bluuebunny/crossref_metadata_2025_split huggingface dataset:
A178 BIOLOGIC THERAPY DURING PREGNANCY AS PER GUIDELINE RECOMMENDATIONS REDUCES ADVERSE PREGNANCY RELATED OUTCOMES
Authors: Tao J J , Govardhanam V , Tandon P , Huang V 
Published: February 2022

Abstract

Background
Inflammatory bowel disease (IBD) disease activity during pregnancy is associated with adverse neonatal and pregnancy-related outcomes. Biologics are used to suppress disease activity but crosses the placenta in the third trimester. Conflicting studies and guidelines on the timing of biologic dosing in pregnancy persist as we try to balance the risk of disease flare and possible adverse drug effects. The American Gastroenterology Association (AGA) recommends timing the final dose according to the half-life and dosing regimen of each biologic agent.

Aims
To compare neonatal and pregnancy-related outcomes in early versus late dosing of biologics.

Methods
This was a single-center retrospective cohort study conducted at Mount Sinai Hospital from 2016–2021. We included patients with an established diagnosis of IBD before pregnancy who were at least 18 years of age at the time of conception. All patients must have been treated with an IBD-specific biologic agent and had a documented final dose during the pregnancy. The early group received their last biologic dose earlier than the AGA recommendations and the late group received it within the recommended interval. A patient was considered to have a flare based on the overall clinical impression of their gastroenterologist informed by reported symptoms, investigations (fecal calprotectin, endoscopy), and response to treatment. Neonatal and pregnancy-related outcomes were compared amongst the two groups using the student’s t-test (for continuous variables) and Fischer’s exact test (for categorical variables) using SPSS Version 27.

Results
Of 322 patients who had a completed pregnancy at Mount Sinai Hospital, 107 were included in this study. 67 (62.6%) were in the early and 40 (37.4%) were in the late groups. Baseline characteristics including age, comorbidities, IBD phenotype and disease activity were similar between the two groups. The late group had significantly later gestational ages (37.4 vs 38.7 weeks, p=0.006), higher 5-minute Apgar scores (8.7 vs. 9.0, p=0.042), fewer NICU admissions (25.4% vs 5.0%, p=0.036), and fewer IBD flares (28.3% vs 11.1%, p=0.039) in the 6-month post-partum period. There were no significant differences in the rates of premature birth, caesarian sections, infections, and congenital abnormalities. Results are displayed in figure 1.

Conclusions
Our study suggests that late dosing of biologics according to the AGA guidelines was associated with favourable outcomes. However, this is an unadjusted analysis based on retrospective data and findings should be confirmed in a prospective manner to account for confounders.

Funding Agencies
None
A179 AUTOLOGOUS BONE MARROW TRANSPLANT FOR REFRACTORY CROHN’S DISEASE: A CASE SERIES
Authors: Buttar J , Akhtar N H , Akhtar D , Barker C , Bressler B , Atkinson K 
Published: February 2022

Abstract

Background
Crohn’s disease (CD), a form of inflammatory bowel disease (IBD) is a chronic, immune mediated condition characterized by gastrointestinal inflammation. Approximately 25% of CD patients have pharmacologically refractory disease, in which stem cell therapy has been shown to play a role.

Aims
A case series was performed to analyze the efficacy of autologous bone marrow transplantation (ABMT) for refractory CD in British Columbia(B.C).

Methods
A chart review was conducted on patients who had undergone ABMT for treatment refractory CD between 2001 to 2021 in B.C. Demographic, clinical, laboratory and endoscopic data was collected.

Results
Case details are summarized in Table 1. 3 patients(2 female and one male) were included. All patients failed conventional therapies prior to ABMT. 2 patients underwent surgical intervention (colectomy with ileostomy) prior to ABMT. Average time from diagnosis to ABMT was 8.83 + 6.6 years. All 3 patients received standard myeloablative therapy. There were no intestinal complications post ABMT. 6 months post-ABMT transplant, all 3 patients showed significant improvement, with CDAI scores &lt;150. Endoscopic assessment post-ABMT revealed endoscopic remission in 2 of the 3 patients. 2 of the 3 patients were in clinical remission at 12 months follow up. 1 patient relapsed and required further immunosuppressive therapy. This patient was trialed on thalidomide at 15 months post-ABMT and ultimately passed away 18 months post-ABMT from an unrelated cause. 10 years post-transplant, the remaining 2 patients remain in clinical and endoscopic remission with CDAI scores &lt;150.

Conclusions
Despite medical and surgical therapeutic advances, a subset of CD patients develop refractive disease associated with significant morbidity and mortality. In this population, there is increasing evidence in support of stem cell therapy as a treatment modality, with acute mortality less than 5% for patients with malignancy driven primarily by infectious complications and treatment-related toxicity. Clinical trials are currently underway to evaluate ABMT in CD. This case series presents the only Canadian data to date on the use of ABMT for refractory CDs and their subsequent follow up.

Funding Agencies
None
A184 REPURPOSING DRUGS FOR SPLEEN TYROSINE KINASE (SYK) PEDIATRIC PATIENTS USING HIGH-THROUGHPUT SCREENING
Authors: Chau S , Jardine S , Guo C , Warner N , Muise A 
Published: February 2022

Abstract

Background
Spleen Tyrosine Kinase (SYK) is a cytosolic, non-receptor tyrosine kinase with an imperative role in immune and non-immune processes. Recently, we identified six gain-of-function SYK variants in patients that presented multi-organ inflammation and immune dysregulation. The SYK variants displayed constitutive SYK phosphorylation in human embryonic kidney (HEK) 293T, colonic epithelial cells (SW480), and in knock-in heterozygous SYK mice. These observations mark SYK as a therapeutic target for autoimmune diseases.
Phenotype drug discovery accelerates this process and can be done successfully with an appropriate phenotype. A possible phenotype displayed by SYK variants is SYK phosphorylation, as high-throughput screening can identify hit compounds that reduce the constitutive activation of phosphorylated SYK (p-SYK).

Aims
Aim 1: Determine the screening phenotype with wildtype (WT) and SYK S550Y variant in HEK293T cells. Recently, we observed increased phosphorylation in gain-of-function SYK variants We hypothesize that we can use phosphorylated-SYK (p-SYK) levels to identify hit compounds that can decrease the kinase activity in these variants. With stable transfected SYK WT and SYK S550Y HEK293T cell-line, protein analyses will be completed to characterize the appropriate screening phenotype.

Aim 2
Establish an assay for high-throughput drug screening. We will utilize homogenous time-resolved fluorescence (HTRF) assay. The signal measured from HTRF is positively proportional to the level of p-SYK; therefore, we expect that S550Y cells will have a higher signal than the WT.

Aim 3
Validate hit compounds in HEK293T and zebrafish. We will create a dose-response curve with the hit compounds in in vitro and in vivo models.

Methods
We will use stable transfection to established overexpressing SYK WT and S550Y HEK293T cells. We will apply homogenous time-resolved fluorescence (HTRF) to quantify p-SYK levels during the drug screening.

Results
Protein analyses have verified high expression of p-SYK in stable transfected HEK293T cells. No stimulation was required, as the cells showed an increased phosphorylation level at baseline. Downstream signaling partners such as p-ERK and p-JNK of the MAPK pathway displayed an upregulation. This suggests that the sustained activation of p-SYK may consequently affect cellular processes and contribute to the clinical manifestations observed in patients.

Conclusions
This research study will identify hit compounds that can produce a safe and effective biological response in pediatric patients with gain-of-function SYK variants. Personalizing medicine throughout high-throughput drug screening can accelerate drug repurposing for pediatric patients with multiple systemic diseases and immune dysregulation.

Funding Agencies
None
A185 DUAL BIOLOGIC THERAPY IN A PATIENT WITH NIEMANN-PICK TYPE C AND CROHN DISEASE: A CASE REPORT AND LITERATURE REVIEW
Authors: Hudson A , Almeida P , Huynh H Q 
Published: February 2022

Abstract

Background
Since the availability of biologics and biosimilars, inflammatory bowel disease (IBD) therapy has been a rapidly expanding field. Dual biologic therapy has become a new area of interest. This is important given that clinical remission rates from biologic monotherapy are only 40% at one year, and that in Canadian children with IBD, up to 33% will need surgery within ten years. It also holds potential in those who are not likely to respond as well to traditional therapy, such as patients with genetic disorders. Mono-/poly-genic IBD and the role of genetics in IBD is an evolving field. Niemann-Pick disease type C (NPC), a neurodegenerative lysosomal storage disorder, is one such genetic disorder, and its’ associated predisposition to IBD is thought to be related to impaired destruction of intracellular bacteria within macrophages (impaired autophagy). The persistence of bacteria in the gut wall leads to an increased cytokine response.

Aims
We present a case of a teenage patient with NPC and crohn colitis, who sustained clinical remission only after escalating to dual biologic therapy (anti-TNF (infliximab) and anti-IL12/IL23 (ustekinumab)).

Methods
A literature review of dual biologic therapy in Pediatric IBD (all types of patients included) was also completed.

Results
The patient presented with one month of abdominal pain, weight loss, and bloody diarrhea, 9 months after her diagnosis of NPC. Endoscopy revealed mild inflammation in the rectosigmoid junction and rectum, with pathology showing granulomatous pancolitis. Induction therapy was rectal 5-ASA. Subsequent flares resulted in the addition of azathioprine, and then infliximab. She was switched to ustekinumab after a flare 21 months later, which did not lead to adequate improvement, so infliximab was added back on as a dual biologic. With this combination therapy she maintained clinical, biochemical, and endoscopic remission, ongoing two years later. A literature review revealed eight studies (case series/reports only). One Pediatric patient case combined ustekinumab with infliximab, while the remaining combined vedolizumab (gut-specific anti- α 4β 7 integrin) with infliximab.

Conclusions
In Pediatric patients with genetic disorders and IBD who are not responding adequately to biologic therapy, adding a second biologic medication with a different mechanism of action may be efficacious. Targeting both TNFa (which induces pro-inflammatory cytokines, among many other roles), and the proinflammatory cytokines themselves (IL12/23), may be important in genetic disorders with impaired macrophage function and increased cytokine response. This is a potential option even several years into treatment. To date, only case studies are available, with the majority combining vedolizumab with infliximab. Our case adds to the sparse literature on the utility of combining ustekinumab and infliximab.

Funding Agencies
None
A200 CROHN’S-ASSOCIATED E. COLI WORSEN COLITIS SEVERITY IN MICE COLONIZED WITH DEFINED MICROBIOTA
Authors: Jackson K , Hann A , Galipeau H J , Constante M , Coombes B K , Verdu E , Hosseinidoust Z 
Published: February 2022

Abstract

Background
Bacterial infections have been postulated to drive the dysregulated inflammation found in inflammatory bowel disease (IBD). In particular, adherent-invasive Escherichia coli (AIEC) isolated from patients with IBD have pathobiont characteristics and have been implicated in IBD pathogenesis.

Aims
Our aim was to characterize and compare the level of intestinal inflammation and potential microbiota shifts induced by E. coli clinical isolates using a gnotobiotic mouse model of colitis.

Methods
Adult germ-free C57BL/6 mice were transferred to ISO positive cages in a gnotobiotic facility and colonized with altered Schaedler flora-like (ASF) microbiota and one of three clinical E. coli isolates: E. coli C0004 (n = 5), E. coli LF82 (n = 9), E. coli NRG857c (n = 6), or ASF alone (n = 6). Three weeks later, mice were treated for 5 days with low dose dextran sodium sulphate in drinking water (2%; DSS), followed by 2 days of water. Mice were monitored daily for clinical symptoms (weight, stool consistency, and occult blood). At sacrifice, colon tissue was collected for histological analysis. Cecum contents were cultured to determine bacterial load. Fecal samples were collected for 16S rRNA gene sequencing analysis before and after DSS treatment.

Results
All mice colonized with an E. coli isolate displayed significantly greater clinical and microscopic scores of colitis compared to ASF alone, but the severity was dependent on the colonized E. coli strain. E. coli NRG857c-colonized mice exhibited more severe symptoms (p &lt; 0.001) two days earlier than mice colonized with other E. coli isolates. Mice colonized with E. coli LF82 or E. coli NRG857c had higher histological scores of colitis compared to mice colonized with E. coli C0004, which were also significantly greater than ASF alone (p &lt; 0.0001). 16S rRNA gene sequencing revealed that ASF-alone-colonized mice lacked Proteobacteria. All E. coli-colonized mice had comparable bacterial loads, which were verified by 16S rRNA analysis. Following DSS, E. coli LF82 and E. coli NRG857c relative abundance remained stable, whereas the relative abundance of Roseburia/ASF 492 declined significantly in all E. coli colonized mice.

Conclusions
The presence of E. coli pathobionts in mice drive the severity of chemically induced colitis, with AIEC NRG857c inducing the greatest severity. This gnotobiotic mouse model enables us to control the severity of colitis in a well-defined microbiota that is dependent on the colonized E. coli isolate. Using this model, we will be able to assess therapeutic candidates that aim to treat colitis at varying stages of its disease progression.

Funding Agencies
CCC, CIHRNSERC
A225 VACCINE-PREVENTABLE DISEASES IN HOSPITALIZED PATIENTS WITH END-STAGE LIVER DISEASE/CIRRHOSIS: A NATIONWIDE COHORT ANALYSIS
Authors: Hudson D , Khanna R , Brahmania M , Qumosani K , Teriaky A 
Published: February 2022

Abstract

Background
Cirrhosis is associated with immune dysfunction, which increases susceptibility to infection and subsequent hospitalization. Vaccination of this high-risk patient population can mitigate the risk of infection.

Aims
Data from the National Inpatient Sample (NIS) was analyzed to compare the prevalence of vaccine-preventable diseases (VPD) among hospitalized patients both with and without cirrhosis.

Methods
The 2013 NIS database was interrogated using ICD-9-CM codes to identify patients with cirrhosis and VPD. Baseline characteristics were compared (see: Table 1). Univariate and multivariate regression models identified risks associated with VPD adjusting for survey procedures.

Results
313,710 patients were hospitalized for VPD, including 13,080 patients (4.1%) with cirrhosis (see: Table 1) Patients with cirrhosis were more likely to be hospitalized with pneumococcal pneumonia (odds ratio [OR] = 1.45 [95% CI 1.29 – 1.63], P &lt;0.001), hepatitis A (OR = 7.04 [95% CI 5.96 – 8.31], P &lt;0.001) and hepatitis B (OR = 14.41 [95% CI 12.53 – 14.36], P &lt;0.001) infections compared to patients without liver cirrhosis. Patients with cirrhosis were less likely to have an infection with influenza (OR = 0.55 [95% CI 0.49 – 0.62], P &lt;0.001), human papillomavirus (HPV) (OR = 0.57 [95% CI 0.43 – 0.75, P &lt; 0.001) and varicella zoster (OR = 0.78 [95% CI 0.69 – 0.89], P &lt;0.001). Minimal differences in hospitalizations for haemophilus influenzae or meningococcal infections were noted between groups.
Odds ratios for VPD adjusting for age, sex, race, patient location, patient income, hospital type and bed-size, mortality risk, type 2 diabetes mellitus, malignancy, human immunodeficiency virus (HIV), organ transplantation and immunodeficiency:
pneumococcal pneumonia (OR = 1.27 [95% CI 1.13 – 1.44], P &lt; 0.001), hepatitis A (OR = 5.99 [95% CI 5.02 – 7.15], P &lt; 0.001); and hepatitis B (OR = 11.07 [95% CI 10.24 – 11.97], P &lt; 0.001).

Conclusions
These results emphasize the importance of vaccinating patients with cirrhosis against pneumococcal pneumonia, hepatitis A and hepatitis B infections to reduce hospitalization

Table 1: Baseline characteristics of patients with cirrhosis and without cirrhosis presenting with a vaccine preventable disease.

Funding Agencies
None
A234 IN VITRO GUT MICROBIOME AND METABOLITE RESPONSES TO RESISTANT STARCH ARE INDIVIDUALIZED
Authors: Dobranowski P , Qin H , Walker K , Butcher J , Gowing A , Singleton R , Mayne J , Mack D R , Figeys D , Stintzi A 
Published: February 2022

Abstract

Background
Gut microbes degrade and ferment resistant starch (RS) into metabolites that help maintain gut homeostasis. Clinical trials have evaluated RS for various health conditions, but individuals respond to RS with profound variability. The reason for this variability is unclear.

Aims
Using in vitro culturing methods and multi-omic analyses, we hypothesize that individuals will elicit variable responses to RS with respect to overall fermentation, bacterial composition, short chain acid production, and metabolite flux.

Methods
As part of an ongoing clinical trial, we have selected 4 pediatric patients with inflammatory bowel disease to better understand microbiome-RS interactions. We cultured stools anaerobically using a high-throughput platform (“RapidAIM”) with 9 different pre-digested RS. After 18-hour incubations, media supernatants were used to measure pH and perform targeted and semi-targeted metabolomic analyses with a panel of 116 compounds. Bacterial pellets were isolated for 16S rRNA gene sequencing analyses to evaluate changes in microbiome compositions. Data were analyzed with generalized linear mixed models, principal component analysis (PCA), random forest (RF) classification with feature selection, and network construction with graphical lasso.

Results
Changes in several microbiome parameters were different across individuals, including the magnitude of pH changes, metabolite signatures, and relative abundances of important bacterial taxa. Bacterial species known to degrade RS were more abundant in individuals showing stronger RS fermentation. Inter-individual discrimination was accomplished with PCA and RF, from which we could identify metabolite signatures. The robustness of microbiome networks corresponded to RS fermentation and butyrate production.

Conclusions
We report a novel perspective on how individuals respond to RS’ differently. Butyrate remains an important hub of the microbiome architecture with respect to RS fermentation. Future work will interrogate the roles of individualized metabolomic responses on host physiology. In vivo responses to RS are being evaluated in an ongoing clinical trial.

Funding Agencies
CCC, CIHRGenome Ontario, Genome Canada
A235 ILEAL MICROBIOME ALPHA DIVERSITY REMAINS LOWER IN ENDOSCOPICALLY AND HISTOLOGICALLY INACTIVE CROHN’S DISEASE COMPARED TO ULCERATIVE COLITIS OR HEALTHY CONTROLS
Authors: Olivera Sendra P A , Borowski K , Nayeri S , Martinez-Lozano H , Leibovitzh H , Lee S , Hernandez-Rocha C , Silverberg M S 
Published: February 2022

Abstract

Background
Crohn’s disease (CD) has been associated with a lower alpha diversity when compared to ulcerative colitis (UC) patients and healthy controls (HC), which also depends on disease location and endoscopic activity. However, it is unclear whether the resolution of histologic inflammation may influence mucosal alpha diversity in the ileum.

Aims
To characterize the ileal mucosa-associated microbiome diversity in subjects with ileal predominant CD (iCD) in endoscopic (ER) and endo-histologic (EHR) remission, compared to subjects with colonic predominant CD (cCD), UC and HC, respectively.

Methods
Data from a large cohort of subjects recruited at Mount Sinai Hospital Toronto (2009–2016) was analyzed. ER was defined as a segmental Simple Endoscopic Score for CD of &lt;3 in the ileum. EHR was defined as ER with the absence of active histologic inflammation in ileal biopsies. CD patients were divided according to the Montreal classification into iCD (L1 and L3) and cCD (L2) and compared against UC patients without backwash ileitis and HC. Patients with history of ileocecal resection and/or antibiotic use at baseline were excluded. Microbial 16S rRNA gene was sequenced using the Illumina MiSeq and processed using QIIME2. Alpha diversity was measured using the Shannon index and compared using Kruskal-Wallis test and further pairwise Wilcoxon with Holm correction. An adjusted p-value &lt; 0.05 was considered significant.

Results
We included 35 CD patients with ileal ER, 81 UC patients and 32 HC. Among CD patients, 20/35 (57.1%) and 15/35 (42.9%) had iCD and cCD, respectively. Ileal mucosal alpha diversity was significantly lower in iCD patients in ER compared with that of UC patients (q=0.004) and HC (q=0.001). No differences in ileal mucosal alpha-diversity were seen between iCD than cCD patients (q=0.12). When histology was included to classify CD and UC patients as EHR, the ileal alpha diversity of iCD patients remained reduced compared to UC patients and HC (q=0.008 and q=0.002, respectively). Again, ileal mucosal alpha-diversity was not significantly lower in iCD than cCD patients among those in ileal EHR (q=0.24).

Conclusions
Ileal mucosa of CD patients in ER and EHR have lower alpha diversity than UC and HC. These findings suggest that the ileal mucosa of CD patients remains dysbiotic despite achieving endoscopic and histologic remission.

Funding Agencies
IBD Genetics Consortium