bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modification of Huntington’s disease by short tandem repeats
Authors: Hong Eun Pyo , Ramos Eliana Marisa , Aziz N Ahmad , Massey Thomas H , McAllister Branduff , Lobanov Sergey , Jones Lesley , Holmans Peter , Kwak Seung , Orth Michael , Ciosi Marc , Lomeikaite Vilija , Monckton Darren G , Long Jeffrey D , Lucente Diane , Wheeler Vanessa C , Gillis Tammy , MacDonald Marcy E , Sequeiros Jorge , Gusella James F , Lee Jong-Min 
Published: January 2024

Abstract
Expansions of glutamine-coding CAG trinucleotide repeats cause a number of neurodegenerative diseases, including Huntington’s disease and several of spinocerebellar ataxias. In general, age-at-onset of the polyglutamine diseases is inversely correlated with the size of the respective inherited expanded CAG repeat. Expanded CAG repeats are also somatically unstable in certain tissues, and age-at-onset of Huntington’s disease corrected for individual HTT CAG repeat length (i.e. residual age-at-onset), is modified by repeat instability-related DNA maintenance/repair genes as demonstrated by recent genome-wide association studies. Modification of one polyglutamine disease (e.g. Huntington’s disease) by the repeat length of another (e.g. ATXN3, CAG expansions in which cause spinocerebellar ataxia 3) has also been hypothesized. Consequently, we determined whether age-at-onset in Huntington’s disease is modified by the CAG repeats of other polyglutamine disease genes. We found that the CAG measured repeat sizes of other polyglutamine disease genes that were polymorphic in Huntington’s disease participants but did not influence Huntington’s disease age-at-onset. Additional analysis focusing specifically on ATXN3 in a larger sample set (n = 1388) confirmed the lack of association between Huntington’s disease residual age-at-onset and ATXN3 CAG repeat length. Additionally, neither our Huntington’s disease onset modifier genome-wide association studies single nucleotide polymorphism data nor imputed short tandem repeat data supported the involvement of other polyglutamine disease genes in modifying Huntington’s disease. By contrast, our genome-wide association studies based on imputed short tandem repeats revealed significant modification signals for other genomic regions. Together, our short tandem repeat genome-wide association studies show that modification of Huntington’s disease is associated with short tandem repeats that do not involve other polyglutamine disease-causing genes, refining the landscape of Huntington’s disease modification and highlighting the importance of rigorous data analysis, especially in genetic studies testing candidate modifiers.
OP03 Efficacy and safety of the oral selective sphingosine-1-phosphate-1 receptor modulator VTX002 in moderately to severely active Ulcerative Colitis: results from a randomised, double-blind, placebo-controlled, phase 2 trial
Authors: Sands B E , Panaccione R , D'Haens G , Schreiber S , DuVall A , Kierkus J , Naik S , Gilder K , Yun C , Sandborn W J , Walczak M , Vermeire S , Rubin D T , Peyrin-Biroulet L , Danese S 
Published: January 2024

Abstract

Background
VTX002 is a novel oral selective sphingosine-1-phosphate-1 (S1P1) receptor modulator in development for the treatment of ulcerative colitis (UC). The efficacy and safety of VTX002 in patients with ulcerative colitis (UC) was assessed in a phase 2, multicentre, randomised, double-blind, placebo-controlled study (NCT05156125).

Methods
Adults (N=213) with moderately to severely active UC (modified Mayo score [MMS] 4-9) and inadequate response/intolerance to conventional and/or advanced (approved biologics or Janus kinase inhibitor) therapies were randomised 1:1:1 to once daily treatment with placebo (n=70), 30 mg (n=73) or 60 mg (n=70) VTX002 tablets for 13 weeks. Patients underwent a 6–8-day dose titration up to the assigned treatment dose. The primary endpoint was clinical remission (MMS stool frequency subscore ≤ 1, rectal bleeding subscore=0, and endoscopic subscore [ES] ≤ 1) at week 13. A protocol amendment limiting eligibility to patients with baseline MMS 5-9 resulted in 213 and 209 patients in the safety and efficacy populations, respectively. Key secondary endpoints were endoscopic improvement, symptomatic remission, histologic remission, and endoscopic improvement-histologic remission. Endoscopic remission and histologic-endoscopic mucosal improvement (HEMI) were also assessed (see Table 1 for outcome definitions). Adverse events (AEs) and laboratory abnormalities were assessed for safety.

Results
The primary endpoint of clinical remission at week 13 was achieved (27.9% of patients who received VTX002 60 mg vs 11.4% of patients who received placebo, ∆=16.5%, p=0.0184). Both doses of VTX002 achieved nominal statistical significance for all key secondary endpoints (Table 1).
Significantly greater proportions of patients who received VTX002 60 mg achieved endoscopic remission and HEMI compared to patients who received placebo (29.4% VTX002 60 mg vs 7.1% placebo, ∆=22.3%, p=0.0012, and 32.4% VTX002 60 mg vs 10.0% placebo, ∆=22.4%, p=0.0026, respectively). A dose-dependent decrease of 67.7% and 53.9% in mean absolute lymphocyte count (ALC) from baseline was observed at week 8 for patients who received VTX002 60 mg and 30 mg, respectively. Most AEs were mild to moderate (Table 2). No AEs of bradycardia, atrioventricular block, serious infections, macular oedema, or deaths were reported.

Conclusion
The S1P1 receptor modulator VTX002 was well-tolerated and statistically superior to placebo for induction of clinical, endoscopic, histologic, HEMI, and symptomatic remission/response at week 13. These positive findings, including a dose-dependent pharmacodynamic reduction in ALC, support phase 3 development of VTX002 for treatment of UC.
OP04 Endoscopic healing in paediatric IBD perpetuates a persistent signature characterized by pathogenic Th17 cells and tissue-associated molecular and microbial drivers of disease
Authors: Siebert K , Köhler N , Faro T , Matchado M , Hölz H , Jarosch S , Koletzko S , Ohnmacht C , List M , Busch D , Haller D , Schwerd T 
Published: January 2024

Abstract

Background
Endoscopic healing (EH) is the major long-term treatment target for inflammatory bowel diseases (IBD) in adults and paediatric patients. However, EH may not represent disease clearance. Hence, risk of relapse remains high and treatment discontinuation after reaching EH often results in disease exacerbation. We aimed to identify persistent cellular, molecular and microbial drivers of IBD under EH and longitudinally collected endoscopic biopsies from paediatric patients for analysis of single T-cell and bulk transcriptomics as well as mucosa-associated microbiota.

Methods
We followed disease trajectories of paediatric IBD patients treated according to international guidelines and collected mucosal biopsies from the terminal ileum (TI) and sigmoid colon (SC) at baseline (T1) and after approximately 3-12 months (T2) to assess EH. Non-IBD controls showed no macroscopic or histologic signs of inflammation. Host RNA and bacterial DNA were simultaneously extracted from single biopsies for bulk RNA-seq, and 16S rRNA seq. A second biopsy was used for isolation of lamina propria mononuclear cells (LPMCs), followed by CD45+, CD3+ cell sorting and single T-cell analysis (10X Genomics). Data were quality controlled and integrated.

Results
217 biopsies (135 simultaneous extraction of host RNA and bacterial DNA; 82 single T-cell analysis) from 32 paediatric IBD patients (mean age 13 ± 3.5 years, 21 Crohn’s disease [CD], 11 ulcerative colitis [UC]; T1 = 32, T2 = 32, T &gt; 2 = 6) and 5 non-IBD controls were analysed. Time between T1 and T2 averages 40 ± 22 weeks. At baseline, 15 patients (14 CD, 1 UC) were newly diagnosed and 31/32 patients had active mucosal inflammation. Twenty-two patients (71%) achieved EH at T2 (SES-CED ≤2 and absence of ulcerations), mostly on anti-TNF therapy. One patient (EH at T1) experienced relapsing disease within 10 weeks after discontinuing medication. In the bulk RNA-seq, we identified 299 differential expressed genes (DEGs; corrected p-value &lt;0.05, FC &gt;2.0), such as DUOX2, SAA2-SAA4, FCGR3B and NOS2, that are associated with active IBD and remained upregulated in EH in contrast to non-IBD controls. In addition single cell analysis revealed an IBD-specific pathogenic Th17 cluster that continued to exist in EH and showed high correlation with top DEGs after data integration. 16S rRNA gene seq highlighted highly individual mucosa-associated bacterial profiles and a reduced α-diversity in active and EH compared to non-IBD controls.

Conclusion
A persisting IBD signature in EH reflects ongoing cellular, molecular and microbial activity in comparison to non-IBD controls despite EH and mucosal regeneration. These markers may provide targets for future or sequential therapies.
OP16 A novel artificial intelligence-assisted Image Enhanced Endoscopy assesses accurately “vascular-healing” and predicts long-term clinical relapse in patients with ulcerative colitis: a prospective cohort study
Authors: Maeda Y , Kudo S E , Kuroki T , Masashi M , Ogata N , Miyachi H , Baba T , Nemoto T , Ohtsuka K , Iacucci M 
Published: January 2024

Abstract

Background
Ulcerative colitis (UC) is a chronic specific inflammatory bowel disease that alternates between remission and relapse statuses. Microvascular finding observed in image-enhanced endoscopy (IEE) has been attracting attention to detect inflammation and predict outcomes in patients with UC; however, this requires specialist endoscopists. Artificial intelligence (AI)-assisted IEE may help to overcome this problem. We developed a novel AI-based narrow-band imaging (NBI) system, using 8853 images from 167 patients, that can be adapted to commercially available various endoscopes and determined if AI-identified ‘vascular-healing’ could predict relapse and guide treatment in patients with UC.

Methods
This prospective cohort study analyzed data from 100 patients with UC in clinical remission. The endoscopists performed colonoscopy using the AI system, which outputs identified the target mucosa as vascular-active or vascular-healing. The Mayo endoscopic subscore (MES), AI outputs, and histological assessment were recorded for six colorectal segments of each patient. Patients were then followed up for 12 months. Clinical relapse was defined as a partial Mayo score &gt;2.

Results
The clinical relapse rate was significantly higher in the AI-based vascular-active group [23.9% (16/67)] compared with the AI-based vascular-healing group [3.0% (1/33)] (P=0.01). In a sub-analysis predicting clinical relapse in patients with MES ≤1, the area under the curve for the combination of complete endoscopic remission and vascular healing (0.70) was increased compared with that for complete endoscopic remission (MES=0) alone (0.65). Colonoscopy by a total of 27 endoscopists, comprising 11 experts and 16 trainees, evaluated 35 and 65 patients, respectively. The sensitivity, specificity, and accuracy for predicting clinical relapse did not differ significantly according to the endoscopist’s experience: 100%, 39.3%, and 51.4%, respectively, for experts and 90.0%, 38.2%, and 46.2%, respectively, for trainees (P&gt;0.95, P&gt;0.95, and P=0.84, respectively).

Conclusion
Colonoscopy using the AI-based NBI system for diagnosing “vascular-healing” identifies patients with UC at high risk of relapse and thus aids future disease management.
DOP61 Up-regulated Gremlin 1 in fibroblasts from Crohn’s Disease fibrotic strictures: A potential therapeutic target
Authors: Acharjee A , Shivaji U N , Santacroce G , Jeffery L , Reynolds G , Majumder S , Akiror S , Zardo D , Gkoutos G V , Iacucci M , Amamou A , Ghosh S 
Published: January 2024

Abstract

Background
Fibrosis is a common complication in Crohn’s disease (CD), often leading to intestinal strictures that are refractory to available biologic drugs and require surgery. Addressing this complication remains a significant unmet need. This study aims to explore the transcriptomic signature of fibrostenotic ileal CD to identify novel therapeutic targets.

Methods
9 CD patients undergoing surgery for fibrotic strictures were prospectively recruited. All patients underwent magnetic resonance enterography, ileoscopy, and assessment of C-reactive protein and faecal calprotectin. A multidisciplinary team adjudicated the presence of fibrotic strictures, warranting surgical resection. Resected specimens were harvested directly from the operating theatre and delivered fresh to pathologists, who dissected samples from the strictured area, and the proximal and distal non-strictured regions. RNA was extracted from all samples for bulk-transcriptomic and single-cell RNA sequencing (scRNAseq) analysis, using the 10x Chromium Controller® platform. Differentially expressed genes (adj. p-value &lt;0.05) were identified. Machine learning analyses, including PCA and PLS-DA, were employed to compare gene expression patterns among different tissue segments. Pathway enrichment analysis pinpointed relevant pathways. Further, the random forest model was constructed to evaluate the predictive significance of genes in relation to strictures, and the resulting ranked list of genes was subsequently validated through qPCR, confirming the significance of selected genes.

Results
Bulk-transcriptomic analysis revealed 64 significantly up-regulated genes in strictures, associated with inflammation, matrix remodeling, adipogenesis and cellular stress. Furthermore, 17 down-regulated genes were linked to epithelial barrier integrity. Normalised gene expression of GREM1, SERPINE1, FGF2, HDAC1 AND LY96 showed high predictive value for strictures compared to distal and proximal segments. Notably, qPCR confirmed the significant up-regulation of GREM1 expression exclusively in the ileal stricture samples (non-stricture vs. stricture: AUC 0.88, 95% CI 0.77-0.95). scRNAseq linked up-regulated GREM1 exclusively to the fibroblast cell population (THY1+, COL1A1+,ACTA2+).

Conclusion
Bulk and single-cell transcriptomics, along with qPCR validation of resected CD ileal strictures, showed the up-regulation of GREM1 in fibroblasts within stricture compared to adjacent proximal and distal intestinal samples. These findings confirmed in ileal CD previous reports from animal models, highlighting the role of GREM1 in promoting intestinal fibrosis. Therefore, GREM1 emerges an attractive target for the treatment of fibrotic strictures in CD.
P345 Application of bowel sound computational analysis in inflammatory bowel disease
Authors: Yao C C , Tai W C 
Published: January 2024

Abstract

Background
Inflammatory bowel disease(IBD) is a chronic disease. Although colonscopy is the gold standard for assessing activity, itcarries a considerable discomfort. We evaluate the value of bowel sound computational analysis (BSCA) as a tool in assist diagnosis and severity in Crohn’s disease(CD) and ulcerative colitis (UC).

Methods
We used homemade BSCA as a tool in assist bowel sound(BS). Five minutes recordings were taken for patients. The BS activity, sound duration, peak frequency (Hz) and bowel sound index (SI) was recorded.

Results
We enrolled 16 CD, 22 UC and 20 healthy controls. In CD patients, BS peak frequency was significantly higher than UC and controls (p=0.01). In UC patients, BS SI was significantly higher than CD and controls (mean 2024 V/min vs 1687 and 1181, p=0.04 and 0.01, respectively). We further evaluated the relation between these two parameters and the degree of severity. In CD patients, BS peak frequency were higher in patients with CDAI over 150 than CDAI under 150 (mean 370.7 Hz vs 358.2 Hz, p=0.045). In UC patients, BS SI was significantly higher in patients with mayo score(MS) larger than 6,compare to MS 3-5, MS 0-2, and controls (mean 2269 V/min vs 1863,1638, and1181, P all=0.01).

Conclusion
CD patients had higher BS peak frequency and UC patients had higher bowel sound index. These characteristic of BS changes seemed correlated to the severity of IBD.
P431 Assessing intestinal barrier healing by fusing ultra-high magnification endoscope and automated spatial multispectral imaging analysis in PSC-colitis patients
Authors: Iacucci M , Majumder S , Santacroce G , Zammarchi I , Maeda Y , Shivaji U N , Abdawn Z , Hejmadi R , Hayes B , Crotty R , Burke L , Ghosh S 
Published: January 2024

Abstract

Background
PSC colitis is associated with an increased risk of colorectal carcinoma. Endoscopic monitoring is crucial since endoscopic and histological activity can persist in PSC even during clinical remission. Recent evidence suggests that the presence of barrier dysfunction may predict relapse in quiescent patients. This study aims to assess mucosal and barrier healing in quiescent PSC colitis and evaluate the potential to predict outcomes by combining an ultra-high magnification endocytoscope (ECS) with intestinal barrier protein markers.

Methods
23 PSC-colitis patients in clinical remission requiring surveillance colonoscopy were prospectively enrolled. Ileal and colonic mucosa were assessed with high definition, virtual chromoendoscopy and ultra-high magnification ECS. Endoscopic remission was defined as MES ≤1, UCEIS≤1, PICaSSO≤3, while histological remission was defined as RHI≤3 without lamina propria or epithelial neutrophils, NHI ≤1 and PHRI=0. A novel ECS score was developed to assess ileal and colonic intestinal barrier (Table 1). The expression of tight junction proteins (Claudin-2, Occludin, and JAM-A) was evaluated through immunohistochemistry and multiplex immunofluorescence, and it was quantified as cell density and mean expression using the automated inForm® Akoya Biosciences digital multiplex platform. The occurrence of significant adverse outcomes (steroid use, flare-ups, hospitalization, colectomy) was evaluated over a 12-month follow-up period.

Results
Of 18 patients in endoscopic remission, 12 and 13 were in histological remission according to RHI and NHI, respectively. The ECS score correlated moderately with endoscopic score (r=0.57 for MES, r=0.44 for UCEIS and r=0.54 for PICaSSO) and strongly with histological scores (r=0.56 for RHI, r=0.61 for NHI and r=0.62 for PHRI), especially in the right colon. Only 5 patients experienced adverse outcomes. Notably, barrier healing, as indicated by an ECS score&lt;3 in the ileum and &lt;5 in the colon, was significantly associated with better outcomes. The three barrier proteins showed a distinct mucosal localisation in both ileum and colon, with higher cell density of Occludin and Claudin-2 in the epithelium, while higher JAM-A cell density in the lamina propria. The combined assessment of the intestinal barrier by ECS and Claudin-2 cell density significantly predicted outcomes in both colon and ileum (p=0.02 and p=0.04, respectively).

Conclusion
ECS combined with automated multispectral imaging analysis of intestinal barrier integrity is an innovative tool to assess barrier healing precisely and predicts significant adverse outcomes in PSC colitis patients in clinical, endoscopic, and histological remission.
P575 Kono-S anastomosis reduces post-op intervention after ileocolic resection for Crohn’s disease
Authors: Uchino T , Alipouriani A , Dominguez O H , Hull T L , Steele S R , Cohen B , Lipman J , Holubar S D 
Published: January 2024

Abstract

Background
Ileocolic resection and anastomosis is the most common intestinal operation for Crohn's disease (CD). However, the choice of anastomosis remains a topic of debate. The SUPRME CD randomized trial demonstrated decreased rates of surgical recurrence after Kono-S anastomosis (KSA). We aimed to compare the long-term recurrence-free survival between KSA and stapled side-to-side (SSTS) anastomosis in a retrospective cohort. We hypothesized that KSA was associated with a lower risk of postoperative recurrence requiring intervention than SSTS.

Methods
We included consecutive patients from a prospectively maintained database who underwent ileocolic anastomosis for terminal ileal CD between 2020 and 2022. Patients with other types of anastomoses were excluded. The short-term postoperative outcomes and interventions for perianastomotic recurrence were compared between the two groups.

Results
Overall, 174 patients underwent ileocolic anastomosis: KSA, 83 (47.7%) and SSTS, 91 (52.3%). In the KSA group, compared to SSTS, median BMI was lower (24.3 vs. 26.4 kg/m2, p=0.04), median operative time was longer (186 vs. 146 minutes, p&lt;0.001), and patients were more likely to have mesenteric excision (53% vs. 15.4%, p&lt;0.001). There were no significant differences in the short-term postoperative outcomes. After 12 months, 12 (30%) patients in the KSA group and 14 (35%) in the SSTS group developed endoscopic recurrence with a Rutgeerts score ≥i2 (p = 0.81). Compared with the SSTS group, the KS group received more postoperative biologics (65.1% vs. 39.6%, p=0.001) and more frequent medical therapy for perianastomotic recurrence [18/20, 90%] vs. [15/22, 68%]; p=0.14). On multivariable analysis, the KSA (OR 0.09, 95% CI 0.01-0.95, p=0.05) was associated with a lower risk of perianastomotic recurrence requiring surgical and endoscopic intervention.

Conclusion
We did not observe any statistically significant differences in overall recurrence-free survival between KSA and SSTS. However, the Kono-S anastomosis was independently associated with a decreased rate of endoscopic or surgical intervention for perianastomotic recurrence.
P938 Effectiveness and safety of switching from original infliximab to GP1111 biosimilar in inflammatory bowel diseases – prospective, cohort study
Authors: Resál T , Bacsur P , Pápista M , Kata D , Farkas B , Bálint A , Fábián A , Bor R , Szepes Z , Farkas K , Molnár T 
Published: January 2024

Abstract

Background
Biosimilars are highly similar to the already approved reference biological medication, and are potentially more accessible widespread due to the better cost-effectiveness. However, both the effectiveness and immunogenicity may differ due to structure characteristics. In 2020, non-medical switch was obligated from originator infliximab (IFX) to biosimilar GP1111 amongst inflammatory bowel disease (IBD, Crohns’s disease [CD], ulcerative colitis [UC]) patients in Hungary. As data regarding GP1111 are lacking in IBD, thus we aimed to assess the pharmacokinetics, effectiveness and safety of biosimilar GP1111 following the financial switch.

Methods
This was a real-world, prospective, single-center cohort study enrolling IBD patients who were switched from original IFX to GP1111 biosimilar. Baseline was defined as the day of the switch, and 52 weeks of follow-up was set. Demographic and clinical data were recorded at w0, w8, w16, w24, and w52, while infliximab serum levels were measured at baseline and at w52. Primary outcome was change in serum trough level of IFX, while sustained steroid-free remission, loss of response rates and adverse events were secondary outcomes.

Results
Overall, data of 142 patients were analyzed (median age: 43.1 years [IQR: 32.3 - 49.6]; male/female ratio: 77/65; CD: 97, UC: 42). Mean follow-up period was 46.2 ± 10.3 weeks. Change in serum IFX level was not observed (baseline 3.2 ± 2.3, µg/mL; w24: 3.7 ± 2.7 µg/mL; p = 0.106). Sustained steroid-free remission rates did not alter at w52 (99/142) from baseline (86/142) (p = 0.11). Overall, treatment was ceased in 24 patients. Following dose escalation and intensification, 9/18 patients discontinued treatment due to loss of response. Further treatments were ceased in 15 patients due to allergy (8), paradoxical reactions (3), malaise (1), pregnancy (1), and non-compliance (2). At w52 83.1% of the patients were on drug, and treatment persistence was not associated with the length of prior IFX treatment period.

Conclusion
Our study revealed convincing effectiveness with reassuring safety profile of switching to GP1111 in long-term, with sustained IFX levels. The usage of this particular biosimilar in daily practice may be suggested.