bluuebunny/crossref_metadata_2025 huggingface dataset:
Aircraft noise exposure induces pro-inflammatory vascular conditioning and amplifies vascular dysfunction and impairment of cardiac function after myocardial infarction
Authors: Molitor Michael , Bayo-Jimenez Maria T , Hahad Omar , Witzler Claudius , Finger Stefanie , Garlapati Venkata S , Rajlic Sanela , Knopp Tanja , Bieler Tabea K , Aluia Melania , Wild Johannes , Lagrange Jeremy , Blessing Recha , Rapp Steffen , Schulz Andreas , Kleinert Hartmut , Karbach Susanne , Steven Sebastian , Ruf Wolfram , Wild Philipp , Daiber Andreas , Münzel Thomas , Wenzel Philip
Published: January 2023

Aims

Traffic noise may play an important role in the development and deterioration of ischaemic heart disease. Thus, we sought to determine the mechanisms of cardiovascular dysfunction and inflammation induced by aircraft noise in a mouse model of myocardial infarction (MI) and in humans with incident MI.

Methods and results

C57BL/6J mice were exposed to noise alone (average sound pressure level 72 dB; peak level 85 dB) for up to 4 days, resulting in pro-inflammatory aortic gene expression in the myeloid cell adhesion/diapedesis pathways. The noise alone promoted adhesion and infiltration of inflammatory myeloid cells in vascular/cardiac tissue, paralleled by an increased percentage of leucocytes with a pro-inflammatory, reactive oxygen species (ROS)-producing phenotype and augmented expression of nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase type 2 (Nox2)/phosphorylation of nuclear factor ‘kappa light chain enhancer’ of activated B-cells (phospho-NFκB) in peripheral blood. Ligation of the left anterior descending artery resulted in worsening of cardiac function, pronounced cardiac infiltration of CD11b+ myeloid cells and Ly6Chigh monocytes, and induction of interleukin (IL) 6, IL-1β, CCL-2, and Nox2, being aggravated by noise exposure prior to MI. MI induced stronger endothelial dysfunction and more pronounced increases in vascular ROS in animals preconditioned with noise. Participants of the population-based Gutenberg Health Cohort Study (median follow-up:11.4 years) with incident MI revealed elevated C-reactive protein at baseline and worse left ventricular ejection fraction (LVEF) after MI in case of a history of noise exposure and subsequent annoyance development.

Conclusion

Aircraft noise exposure before MI substantially amplifies subsequent cardiovascular inflammation and aggravates ischaemic heart failure, facilitated by a pro-inflammatory vascular conditioning. Our translational results suggest that measures to reduce environmental noise exposure will be helpful in improving the clinical outcome of subjects with MI.

Key question

Key finding

Take-home-MessageAircraft noise exposure before MI substantially amplifies cardiovascular inflammation and aggravates cardiac impairment after MI.
“I Have a Dream and I Wish it Would Come True”
Authors: Alhuzail Nuzha Allassad , Levinger Miriam
Published: January 2023

Deaf Bedouin young women in Israel experience marginalization, discrimination, and institutional neglect, which, coupled with the traditions of Bedouin society, pose a complex challenge to social inclusion. This qualitative study of 14 deaf Bedouin young women, using a semi-structured questionnaire, found that instead of providing support, their socio-ethnic affiliation is a source of suffering, whereas their deaf identity and their belonging to the deaf community are sources of strength and self-esteem. The study’s contribution is that it presents the unique story of deaf Bedouin young women and reveals how belonging to the deaf community helps them to accept their deafness as uniqueness rather than as a disability and enables them to hold on to their dreams of higher education, obtaining rewarding work, and marrying and raising a family.
Long-term outcomes of perioperative myocardial infarction/injury after non-cardiac surgery
Authors: Puelacher Christian , Gualandro Danielle M , Glarner Noemi , Lurati Buse Giovanna , Lampart Andreas , Bolliger Daniel , Steiner Luzius A , Grossenbacher Mario , Burri-Winkler Katrin , Gerhard Hatice , Kappos Elisabeth A , Clerc Olivier , Biner Laura , Zivzivadze Zaza , Kindler Christoph , Hammerer-Lercher Angelika , Filipovic Miodrag , Clauss Martin , Gürke Lorenz , Wolff Thomas , Mujagic Edin , Bilici Murat , Cardozo Francisco A , Osswald Stefan , Caramelli Bruno , Mueller Christian ,   for the BASEL-PMI Investigators, Hidvegi Reka , Freese Michael , Arslani Ketina , Weder Samantha , Maiorano Silvia , Rentsch Katharina , Buser Andreas , Mitrovic Sandra , Strebel Ivo , Seeberger Esther , Lardinois Didier , Schaeren Stefan , Meister Rebecca , Pargger Mirjam
Published: January 2023

Aims

Perioperative myocardial infarction/injury (PMI) following non-cardiac surgery is a frequent cardiac complication. Better understanding of the underlying aetiologies and outcomes is urgently needed.

Methods and results

Aetiologies of PMIs detected within an active surveillance and response programme were centrally adjudicated by two independent physicians based on all information obtained during clinically indicated PMI work-up including cardiac imaging among consecutive high-risk patients undergoing major non-cardiac surgery in a prospective multicentre study. PMI aetiologies were hierarchically classified into ‘extra-cardiac’ if caused by a primarily extra-cardiac disease such as severe sepsis or pulmonary embolism; and ‘cardiac’, further subtyped into type 1 myocardial infarction (T1MI), tachyarrhythmia, acute heart failure (AHF), or likely type 2 myocardial infarction (lT2MI). Major adverse cardiac events (MACEs) including acute myocardial infarction, AHF (both only from day 3 to avoid inclusion bias), life-threatening arrhythmia, and cardiovascular death as well as all-cause death were assessed during 1-year follow-up. Among 7754 patients (age 45–98 years, 45% women), PMI occurred in 1016 (13.1%). At least one MACE occurred in 684/7754 patients (8.8%) and 818/7754 patients died (10.5%) within 1 year. Outcomes differed starkly according to aetiology: in patients with extra-cardiac PMI, T1MI, tachyarrhythmia, AHF, and lT2MI 51%, 41%, 57%, 64%, and 25% had MACE, and 38%, 27%, 40%, 49%, and 17% patients died within 1 year, respectively, compared to 7% and 9% in patients without PMI. These associations persisted in multivariable analysis.

Conclusion

At 1 year, most PMI aetiologies have unacceptably high rates of MACE and all-cause death, highlighting the urgent need for more intensive treatments.

Study registration

https://clinicaltrials.gov/ct2/show/NCT02573532.
Quantifying rupture characteristics of microearthquakes in the Parkfield Area using a high-resolution borehole network
Authors: Pennington Colin N , Wu Qimin , Chen Xiaowei , Abercrombie Rachel E
Published: January 2023

It is well known that large earthquakes often exhibit significant rupture complexity such as well separated subevents. With improved recording and data processing techniques, small earthquakes have been found to exhibit rupture complexity as well. Studying these small earthquakes offers the opportunity to better understand the possible causes of rupture complexities. Specifically, if they are random or are related to fault properties. We examine microearthquakes (M < 3) in the Parkfield, California, area that are recorded by a high-resolution borehole network. We quantify earthquake complexity by the deviation of source time functions and source spectra from simple circular (omega-square) source models. We establish thresholds to declare complexity, and find that it can be detected in earthquakes larger than magnitude 2, with the best resolution above M2.5. Comparison between the two approaches reveals good agreement (>90 per cent), implying both methods are characterizing the same source complexity. For the two methods, 60–80 per cent (M 2.6–3) of the resolved events are complex depending on the method. The complex events we observe tend to cluster in areas of previously identified structural complexity; a larger fraction of the earthquakes exhibit complexity in the days following the Mw 6 2004 Parkfield earthquake. Ignoring the complexity of these small events can introduce artefacts or add uncertainty to stress drop measurements. Focusing only on simple events however could lead to systematic bias, scaling artefacts and the lack of measurements of stress in structurally complex regions.
THE USE OF IMMUNOMODULATORS, BIOLOGIC THERAPIES AND SMALL MOLECULES IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE AND SOLID ORGAN TRANSPLANTS
Authors: Ghusn Wissam , Francis Fadi , Farraye Francis , Hashash Jana G
Published: January 2023

INTRODUCTION

Over the past 20 years, the number of solid organ transplants (SOT) for a variety of indications has been on the rise. Consequently, more patients with inflammatory bowel diseases (IBD) are also receiving SOT. Although SOT related immunosuppression may at times control IBD related inflammation, many patients still require additional immunosuppressive medications for control of their IBD. With the growing therapeutic armamentarium for IBD, physicians are in search for guidance on the safety of using additional immunosuppressive medications in patients who are already receiving transplant related immunosuppressive medications.

METHODS

We performed a review of published literature that addressed the use of immunomodulators, biologic agents, and small molecules in patients with IBD who also had a SOT. We searched PubMed, Scopus, MEDLINE, and Google Scholar databases for studies published on the topic in English between January 1st, 1910, and August 1st, 2022. We have included data from systematic reviews, meta-analyses, case reports and case series to assess the safety, effectiveness, and side effects of immunomodulators, biologic therapies and small molecules in patients with liver, renal and/or heart transplantations.

RESULTS

We identified 25 publications on liver transplants, 6 on renal transplants, and 1 on heart transplants in patients with IBD. Among liver transplant patients, the most common immunosuppressive medications used were tacrolimus, mycophenolate mofetil, cyclosporine and steroids. In patients with IBD, anti-TNF agents (infliximab and adalimumab) were used in SOT with no major adverse safety concerns. The most common adverse events included infections (Clostridioides difficile and CMV) and malignancies (colon cancer). As for anti-integrin agents (vedolizumab and natalizumab) and ustekinumab, their efficacy and safety were mainly reported in patients with liver transplant on tacrolimus with no major adverse events reported. For patients with renal transplant, the main immunosuppression used were cyclosporine and tacrolimus. The combination of these immunosuppressive drugs with either anti-TNF therapy or ustekinumab had a good safety profile with rare malignancy occurrence. In one case report with heart transplant in a patient with IBD and on tacrolimus, no complications were reported.

CONCLUSION

SOT has become the mainstay for treating several common diseases. As such, gastroenterologists will care for more patients with IBD who have had a SOT. From this extensive review, the use of anti-TNF, anti-integrin agents and ustekinumab seem to be safe in patients with SOT, regardless of their transplant related immunosuppression which is usually comprised of tacrolimus, cyclosporine, and prednisone. More studies are needed in patients with renal and heart transplant and in patients treated with small molecules for their IBD.
A NOVEL GUT-RESTRICTED ARYL HYDROCARBON RECEPTOR AGONIST WITH ACTIVITY IN THE DEXTRAN SODIUM SULFATE COLITIS MURINE MODEL
Authors: Davidson Matt , Saiki Julie
Published: January 2023

BACKGROUND

Patients with inflammatory bowel disease (ulcerative colitis, Crohn’s disease) have decreased production of endogenous aryl hydrocarbon receptor (AhR) ligands in colon tissue. Activation of the AhR is a potential novel therapeutic target for ulcerative colitis and may play an important role in promoting immune homeostasis through increased IL-22 production, downregulation of proinflammatory mediators, and improved epithelial barrier function. Indigo naturalis, a botanical extract containing potent AhR agonists, has been effective for the treatment of moderate-to-severe and treatment-refractory ulcerative colitis in multiple clinical studies. The most potent AhR agonist in indigo naturalis is indirubin.

OBJECTIVE

The objective was to develop novel indirubin prodrugs that maximize local colonic delivery and minimize systemic exposure to reduce the risk of potential systemic side effects.

RESULTS

We developed a novel synthetic small molecule prodrug of indirubin that maximizes colonic exposure and minimizes systemic exposure. In a dextran sodium sulfate (DSS)-induced colitis murine model, oral administration of our lead prodrug significantly reduced Disease Activity Index and weight loss similar in magnitude to indirubin. The prodrug resulted in colon concentrations of indirubin that were over 100-fold greater than plasma concentrations, and low systemic organ exposure.

CONCLUSION

Azora’s novel indirubin prodrug enhanced colonic delivery of indirubin while maintaining minimal systemic exposure in a DSS colitis murine model and may reduce the risk of systemic side effects. This compound may be suitable for development as a first-in-class oral AhR agonist for the treatment of ulcerative colitis.
EFFICACY AND SAFETY OF VEDOLIZUMAB AND TUMOR NECROSIS FACTOR INHIBITORS IN THE TREATMENT OF STEROID-REFRACTORY MICROSCOPIC COLITIS: A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Chehade Nabil El Hage , Shah Sagar , Pardi Darrell , Farraye Francis , Al Hashash Jana
Published: January 2023

BACKGROUND

Tumor necrosis factor (TNF-α) inhibitors and the α4β7 integrin antagonist, vedolizumab have been investigated as a treatment option for patients with steroid-refractory microscopic colitis (MC) with controversial findings.

AIMS

To perform a systematic review and meta-analysis to evaluate the benefit of vedolizumab and TNF-α inhibitors in patients with steroid-refractory MC.

METHODS

Retrospective cohort studies and case series involving adult patients with steroid-refractory MC who either received vedolizumab, adalimumab, or infliximab were eligible for inclusion. Outcomes of interest included the rate of clinical remission at induction, clinical response, maintenance of remission, histologic remission, and overall medication related adverse effects. Pooled proportional meta-analyses were used to calculate the overall rates of the primary and secondary endpoints. Heterogeneity was assessed using the I2 statistic. Publication bias was assessed via visual inspection of the funnel plots and using Egger’s regression. All statistical analysis was performed in R using the metafor and meta packages.

RESULTS

A total of 14 retrospective case series/studies involving 164 patients were included. Pooled analysis showed a clinical remission rate of 63.5% (95% CI [0.483; 0.776], I2=43% P=0.08), 57.8% (95% CI [0.3895; 0.7571], I2=0%, P=0.7541), and 39.3% (95% CI [0.0814; 0.7492, I2=66%, P=0.02) for vedolizumab, infliximab, and adalimumab, respectively. The maintenance of remission rate was 60.5% (95% CI [0.2772; 0.8953], I2=67%, P=0.03), 45.3% (95% CI [0.1479; 0.7747], I2=0%, P=0.36) and 32.5% (95% CI [0.000; 0.8508], I2=53%, P=0.14) in patients who received vedolizumab, infliximab, and adalimumab, respectively. Rate of biologic-related adverse events warranting discontinuation of therapy was 12.2%, 32.9%, and 23.0% for the vedolizumab, infliximab, and adalimumab groups, respectively.

CONCLUSION

Vedolizumab and anti-TNF-α agents demonstrated a clinical benefit in the treatment of steroid-refractory MC and with a tolerable safety profile. Given the nature of included studies, superiority of either therapy could not be elucidated. Future randomized controlled trials are needed to standardize study protocols, compare vedolizumab with TNF-α inhibitors, and further examine data on patients’ quality of life.

Forest plot showing the pooled clinical remission rate at induction in patients with steroid-refractory microscopic colitis receiving (A) vedolizumab or TNF inhibitors (B)

Data summary of the meta-analyses of the studies investigating secondary endpoints in patients with refractory MC receiving either (A) vedolizumab or (B) TNF inhibitors

ABBREVIATIONS

MR, maintenance remission; CR, clinical response; HR, histologic remission; OAE, overall adverse effects.
LONG RECTAL CUFF SYNDROME AFTER ILEOANAL POUCH FOR INFLAMMATORY BOWEL DISEASE
Authors: Maspero Marianna , Liska David , Kessler Hermann , Lipman Jeremy , Steele Scott , Hull Tracy , Qazi Taha , Rieder Florian , Cohen Benjamin , Holubar Stefan
Published: January 2023

BACKGROUND

Restorative proctocolectomy with ileal pouch anal anastomosis (IPAA) removes the entire rectum to the anal canal, but is technically challenging, especially with minimally invasive (MIS) approaches. Pouches are most commonly double-stapled, leaving a 1-2 cm “rectal cuff”. If the cuff is longer, patients may develop recurrent ulcerative proctitis (UP) or rectal stricture (RS) of the retained rectum. The aim of this study is to describe long rectal cuff syndrome (LRCS) and its outcomes after redo IPAA performed for long rectal cuffs.

METHODS

We defined LRCS as a constellation of UP or RS symptoms related to a long (≥ 4 cm) rectal cuff. We retrospectively reviewed our prospectively maintained Pouch Registry to identify patients whose indication for redo pouch was LRCS. We report their presentation and outcomes after redo IPAA for LRCS. Figures are frequency (percentage) and median (interquartile range).

RESULTS

LRCS was the primary indication for redo IPAA in 40 patients (7% of the redo IPAA cases at our Center); median age at redo surgery, 42.5 (29 – 49 years); 18 (42%) were females; 36 (90%) patients were referral cases. Diagnosis at index IPAA was ulcerative colitis in 39 (97.5%), and Crohn’s in 1 (2.5%) case. The index pouch was performed MIS in 14 (35%). The median rectal cuff length was 6 (5 – 8) cm, with 13 (32.5%) patients having a cuff ≥ 8 cm.

After a median of 21 (16 – 68) months, patients most commonly presented (31, 77.5%) with UP-symptoms (urge-incontinence, frequency, abdominopelvic or rectal pain) or with obstructive (9, 22.5%) symptoms (crampy abdominopelvic pain, outlet obstruction). Preoperative pouchoscopy was available in 32 (80%) cases: pouchoscopy findings included proctitis (18, 56%), rectal stricture (16, 50%), and/or dilated pouch (7, 22%). The median interval between the index pouch and redo pouch was 31 months (16 – 67.5). The pouch was disconnected and re-anastomosed to anus in 16 (40%), while excised with neo-pouch construction in 24 (60%) of cases. The anastomosis was stapled vs. handsewn 25 (62.5%) vs. 15 (27.5%). Pathologic exam revealed chronic active proctitis in 38 (90%) cases; the remained showed other pathologic changes.

In terms of long-term outcomes, two (5%) patients never had their stoma closed after redo due to Crohn’s-related pouch complication, and fistulae development, respectively. After a median follow up of 34.5 (12 – 109) months, pouch failure occurred in 9 (22.5%) cases. The median interval between redo IPAA and pouch failure was 10 (4 – 34) months. Pouch survival at 3-, 5- and 10-years was 78%, 72%, and 63%.

CONCLUSION

Long rectal cuff syndrome is a potentially avoidable complication which presents with symptoms from either ulcerative proctitis or stricture. Redo IPAA can be offered as treatment to maintain intestinal continuity and may allow long-term pouch salvage in many cases.
THE IMPACT OF INFLAMMATORY BOWEL DISEASES ON THE OUTCOMES OF PATIENTS ADMITTED WITH ACUTE VIRAL HEPATITIS: A 2016-2019 NATIONWIDE ANALYSIS
Authors: Kilani Yassine , Arshad Iqra , Aldiabat Mohammad , Kamal Syeda Ashna Fatima , Favour Markson , Sohail Haris
Published: January 2023

INTRODUCTION

Inflammatory bowel diseases (IBD) are thought to be caused by a dysregulated immune response in the digestive tract, amongst other factors (environmental, genetic predisposition, microbiota). Data on acute viral hepatitis (AVH) infection outcomes in patients with underlying IBD are scarce. We aimed to investigate the relationship between IBD and outcomes of patients with AVH.

METHODS

This is a retrospective longitudinal study of patients admitted with a primary diagnosis of AVH (A,B,C,D,E). We retrieved data from the Nationwide Inpatient Sample (NIS) databases from the years 2016 to 2019 using ICD-10 CM codes for AVH. Multivariate logistic regression analysis was performed in patients with IBD to estimate the effect of IBD on the primary outcomes of mortality, hospital utilization, and acute hepatitis complications, adjusted for patient and hospital confounders. A T-Test and Chi Square test were performed to compare baseline characteristics in patients admitted for AVH with and without a secondary diagnosis of IBD. We used STATA® Version 17.0 Software (STATACORP, TEXAS, USA) for analysis. The p-value was set at p < 0.05 for statistical significance.

RESULTS

A total of 47614 adult patients with a primary diagnosis of AVH were identified; four hundred twenty five (0.9%) had a secondary diagnosis of IBD. Most were middle-aged (mean age: 44 years), male (53%) white (78%), and were admitted in large sized (51%) and teaching hospitals (68%). There was no statistically significant change in the length of stay or total healthcare cost associated with the presence of IBD. Having IBD was associated with no change in the risk of fulminant hepatitis (OR = 0.55, p= 0.262, CI: 0.19 - 0.55), hypoglycemia (OR = 1.14, p= 0.904, CI: 0.13 - 9.56), thrombocytopenia (OR = 0.46, p= 0.209, CI: 0.14 - 1.53), and coagulopathy (OR = 1.22, p= 0.781, CI: 0.29 - 5.12). No case of mortality, hepatorenal syndrome or liver transplant was reported.

DISCUSSION

Despite the fact that IBD is associated with a dysregulated immune response in the digestive tract, our study showed that the presence of IBD in patients affected by acute viral hepatitis does not carry a significant impact on the outcomes of IBD (hospital utilization, morbidity, mortality). Broader studies are required to establish an association between IBD and AVH outcomes.
REAL-WORLD USTEKINUMAB PERSISTENCE IN PATIENTS WITH ULCERATIVE COLITIS ATTAINING THE MAINTENANCE PHASE
Authors: Zhdanava Maryia , Kachroo Sumesh , Shah Aditi , Ding Zhijie , Holiday Christopher , Lefebvre Patrick , Zhao Ruizhi , Kerner Caroline , Pilon Dominic
Published: January 2023

BACKGROUND

Sustained use of biologics and small molecule/advanced therapy has proven to be effective for controlling disease activity in ulcerative colitis (UC). The anti-interleukin agent ustekinumab was recently approved for UC in 2019. This study aimed to describe real-world ustekinumab persistence among patients with UC attaining the maintenance phase.

METHODS

Adults with UC selected from the Komodo Health’s comprehensive dataset had the first claim for ustekinumab (index date) between 10/21/2019 and 08/13/2021. Patients had ≥12 months of continuous insurance eligibility pre-index (baseline period), ≥1 claim with a diagnosis of UC at baseline or on the index date and persisted to their first subcutaneous ustekinumab claim (maintenance phase). Patients with diagnoses for other immune disorders at baseline or diagnoses for Crohn’s disease at any time were excluded. Persistence to ustekinumab was defined as absence of a therapy exposure gap of >120 days between days of supply or end of follow-up. Composite endpoints were persistence while being corticosteroid-free (no corticosteroids with ≥14 days of supply after day 90 post-index), and persistence while on monotherapy (no immunomodulators/non-index biologics or advanced therapies). Persistence endpoints were described post-maintenance phase until the earlier of 12 months, end of insurance eligibility, or data. Kaplan-Meier curves were used to assess persistence outcomes in all patients and among patients without prior biologic/advanced therapy exposure pre-index (bio-naïve).

RESULTS

778 patients attaining the ustekinumab maintenance phase were selected, 236 (30.3%) were bio-naïve (Fig. 1). Mean follow-up time post-index was 13.5 months overall and 12.7 months for bio-naïve patients. By 12 months post-maintenance, 73.2% of all patients and 75.5% of bio-naïve patients were persistent to ustekinumab (Fig. 2). Additionally, amongst patients who were persistent and corticosteroid-free between the index date and the start of maintenance phase, 47.0% of all patients and 55.1% of bio-naïve patients remained persistent and corticosteroid-free 12 months after their first maintenance claim. Further, among patients who were persistent on monotherapy at the start of maintenance phase, 63.6% of all patients and 68.1% of bio-naïve patients remained persistent on monotherapy at 12 months.

CONCLUSIONS

In this study, 12 months after their first ustekinumab maintenance claim for UC, most patients who attained the maintenance phase were persistent to treatment, around half of patients who were also corticosteroid-free at the start of the maintenance phase remained persistent and corticosteroid-free, and most patients who were persistent on monotherapy at the start of the maintenance phase remained persistent on monotherapy.
FUNCTIONAL DISABILITY INVENTORY AND ASSOCIATIONS WITH RACE, ETHNICITY, INCOME AND FOOD INSECURITY
Authors: Zeky Nicole , LeBlanc Colleen , McDonough Elizabeth , Moulton Dedrick
Published: January 2023

PURPOSE

Inflammatory bowel disease (IBD) is an autoimmune disease that consists of Crohn’s Disease (CD) and ulcerative colitis (UC). Food insecurity is defined as limited or uncertain access to enough food. It is estimated that 1 in 7 children in the United States experience food insecurity or about 13 million children. Louisiana has one of the higher rates of food insecurity in the country with over 249,000 children affected. Food insecurity has been associated with worse health outcomes in children including developmental risks, poor mental health, and poor educational outcomes. Functional Disability Inventory (FDI) is a measure of limitations in both physical and psychosocial functioning secondary to physical health. Our hypothesis is that patients in food insecure homes will have higher FDI scores compared to those in food secure homes.

METHODS

This study is a prospective study of newly diagnosed IBD patients seen by the Division of Pediatric Gastroenterology at Children’s Hospital of New Orleans. Patients were screened for food insecurity using the United States Department of Agriculture’s food insecurity screening questionnaire and the American Academy of Pediatrics’ Food Insecurity 2-Question Screen. Disability scores were obtained at diagnosis using the FDI self-reporting questionnaire if older than 12 years of age or a parent form was completed for patients less than 12.

RESULTS

Our study consisted of 20 newly diagnosed pediatric IBD patients with an average age of 14.5 years. Nineteen (95%) patients had CD. Most patients were female (70%), non-Hispanic white (50%) with Medicaid (55%) as their primary insurance. Eight (40%) patients were African American and two (10%) were listed as other. Eight patients or their caregivers identified as living in a food insecure home (40%) and these patients averaged a FDI score of 10.2 The food secure group had an average FDI of 9.3. Non-Hispanic, white patients had an average FDI score of 10.5 while the minority patients had an average FDI of 8.5. Only two patients lived in an area with a median household income below poverty with an average FDI of 15.5. Ten patients lived below the state median income and had an average FDI was 8.2. Those patients living in areas above the state median income level, 8 total, had the highest FDI scores, 10.8.

CONCLUSION

Food insecurity had higher rates of disability scores compared to families from food secure homes. Families in higher income areas and who were non-Hispanic white had higher FDI scores compared to minority patients and those in lower income areas. Further data will be collected with changes in FDI through the first 6 months of diagnosis. Additional larger studies are needed to determine a relationship between FDI scores and food insecurity in pediatric IBD.
ACONITATE DECARBOXYLASE 1 IS A KEY REGULATOR OF COLITIS
Authors: McNamara Kara , Latour Yvonne , Smith Thaddeus , Barry Daniel , Allaman Margaret , Delgado Alberto , Piazuelo M Blanca , Washington Mary , Zhao Shilin , Coburn Lori , Gobert Alain , Wilson Keith
Published: January 2023

INTRODUCTION

Aconitate decarboxylase 1 (ACOD1; also known as IRG1) is highly expressed in activated macrophages and converts cis-aconitate to itaconate, which contributes to the antimicrobial activity of macrophages. The role of ACOD1 in intestinal inflammation remains unknown. Therefore, we investigated the role of ACOD1 during colitis induced by Citrobacter rodentium (C. rodentium), a murine bacterial pathogen used to model the pathogenesis of enteropathogenic Escherichia coli, and dextran sulfate sodium (DSS) a model of epithelial injury-mediated inflammation.

METHODS

The GEO database was utilized to examine ACOD1 mRNA levels in ulcerative colitis (UC) and Crohn’s disease (CD) patients, and normal controls. C57BL/6 wild-type (WT) and Acod1–/– mice were infected with C. rodentium for 14 days or given 4% DSS for 5 days and then normal drinking water for 5 days. Mice were weighed daily. Histology was analyzed by H&E staining on colon Swiss rolls using a 0-21 scale for C. rodentium infection and a 0-40 scale for DSS. DNA was extracted from stool to use for 16S microbiome analysis from 5 naïve WT and 5 Acod1–/– mice.

RESULTS

ACOD1 expression is increased in the colon of UC and CD patients compared to normal controls (GEO GSE16879). Further ACOD1 is significantly increased in active UC compared to inactive (P=0.0256) (GEO GSE75214). C. rodentium-infected Acod1–/– mice lost significantly more body weight compared to infected WT mice (P<0.0001). There was a significant increase in histologic injury score in the infected Acod1–/– mice (12.07 ± 0.93; n=19) compared to infected WT mice (7.65 ± 1.04; n=20; P=0.0087). In the DSS model, we observed a significant decrease in body weight (P=0.0002) in Acod1–/– mice compared to controls. A significant decrease in colon length, commonly associated with colitis in mice, was observed in the DSS-treated Acod1–/– animals (6.07 ± 0.29 cm compared to 7.22 ± 0.32 cm; P=0.0164). This was accompanied by a significant increase in histologic injury score (23.89 ± 2.14) compared to treated WT mice (13.47 ± 2.03; P=0.0004), which was driven by inflammation, epithelial injury, and crypt damage. 16S microbiome analysis on naïve mice from each genotype revealed significant differences in both the phylum and genus. Acod1–/– mice had significantly more Bacteroidetes (P=0.03) and Proteobacteria (P=0.03), specifically more Alloprevotella (P=0.029) and Prevotellaceae (P=0.029).

CONCLUSION

While ACOD1 is increased in human IBD tissues, our data indicates that this enzyme has a protective role in experimental colitis. Notably, Acod1 deletion is associated with an altered microbiome. Together our findings suggest that enhancement of ACOD1 activity may represent a new therapeutic strategy for IBD.
BUTYRATE AMELIORATES PANETH CELL DEFECTS, TOTAL INFLAMMATION, AND EPITHELIAL CELL APOPTOSIS DURING MITOCHONDRIAL DYSFUNCTION DRIVEN BY PROHIBITIN 1-DEFICIENCY
Authors: Alula Kibrom , Dowdell Alexander , Lee Joseph , Colgan Sean , Theiss Arianne
Published: January 2023

INTRODUCTION

Prohibitin 1 (PHB1) is a mitochondrial chaperone protein important for maximal activity of the electron transport chain. PHB1 deficiency in intestinal epithelial cells (IECs) or specifically in Paneth cells (PCs) induces epithelial mitochondrial dysfunction, PC defects, gut microbiota dysbiosis, and spontaneous ileitis in mice by 20 weeks-of-age. Dysbiotic gut microbiota has been implicated in inflammatory bowel diseases and is associated with the decreased abundance of short chain fatty acids (SCFAs; acetate, propionate, and butyrate)-producing bacteria. SCFAs play a significant role in reducing intestinal inflammation and epithelial barrier dysfunction. We tested the hypothesis that luminal SCFA levels were decreased in mice with PHB1 deficiency and that supplementation of SCFAs will ameliorate intestinal inflammation during mitochondrial dysfunction driven by loss of PHB1.

METHODS

Ileal luminal contents were collected from Phb1fl/fl (control) and Phb1iΔIEC (Phb1-deficient in IECs) mice at 20 weeks of age and SCFAs were measured by gas chromatography-mass spectrometry. Phb1iΔIEC and Phb1fl/fl littermate mice were treated with 20 mM butyrate dissolved in their drinking water from 16 to 20 weeks-of-age and PC defects were measured by antimicrobial peptide expression (Lysozyme, Cryptdin 3, Cryptdin 5, and Ang4) and Lysozyme staining allocation into secretory granules. Ileitis was measured by histological scoring and pro-inflammatory cytokine expression. To test epithelial intrinsic responses, ileal crypt enteroids derived from Phb1iΔIEC and Phb1fl/fl littermate mice were treated with 200 µg/ml healthy ileal stool lysates (from Phb1fl/fl mice) or dysbiotic stool lysates (from Phb1iΔIEC mice) for 16 hours with or without 0.05 mM butyrate, 0.5 mM propionate, 0.5 mM acetate, alone or in combination. Enteroid viability and apoptosis were measured by morphological change and cleaved Caspase 3 expression.

RESULTS

Butyrate was significantly decreased in ileal stool of Phb1iΔIEC mice. Butyrate supplementation in Phb1iΔIEC mice protected against ileitis and PC defects. Dysbiotic stool lysate decreased viability and increased apoptosis in Phb1-deficient enteroids that were prevented by butyrate supplementation.

CONCLUSION

Mitochondrial health in IECs cells is crucial for healthy gut microbiota composition and for epithelial defense when the microbiome becomes dysbiotic. Butyrate rescues IECs from insults caused by dysbiotic gut microbiota during mitochondrial dysfunction driven by PHB1 deletion.
COMMENSAL GUT BACTERIA REGULATE HIF ACTIVITY TO PROMOTE INTESTINAL HOMEOSTASIS
Authors: Dowdell Alexander , Mahjoob Omemh , Colgan Sean
Published: January 2023

Inflammatory bowel disease (IBD) is a disorder marked by chronic, relapsing inflammation of the gastrointestinal tract. Although the precise etiology of IBD is unclear, pathogenic immune response to the gut microbiota is considered a contributing factor. The importance of the gut microbiota in the development of intestinal inflammation has been previously shown through associative studies that correlate dysbiosis of the gut microbiota with active IBD, particularly through the loss of fiber-fermenting obligate anaerobes, an increased presence of pathobionts, and an overall decrease in microbial species diversity. Although the gut microbiota clearly plays an essential role in the development and progression of IBD, the mechanisms by which these micro-organisms regulate gut homeostasis remain to be fully elucidated.

Previously, we found that Salmonella Typhimurium (STm), a model invasive pathogen, activated hypoxia inducible factor-1α (HIF-1α) in intestinal epithelial cells (IECs) to regulate anti-bacterial autophagy. HIF-1α is a member of a transcription factor family that senses and responds to environmental stressors, in particular low oxygen tensions. Such stressors stabilize HIF-1α in the cytoplasm and prevent its usual oxygen-dependent degradation. Of note, HIF-1α has been previously shown to be essential for intestinal homeostasis in animal models of IBD, and stabilization of HIF has been demonstrated to be protective during various models of colitis in mice.

As an extension of these studies, we asked whether bacterial stabilization of HIF was unique to STm in the intestinal epithelium. We found that stabilization of HIF in IECs was not restricted to STm but was, surprisingly, recapitulated by a wide variety of bacteria, including bacteria rendered non-invasive by genetic manipulation and nonpathogenic/commensal enteric bacterial isolates. Further, we observed that stabilization of HIF was dependent on live bacteria and not due to a secreted factor, suggesting an innate HIF response by the intestinal epithelium to enteric bacteria. Finally, we found modulation of HIF signaling by enteric bacteria including regulation of numerous genes previously implicated in gut homeostasis. These results, taken together, suggest that commensal bacteria regulate intestinal homeostasis through activation of the transcription factor HIF.
THE PRECIOUS STUDY: A PROSPECTIVE, OBSERVATIONAL STUDY OF CD8+ BIOMARKER BASED PROGNOSTIC TEST IN NORTH AMERICAN IBD PATIENTS
Authors: Chen Lea Ann , Sultan Keith , Weidner Melissa , Lukin Dana , Axelrad Jordan , Saubermann Lawrence , Deepak Parakkal , Oneto Caterina , Yu Huimin , Damas Oriana , Sauk Jenny , Oliva-Hemker Maria , Sheibani Sarah , Hills Karen , Ardolli Lediona , Lee James
Published: January 2023

BACKGROUND

The clinical course of IBD varies considerably among patients1. One barrier to personalized medicine in IBD is the lack of a reliable prognostic assay that can be used at diagnosis to guide effective therapy for each patient, to optimize clinical outcomes and minimize complications. To address this need, a whole-blood qPCR-based prognostic assay was developed to divide IBD patients into two subgroups2. This transcriptional signature yields CD8 T-cell exhaustion level data that correlated with disease outcomes among IBD patients in UK2. Here, we aimed to determine if this prognostic assay could stratify an ethnically diverse North American cohort of IBD patients at diagnosis into low and high-risk subgroups.

METHODS

PRECIOUS (Predicting Crohn’s & Colitis Outcomes in the United States) is a multi-centre, observational, double-blinded study of patients with active IBD, who are not receiving systemic steroids, immunomodulator, advanced small molecules or biologics. The study is recruiting up to 200 patients between 16-80 years of age, from 14 centres across the US and Canada. Patients are prospectively followed for >12 months after enrolment to monitor disease course, including the requirement for IBD-related surgery or treatment escalations. Patients and clinicians are blinded to the biomarker results and patients are treated according to local practice.

RESULTS

Of 120 patients recruited to date, 86 have reached the 12-month follow-up timepoint (Table 1). Of the 102 patients with complete race and ethnicity data (Table 1), 63.5% are non-Hispanic Whites, 13.7% identified as Hispanic/Latino, 11.8% Asian and 9.8% Black/African American. Biomarker results were obtained for 80 (88.8%) of the 90 samples tested to date – 10 (11.1%) of samples failed quality control. Of these 80 results, 38 patients (47.5%) were identified as high risk for disease progression and 42 (52.5%) as low risk – a similar breakdown to that seen in the UK cohort2.

DISCUSSION

This is the first trial of a prognostic biomarker for patients with CD and UC in North America. This patient population was significantly more diverse than the UK cohort which had ~98% White. This diversity is not generally reflected in clinical trials performed in the United States in which approximately 90% of participants for all conditions are White whereas non-Hispanic Whites represent approximately 60% of the U.S. population. 4,5. Our enrolment of only 63.5% non-Hispanic White subjects speaks to our targeted efforts to recruit a representative level of diversity into our study population to that represents the diversity of patients with IBD that are being diagnosed globally6.
NON-MEDICAL SWITCHING FROM INFLIXIMAB TO A BIOSIMILAR IN ADOLESCENTS AND YOUNG ADULTS WITH INFLAMMATORY BOWEL DISEASE
Authors: McNicol Megan , Abdel-Rasoul Mahmoud , Morris Grant , Boyle Brendan , Dotson Jennifer , Michel Hilary , Maltz Ross
Published: January 2023

BACKGROUND

Studies in adults with inflammatory bowel disease (IBD) have demonstrated that a one-time switch from the originator to a biosimilar has not resulted in loss of response, increased side effects, or antibody development. Data describing non-medical switching is limited in adolescents and young adults. The objective of this study was to evaluate clinical outcomes of one-time switches from the originator to a biosimilar in adolescents and young adults with IBD.

METHODS

Patients with IBD that underwent a non-medical switch from infliximab originator to a biosimilar were retrospectively reviewed. Demographic data, physician global assessments (PGA), and laboratory values (albumin, hemoglobin, sedimentation rate (ESR), c-reactive protein (CRP), anti-TNF level, and anti-TNF antibody level) were recorded up to one year prior to the switch and up to one year after the switch. Rates of continuation on the biosimilar was reported at 6 and 12 months post-switch. Linear mixed effect models with random intercepts accounting for within patient correlation were used to compare continuous lab values before and after switching.

RESULTS

A total of 53 patients completed a switch from infliximab originator to a biosimilar. The mean age at the time of the switch was 18 (+/- 2.86) years old. Fifty-three percent of those undergoing a switch were female, 74% had Crohn’s disease, and 96% were switched to the biosimilar infliximab-dyyb. At the time of the switch, 52 (98%) patients had quiescent disease activity based on PGA and 1 (2%) patient had mild disease. At follow up after receiving at least 2 biosimilar infusions, 51 (96%) patients had quiescent disease and 2 (4%) patients had mild disease based on the PGA. At 6 months post switch, 48 (90%) patients were still on the biosimilar. Three (6%) patients switched back to the originator due to worsening symptoms, one (2%) patient developed worsening psoriasis, and one (2%) patient had ongoing issues with IV access. Of the 33 patients who had a full 12 months of follow-up data, 91% (30/33) remained on the biosimilar, one patient switched back to the originator due to worsening symptoms, and two switched to adalimumab due to the development of psoriasis and an underlying social situation, respectively.

There was no statistically significant difference in albumin, hemoglobin, ESR, CRP, or anti-TNF levels when comparing pre- and post- switch values. The mean anti-TNF level prior to the switch was 17.3 ug/ml (95% CI: 13.7 -19.0) and 15.1 ug/ml (95% CI: 12.5 - 17.8) after the switch. No patients developed anti-drug antibodies or infusion reactions.

CONCLUSION

A one-time non-medical switch to an infliximab biosimilar in an adolescent and young adult cohort had no significant effect on clinical remission rates, laboratory markers of inflammation, serious adverse events, anti-TNF levels, or anti-drug antibodies.
IMPACT OF NON ST- ELEVATION MYOCARDIAL INFARCTION (NSTEMI) ON PATIENTS WITH INFLAMMATORY BOWEL DISEASE
Authors: Suga Herman , Chhoun Christopher , Patel Rahul , Blair Brian , Dasu Neethi , Khalid Yaser , Joo Lucy
Published: January 2023

INTRODUCTION

Inflammatory Bowel disease is a long-term illness which can lead to numerous hospital admissions and accounts for a large amount of health care costs. IBD is a pro-inflammatory state and these patients have known elevated inflammatory markers and thus there is a known association between IBD and cardiovascular disease. The aim of this study was to evaluate the economic burden and hospital outcomes associated with IBD in patients with concomintant NSTEMI.

METHODS

Patients aged 18 years with IBD and NSTEMI versus IBD alone were identified from the US Nationwide Inpatient Sample (NIS), from the years 2015-2019. ICD 10 codes were utilized Multivariate regression analysis was used to estimate the odds ratios of in-hospital mortality, average length of hospital stay, and hospital charges, 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

This study identified approximately 447,300.04 patients with either UC or Crohn’s disease (IBD) from the years 2015 to 2019. Of these patients, 89,460 had a concomitant diagnosis of an NSTEMI. Mean age of patients was 56.61 years. The analysis revealed that mortality (OR 2.16, p= 0.003, CI: 1.29- 3.66), length of stay (LOS) (+2.25, p= 0.002, CI: 0.82- 3.67), and total hospital charges (THC) were all increased ($42,710.89 , p=0.000, CI: $21,379.01-$ 64,042.77) for patients with IBD and NSTEMI compared to patients with only IBD. Independent positive predictors of mortality, LOS, and increased total hospital charges were sepsis, AKI, malnutrition, and an aspiration event.

CONCLUSIONS

Our study revealed that patients with IBD and NSTEMI had higher mortality, hospital LOS, and total hospital charges compared to patients with only IBD. Common and overlapping inflammatory pathways contribute to that both IBD and NSTEMI which likely increases the risk for complications and mortality for these patients and demonstrated by our study. A mutli-discplinary approach should be utilized on treating patients with IBD and NSTEMI due to the significant morbidity and mortality. Further studies are needed to further evaluate the impact of NSTEMI on IBD.
TREATMENT PREFERENCES IN CROHN’S DISEASE PERIANAL FISTULA: PERSPECTIVES OF HEALTHCARE PROFESSIONALS
Authors: Jiang Jeanne , Cazzetta Susan , Chen Lily , Athavale Amod , Edelblut Josiah , Fan Tao , Hadker Nandini , Nazarey Pradeep
Published: January 2023

INTRODUCTION

Crohn’s perianal fistulas (CPFs) are a common complication of Crohn’s disease and treated with both medical and surgical interventions. This study aimed to characterize the experience and satisfaction of healthcare professionals (HCPs) with current CPF treatments and assess HCP preferences for future CPF treatment attributes.

METHODS

A US observational study recruited gastroenterologists (GEs) and surgeons who managed at least three patients with CPF in the past 12 months and spent ≥ 70% of their professional time treating patients. Using a web-enabled questionnaire, HCP satisfaction with CPF treatments and attitudes towards CPF care were rated using a 1–9 scale (1 = not at all satisfied/strongly disagree, 9 = extremely satisfied/strongly agree). A discrete choice experiment (DCE) evaluated HCP preferences for future treatment attributes. Data were analyzed using descriptive statistics and hierarchical Bayesian modeling for DCE.

RESULTS

In total, 137 HCPs were recruited (GEs, n = 77; surgeons, n = 60) with a mean (standard deviation [SD]) of 15.6 (7.8) years in active clinical practice. The mean (SD) number of patients with CPF per HCP was 29.4 (16.7), and 41% of patients had moderate disease severity.

Overall, HCPs reported moderate satisfaction with current CPF treatment (medication or surgical) attributes (Table). HCP satisfaction scores for each CPF medication and surgical procedure were low to moderate (mean range [SD]: 3.4 [2.1]–6.7 [1.5]; 4.2 [2.2]–5.7 [1.6], respectively) with biologics rated highest for medications (4.7 [2.2]–6.7 [1.5]), and short- or long-term seton placement highest for surgical procedures (mean [SD]: 5.7 [1.6] and 5.5 [1.7], respectively).

HCP attitudes towards current CPF interventions (mean score [SD]) revealed a need for better treatments (7.4 [1.5]), a concern for CPF recurrence despite treatment (7.2 [1.4]), that current treatments may not reduce risk of fecal incontinence (FI) (6.8 [1.4]), and that setons are a good short- but not long-term solution for CPF (6.5 [1.8]).

Achieving fistula closure was the most important treatment goal for HCPs (57%), with improvement in quality of life (mean score [SD]: 7.7 [1.3]), low chance of symptom recurrence (7.5 [1.4]), minimal risk of FI (7.5 [1.4]) and sustained efficacy post treatment (7.5 [1.5]) the main attributes influencing treatment decisions.

The DCE identified symptom control and/or fistula closure and low FI rates as the most important future CPF treatment attributes (Figure).

CONCLUSIONS

HCPs were unsatisfied with current CPF treatments, highlighting a need for better treatments. From an HCP’s perspective, future CPF therapies should control symptoms, promote fistula closure, and low rates of FI.