); suggesting that A. calcoaceticus colonized the murine gut. To examine the ability of A. calcoaceticus to enhance inflammation, we oral gavaged mice with either a vehicle control (PBS) or A. calcoaceticus and the following day we administered 2,4,6-trinitrobenzene sulfonic acid (TNBS) to induce colitis. Mice treated with A. calcoaceticus and TNBS lost more weight and had worse histological scores than mice treated with vehicle control and TNBS; indicating A. calcoaceticus worsens intestinal inflammation. Finally, to expand the niche of Acinetobacter, we pre-treated mice with antibiotics and then subsequently administered bacteria and TNBS. In this model, A. calcoaceticus exacerbated inflammation above that of non-antibiotic treated mice.

CONCLUSIONS
These data show that A. calcoaceticus can promote intestinal inflammation and may be a contributing factor to the inflammation experienced by IBD patients.
MICROBIAL DRIVERS OF REGION-SPECIFIC SUSCEPTIBILITY TO CHRONIC, TNF-INDUCED INTESTINAL INFLAMMATION
Authors: Vega Paige , Wang Jiawei , Simmons Alan , Xu Yanwen , Yang Yilin , Ro James , Banerjee Amrita , Harned Mariah , Roland Joseph , Washington Mary , Liu Qi , Lau Ken 
Published: January 2024

Abstract

BACKGROUND
The majority of Crohn’s disease patients present with ileitis or ileocolitis, however, the factors that drive the development of inflammation in these different sites remain elusive. The TnfΔARE mouse model recapitulates many features of Crohn’s disease and is driven by systemic overexpression of TNF.

AIMS
To-date, the TnfΔARE model is published as a spontaneous intestinal inflammation model that is specific to the ileum, however, we observe severe colonic inflammation that is dependent on the murine housing facility. We aimed to use experimental approaches to investigate the epithelial and microbial factors that drive ileal and colonic inflammation in the TnfΔARE model of Crohn’s disease.

METHODS
Tnf ΔARE mice were housed in two murine housing facilities, termed “restrictive” and “permissive”. Pathological scoring was used to assess intestinal inflammation in TnfΔARE mice. Murine co-housing methods were used to expose non-colitic mice to those with colitis. Shotgun metagenomics was performed to determine differences in the intestinal microbiota between the two murine housing facilities. Doxycycline treatment was used to treat Chlamydia muridarum (CM) infection in mice. Various in vivo and in vitro perturbations were performed to test the role of intestinal epithelial cell expression of indoleamine 2,3-dioxygenase (IDO1) in ileal and colonic inflammation. Human single-cell RNA-sequencing (scRNA-seq) data, along with tissue samples, were analyzed to determine whether epithelial cell signaling pathways and microbiota were conserved in Crohn’s disease patients.

RESULTS
Tnf ΔARE mice from the restrictive murine housing facility developed the expected phenotype of ileitis, while TnfΔARE mice from the permissive murine housing facility developed ileocolitis. Upon co-housing, restrictive facility TnfΔARE mice develop ileocolitis. Permissive facility mice, but not restrictive facility mice, harbored the obligate intracellular bacterium CM in proximal colonic epithelia. Doxycycline treatment effectively cleared CM colonization and was associated with a reduction in colonic inflammation. IDO1 expression was upregulated in intestinal epithelial secretory cells in CM-infected mice and perturbation of this pathway resulted in a reduction of intestinal inflammation. Analysis of patient scRNA-seq and tissue samples revealed IDO1-expressing epithelial cells in the ascending colon and the presence of epithelia-associated microbiota.

CONCLUSION
Here, we associate CM infection with the development of ileocolitis the TnfΔARE mouse model of Crohn’s disease. We reveal the role of IDO1-expressing intestinal secretory cells in TnfΔARE mice with and without colonic involvement. Finally, we demonstrate conservation of these pathways and microbiota in human Crohn’s disease samples.
INFLAMED INTESTINAL ENDOTHELIAL CELLS ESTABLISH SELF-REGULATORY NICHES VIA IL16 DEPENDENT RECRUITMENT OF CD4 EXPRESSING VESSEL-ASSOCIATED MACROPHAGES
Authors: Ren Xingsheng , Manzanares Laura , Sumagin Ronen 
Published: January 2024

Abstract
Macrophages, play important roles in initiation and resolution of inflammation. Notably, a subset of tissue macrophages strategically localizes to the blood vessels, exerting essential regulatory functions at the blood-tissue interface, including regulation of vascular permeability and neutrophil (PMN) transendothelial migration (TEM). Although the number of vessel-associated macrophages (VAMs) is increased in inflamed tissue, the underlying mechanisms of VAMs recruitment are unknown.
Our current study uncovers a novel mechanism whereby inflamed intestinal vascular endothelial cells (ECs) release IL-16 to selectively recruit CD4+ tissue macrophages to become VAMs.
Whole-mount confocal microscopy studies in CX3CR1-EGFP macrophages reporter mice confirmed significant increases in VAMs numbers in several murine models of intestinal inflammation. Surprisingly, the majority of VAMs were found to express a classical T cell marker, CD4 and to be of an inflammatory phenotype, enriched for ICAM-1 and TNFα expression. VAMs-derived TNFα was previously found to prime ECs to form PMN TEM hot spots.
Whole genome mRNA sequencing, and flow cytometry protein expression analyses revealed heightened expression of the CD4 ligand, IL-16 by inflamed intestinal lamina propria ECs.
In vitro, using transwell assays, recombinant IL-16 and supernatants derived from murine (bEnds.3) endothelial cells induced robust migration of murine, LPS/IFNγ-stimulated bone marrow-derived macrophages. Whereas antibody-mediated IL-16 or CD4 neutralization in cultures and in vivo reduced VAMs recruitment.
Collectively, our findings establish CD4 as a novel marker of VAMs and identify the regulatory role of ECs IL-16 and macrophages CD4+ axis in VAMs recruitment in inflamed mucosal tissues.
VEDOLIZUMAB RESPONSE AND NON-RESPONSE IN ULCERATIVE COLITIS: INSIGHTS FROM SPATIAL TRANSCRIPTOMICS
Authors: Mennillo Elvira , Lee Gyehyun , Lotstein Madison , Tsui Jessica , Mahadevan Uma , Fragiadakis Gabriela , Combes Alexis , Kattah Michael 
Published: January 2024

Abstract

BACKGROUND
Vedolizumab (VDZ) is an anti-a4b7 integrin monoclonal antibody effective for treating ulcerative colitis (UC). The cellular and genetic factors that mediate VDZ response and non-response remain unclear. Our previous data employing different multi-omics revealed an impact of VDZ on myeloid dendritic cells (mDCs) and mononuclear phagocytes (MNPs), in addition to lymphocytes, influencing stromal and epithelial compartments.

METHODS
We performed a mass cytometry (CyTOF) experiment on peripheral blood and colon biopsies in healthy controls (HC, n=6), patients with UC on anti-TNF or 5-ASA (UC, n=5/6) and patients with UC on VDZ (UC-VDZ, n=5). Subsequently, we carried out a retrospective longitudinal spatial analysis using 1000-plex RNA and 62-plex protein CosMx on archived formalin-fixed paraffin-embedded (FFPE) biopsies before and after treatment in VDZ responders (VDZ-R) and non-responders (VDZ-NR) (Fig.1). Lastly, gene set enrichment analysis (GSEA) using VDZ response and non-response signatures obtained from our longitudinal spatial transcriptomic data were validated in an external publicly available dataset.

RESULTS
CyTOF results confirmed that VDZ is associated with a shift of a4b7+ cells from tissue to blood across multiple subsets. Spatial data showed elevated activated MNPs in UC compared to HC and UC-VDZ. Following treatment, these levels decreased in VDZ-R but increased in VDZ-NR. Neighborhood enrichment analysis revealed a trend toward increased proximity of activated fibroblasts and activated MNPs in UC, which was reduced following treatment. Furthermore, to explore differences pre-treatment, we performed pseudobulk differentially expressed (DE) gene analysis comparing VDZ-NR versus VDZ-R. Stromal and MNP-expressed genes including MMP1, MMP2, and THBS1 were among the top DE genes in VDZ-NR, while genes associated with the IEC crypt base including REG1A, OLFM4, AGR2, SPINK1, and LYZ were related to VDZ-R. GSEA confirmed significant enrichment of the identified VDZ-NR and VDZ-R gene signatures in patients pre-VDZ, aligning with their outcome. The VDZ-R signature was specific to VDZ and was not associated with anti-TNF response. The VDZ-NR signature was also associated with anti-TNF non-response.

CONCLUSION
Longitudinal spatial transcriptomics of archived FFPE specimens highlighted potential pathways associated with VDZ responsiveness, identifying epithelial-, MNP-, and fibroblast-enriched genes. Validation in an external dataset emphasized the specificity of the VDZ-associated response signature.

Fig1. a, Schematic of retrospective, longitudinal analysis of archived FFPE specimens using 1000-plex CosMx spatial transcriptomics of 126,368 cells. b, Dot plot representation of a subset of genes from pseudobulk DE gene analysis for the indicated subsets.
INFLAMMATORY BOWEL DISEASE IN YOUTH UNDER 20 FROM 1990-2019: A GLOBAL PERSPECTIVE ON REGIONAL AND NATIONAL VARIATIONS FROM THE GBD 2019 ANALYSIS
Authors: Patel Rahul , Mohammed Yassmeen Sharafeldin , Akula Sai Bhavani , Aramin Mohammed A S , Naradasu Pranathi Royal , Patel Sneh , Desai Hardik Dineshbhai 
Published: January 2024

Abstract

BACKGROUND
Inflammatory Bowel Disease (IBD) ranks as the 9th primary cause of mortality and the 10th main source of disability worldwide among individuals aged under 20. Grasping the worldwide implications for this age bracket is pivotal for shaping health care approaches and optimizing patient care.

METHOD
Leveraging the Global Burden of Disease instrument, we discerned the incidence, prevalence, mortality, and Disability Adjusted Life Years (DALYs) of IBD by age, gender, and year across 204 nations and territories spanning 1990-2019. The DisMod-MR 2.1 tool shed light on non-fatal health metrics like incidence and prevalence, whereas the Cause of Death Ensemble Model (CODEm) framework illuminated fatal health outcomes.

RESULTS
From 1990 to 2019, the overall prevalence of IBD escalated from 74,975 (95%UI: 60,678-92,219) to 88,828 (72,606-108,301), marking an Annual Percentage Change (APC) of 18% (16-22). Incidence exhibited an APC surge of 23% (20-26). Conversely, deaths and DALYs plummeted by 56% and 53% respectively during the same period. Delving into global regions, Sub-Saharan Africa noted a 6% death upswing, trailed by the African Union at 65% and Low SDI nations at 1%. Southeast Asia, East Asia, and Oceania recorded the steepest APC in age-standardized incidence rates at 67%, followed by High-SDI regions at 35%, OECD nations at 31%, and affluent countries at 30%. The 15-19 age bracket registered the most pronounced incidence rise by 24%. Males witnessed a steeper APC in incidence (24% vs. females at 21%) and prevalence (21% vs. females at 16%) from 1990-2019.

CONCLUSION
In 2019, IBD was responsible for 1.61% of all mortality linked to digestive diseases and contributed to 1.50% of the total digestive disease-induced disabilities. For pediatric clinicians, these findings underline the necessity for early intervention, tailored care strategies, and rigorous research into pediatric IBD. From a policy-making perspective, there is an urgent demand for resource allocation, enhanced public health campaigns, and international collaboration to mitigate the growing threat of IBD among the youth.

Source: Global Burden of Disease 2019, IHME
INSURANCE DENIALS AND DELAYS IN CARE FOR PEDIATRIC PATIENTS WITH INFLAMMATORY BOWEL DISEASE
Authors: Behbahani-Nejad Pareenaz , Finkler Michael , Momotaz Hasina , Perry Sharon , Young Denise , Sferra Thomas , Moses Jonathan 
Published: January 2024

Abstract

INTRODUCTION
Biologics are effective medications used for induction and maintenance of remission in pediatric patients with inflammatory bowel disease (IBD). Insurance companies often require clinicians to obtain prior authorization (PA) prior to administration of biologics. Recent data determined that PA was associated with delays in care in pediatric IBD patients and an increased risk of subsequent healthcare utilization. Our study aim was to assess the effect of the PA process and its impact on care delivery for pediatric patients with IBD.

METHODS
A retrospective chart review of pediatric patients with IBD was conducted, including those with the diagnosis of ulcerative colitis or Crohn’s disease prescribed a biologic medication. Data obtained from medical records included demographics, IBD characteristics, insurance PAs, and clinical outcomes from 2015 to 2023. Outcome measures included time from initial PA submission to completion of the PA process, time from initial PA submission to first outpatient dose, frequency of insurance mandated medication changes, and number of hospitalizations for an inpatient dose. Analyses examined differences between those with PAs that were approved versus those who were initially denied.

RESULTS
We analyzed 134 patients who received a new biologic during our study period, of which 100 were newly diagnosed patients. Of the total sample, mean age was 12.5 years, 53.7% were male, with 96.2% non-Hispanic, 77.6% white, and 69.4% patients had Crohn’s disease. The most common medication prescribed was infliximab (81.3%). Of the patients in the approved group, 72.9% of patients had commercial insurance compared to 52.1% in the denied group (p=0.0152). Median time from initial PA submission to completion of PA process was 13 days for those denied vs. 3 days for those approved (p&lt;0.0001). Of the patients denied, median time from initial PA submission to denial was 4 days (0-27) and median time from denial to subsequent approval was 7 days (0-75). Median time from initial PA submission to first outpatient dose was 30 days in the denied group vs. 13 days for the approved group (p&lt;0.0001). 51% of patients in the denied group required hospitalization for their first biologic dose after PA initiation compared to 20% in the approved group (p=0.0002).

CONCLUSION
We found a significant delay in care for patients who received a prior authorization denial from insurance. Time from initial authorization submission to first dose was significantly different between the approved and denied groups. Prior authorization denials were also associated with significantly higher rate of hospitalizations for an infusion, potentially driving up overall cost of care.
IDENTIFYING FACTORS THAT WORSEN IN-HOSPITAL OUTCOMES IN PATIENTS WITH VENTRICULAR TACHYCARDIA (VT) AND INFLAMMATORY BOWEL DISEASE (IBD)
Authors: John Jason , Kapoor Akshay , Dasu Neethi , Khalid Yaser , Blair Brian , Joo Lucy 
Published: January 2024

Abstract

BACKGROUND
IBD is a proinflammatory state that can have numerous complications involving all systems of the body. There is a known association with cardiovascular disease. However, there are limited studies that have examined the impact of cardiac arrhythmias such as VT on patients with IBD (Crohn’s Disease and Ulcerative Colitis). The aim of this study was to evaluate the economic burden and various hospital outcomes associated with patients with IBD with and without VT.

METHODS
Patients aged 18 years with IBD and VT versus IBD alone were identified from the US Nationwide Inpatient Sample (NIS), from the years 2010-2019. ICD 9 and 10 codes were utilized and multivariate regression analysis utilizing propensity matching (Kernel method) was used to estimate the odds ratios of in-hospital mortality, the average length of hospital stay (LOS), and hospital charges (TOTHC), after adjusting for age, gender, race, primary insurance payer status, hospital type and size (number of beds), hospital region, hospital teaching status, and other demographic characteristics. Weighted analysis utilizing Stata 17 MP was performed.

RESULTS
For patients with Crohn’s disease and depression, mean age at readmission was 51.6 years and there was a high readmission rate and mortality at 30 days (readmission rate 5.2%, p&lt;0.01 and mortality rate 2.8%, p&lt;0.01) which increased significantly at 90 days (readmission rate 8.4%, p&lt;0.01). Hospital LOS and TOCHG remained relatively the same compared to the index admission for both 30 day and 90 day readmissions (Table 1). A very similar trend was seen for UC and depression as well: mean age at readmission was 51.4 years and there was a high readmission rate and mortality at 30 days (readmission rate 5.0%, p&lt;0.01 and mortality rate 2.6%, p&lt;0.01) which increased significantly at 90 days (readmission rate 8.4%, p&lt;0.01 and mortality rate 2.9%, p&lt;0.01). The top 10 causes of readmission at 30 days and 90 days for both UC and Crohn’s are summarized in Table 1.

CONCLUSION
Our study revealed that patients with IBD and VT had increased mortality, LOS, and TOTHC were increased compared to patients with IBD only. Further studies are required to further evaluate this patient population.
DEPRESSION MAY BE A STRONGER UNIQUE PREDICTOR OF FATIGUE THAN SELF-REPORTED IBD DISEASE ACTIVITY
Authors: Duarte Brooke , Salwen-Deremer Jessica 
Published: January 2024

Abstract
Fatigue is a frequent and debilitating symptom of inflammatory bowel disease (IBD) and can include mental and physical exhaustion, tiredness, or weakness. Modifiable psychosocial factors, such as depression and anxiety, are associated with fatigue in IBD, and provide insight into potential treatment targets. However, little is known about distinct ways in which psychosocial factors relate to subtypes of fatigue. The current study examined associations between psychosocial factors and 5 fatigue subtypes: general, physical, mental, reduced motivation, and reduced activity.
Patients 18 and above from Dartmouth-Hitchcock’s IBD Center with Crohn’s disease or ulcerative colitis were invited to participate in a survey via an electronic medical record system message. Measures included the Patient Reported Outcomes-3, Multidimensional Fatigue Inventory, Pain Catastrophizing Scale, Generalized Anxiety Disorder-7, Patient Health Questionnaire-9, Insomnia Severity Index, and Brief Pain Inventory. Five forward linear regressions were performed with step 1 including disease activity, step 2 including covariates (age, gender, IBD diagnosis) and step 3 allowing for the inclusion of insomnia, pain severity, depression, anxiety, and pain catastrophizing.
Participants were 312 individuals above the age of 18 (M=48.62, SD=16.10). Participants were 66.3% women and 96.5% White. 60.9% were diagnosed with Crohn’s disease and 39.1% with ulcerative colitis. 54.8% were categorized as having active disease based on self-reported symptoms. For all five subtypes of fatigue, depression emerged as the most influential psychosocial predictor. Depression accounted for 21% of the variance in general fatigue, 14% in physical fatigue, 18% in activity avoidance, 19% in reduced motivation, and 29% in mental fatigue. Regarding differences among subtypes, insomnia was only significant in the model predicting general fatigue, accounting for an additional 2% of the variance, and anxiety was only significant in the model predicting activity avoidance, accounting for an additional 3% of the variance. In comparison, self-reported disease activity accounted for 23% of the variance in general fatigue, 7% in physical fatigue, 8% in activity avoidance, 12% in reduced motivation, and 10% in mental fatigue.
Depression is a notable factor associated with all subtypes of fatigue in IBD, especially mental fatigue. There are differences in how psychosocial factors relate to fatigue subtypes such that anxiety is uniquely associated with activity avoidance and severity of insomnia is uniquely associated with general fatigue. Results suggest that assessment of fatigue in IBD should also include assessment of depression as standard of care. Additionally, helping patients engage in behavioral interventions to reduce depression, anxiety, and insomnia may be critical for managing fatigue.

Results of forward regressions predicting fatigue subtypes