bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Effectiveness and Safety of Bedaquiline, Pretomanid, and Linezolid (BPaL)–Based Regimens for Rifampicin-Resistant Tuberculosis in Non-Trial Settings—A Prospective Cohort Study in Belarus and Uzbekistan
Authors: Sinha Animesh , Klebe Roland , Rekart Michael L , Alvarez Jose Luis , Skrahina Alena , Yatskevich Natalia , Solodovnikova Varvara , Viatushka Dzmitry , Parpieva Nargiza , Safaev Khasan , Liverko Irina , Tigay Zinaida , Moe Soe , Khristusev Aleksandr , Allamuratova Sholpan , Mirzabaev Sanjar , Achilov Muzaffar , Samieva Nazgul , Lachenal Nathalie , Merle Corinne Simone , Sall Fatimata Bintou , Restrepo Camilo Gomez , Tan Cecilio , Sitali Norman , Saunders Matthew J 
Published: January 2025

Abstract

Background
Only 63% of patients initiating multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB) treatment in 2020 were treated successfully. 24-Week all-oral bedaquiline, pretomanid, and linezolid (BPaL)–based regimens have demonstrated higher rates of treatment success and have been recommended by the World Health Organization. Operational research is urgently required to evaluate these regimens in non-trial settings.

Methods
This was a prospective cohort study of patients with microbiologically confirmed MDR/RR-TB and pre–extensively drug-resistant TB (pre-XDR-TB) initiated on BPaL-based regimens in Belarus and Uzbekistan (February 2022–June 2023). All clinical care and research procedures were delivered by treating physicians. After treatment completion, patients were followed up at 6 and 12 months, including collecting sputum to ascertain recurrence. The primary objective was to estimate the effectiveness (cured or treatment completed) and safety (the occurrence of serious adverse events) of BPaL-based regimens.

Results
A total of 677 patients initiated treatment with BPaL-based regimens during the study. We documented successful treatment outcomes in 95.3% (427/448) of patients with MDR/RR-TB treated with BPaL plus moxifloxacin and 90.4% (207/229) of patients with pre–XDR-TB treated with BPaL plus clofazimine. 10.2% (69/677) experienced serious adverse events including 24 deaths (3.5%), 11 of which occurred during treatment. 83.3% (20/24) of deaths were not related to TB or TB treatment. Of patients who were successfully treated and completed 12-month follow-up, 0.5% (2/383) had recurrence.

Conclusions
BPaL-based regimens for MDR/RR-TB and pre–XDR-TB are safe and highly effective in non-trial settings. These regimens should be considered for widespread implementation globally, and further research is needed to evaluate their performance in other key populations.
OP01 Systemic antibody responses predict the onset of Inflammatory Bowel Disease up to 10 years before diagnosis
Authors: Bourgonje A R , Innocenti G , Livanos A E , Prinzensteiner M , Magee J S , Riddle M S , Laird R M , Dervieux T , Porter C K , Gnjatic S , Petralia F , Torres J , Suarez-Fariñas M , Vogl T , Colombel J F , Mehandru S 
Published: January 2025

Abstract

Background
Identification of immune signatures in pre-clinical IBD provides a unique window of therapeutic intervention with disease-modifying potential. This study aimed to define the antigen specificities, breadth, longitudinal stability, and predictive ability of pre-clinical serum antibody repertoires using a novel, high-throughput phage-display immunoprecipitation sequencing assay (PhIP-Seq).

Methods
Longitudinal serum samples from active component US military personnel collected at diagnosis and at ~10, ~4, and ~2 years pre-Crohn’s disease (CD, n=200), pre-ulcerative colitis (UC, n=200) and in age- and sex-matched healthy controls (HC, n=100) were analysed (Fig. 1A-B). Serum antibody repertoires were defined against 357,000 microbial-, viral-, food-, and immune-associated peptide antigens (Fig. 1C). Conditional logistic regression analyses were performed to identify differentially abundant antibodies per timepoint. Temporal stability of antibodies was assessed using point-biserial correlations. Longitudinal sample analyses were performed using generalized linear mixed-effects models. Finally, machine learning models, including tree-based ensemble methods, were used for prediction of disease.

Results
Across 2,000 samples, 123,980 unique antibodies were identified (Fig. 1D). Antibody repertoire diversity was significantly lower in pre-CD (P&lt;0.05) and pre-UC (P&lt;0.001) sera compared to HC sera (Fig. 1E). Up to ~4 years pre-diagnosis, pre-CD samples exhibited more fluctuations in antibody repertoires compared to pre-UC and HC samples (both P&lt;0.001, Fig. 2A). Distinct antibody responses were evident up to 10 years pre-CD and pre-UC versus HCs (Fig. 2B-C). Pre-CD individuals demonstrated escalating trajectories of antibody responses against herpesviruses including Epstein-Barr virus (EBV), cytomegalovirus, and varicella zoster virus, and against a wide range of bacterial flagellins (Fig. 2D-E). Pre-UC individuals exhibited rising antibody responses against herpesviruses and autoantigens including MAP-kinase-activating death domain protein and reduced reactivity against encapsulated pathogens (e.g., Streptococcus pneumoniae- and Haemophilus influenzae) (Fig. 2F-G). Machine learning models identified antibody signatures highly predictive of CD (AUC=0.90) and UC (AUC=0.84) up to 10 years pre-diagnosis (Fig. 2H-K). Additionally, antibody repertoires differentiated complicated from non-complicated CD up to ~10 years pre-diagnosis with high accuracy (AUC=0.85).

Conclusion
Antibody profiling delineates a previously unappreciated landscape of serological responses against microbial and non-microbial antigens up to 10 years before disease onset in patients with CD and UC, allowing for novel insights on IBD pathogenesis and disease prediction.
OP02 Tasty & Healthy Flexible Diet Induces clinical and biological Remission in Children and Young Adults with Mild-Moderate Crohn's Disease similar to EEN: results from the "TASTI-MM" randomized, physician-blinded, controlled trial
Authors: Aharoni Frutkoff Y , Plotkin L , Shavit Z , Focht G , Livovsky J , Lev-Zion R , Ledder O , Assa A , Yogev D , Orlanski-Meyer E , Broide E , Kierkus J , Kang B , Weiss B , Aloi M , Schwerd T , Shouval D , Griffiths A , Turner D ,   T&H
Published: January 2025

Abstract

Background
Exclusive enteral nutrition (EEN) is effective for inducing remission in Crohn's disease (CD) but has adherence challenges. The CD-Exclusion Diet (CDED) is an effective alternative but requires partial enteral nutrition (PEN) with formula and mandatory ingredients. The Tasty&HealthyTM (T&H) diet excludes processed food, gluten, red meat, and dairy (except plain yogurt) without mandatory ingredients or PEN. This randomized controlled trial assessed the tolerability and effectiveness of the T&H diet compared to EEN in children and young adults with CD (NCT#04239248; TASTI-MM, T&H to Induce remission in Mild-Moderate CD).

Methods
Patients aged 6-25 years with mild-moderate CD were randomized to follow T&H or EEN for 8 weeks, receiving weekly dietary support. The caring physician was blinded to the allocation. Data on nutrition, clinical symptoms, and calprotectin were collected at baseline and bi-weekly. Tolerability was defined as discontinuation of the intervention or low adherence, judged by weekly interviews and 24-hour intake diary. Effectiveness outcomes included clinical remission (wPCDAI/CDAI), MINI index (&lt;8 points reflecting mucosal healing), CRP, ESR, and calprotectin. Those not tolerating either intervention during the first 24 hours were excluded; otherwise, figures reflect intention to treat (ITT) results, unless per-protocol (PP) analyses is specified.

Results
A total of 83 patients were included (41 to T&H and 42 to EEN; mean age 14.5±3.7 years). The primary endpoint was met with 36 (88%) patients tolerating T&H vs. 22 (52%) tolerating EEN (OR 6.3 (95%CI 2.2-22; p&lt;0.001). Clinical remission was achieved in 56% of the T&H arm and 38% of EEN (p=0.1; PP: 67% vs. 76%, respectively, p=0.47). MINI&lt;8 at week 8 was higher in the T&H arm (54% vs. 41%; p=0.026) while there was no difference in the PP analysis. Calprotectin decreased significantly from baseline in both arms, without a difference across groups at week-8 (calprotectin &lt;250 was noted in 38% with T&H vs 41% with EEN; p=0.84). Similarly, CRP and ESR decreased significantly in both groups (all p&lt;0.05), with no between-group differences in either the ITT or PP analyses. There were 3 adverse events reported in this trial with at least possible association with the intervention, all mild, 2 in the EEN arm (nausea and dizziness) and 1 in the T&H arm (constipation).

Conclusion
The T&H diet showed comparable effectiveness to EEN for inducing clinical and biological remission in mild-moderate CD but had better tolerability. T&H offers a flexible alternative without the need for PEN.
OP08 Histology-derived cell-cell interaction networks, linked to transcriptome profiling, define path to resolution in UC
Authors: Dylus D , Paun A , Mueller-Breckenridge A J , Christ A D , Scherl A , Leipner M 
Published: January 2025

Abstract

Background
Despite therapeutic advancements, the cellular and molecular heterogeneity of UC hinders effective treatment. We applied machine learning-based approaches to whole scanned images (WSI) of H&E stained slides prepared from formalin-fixed, paraffin embedded intestinal mucosal biopsies from the etrolizumab clinical trials, aiming to identify cellular interactions and molecular signatures that define disease subtypes and treatment responses. We hypothesised that the cellular-basis of non-response could be derived by linking cell-cell relationships with paired transcriptomic profiles.

Methods
We analysed 2297 WSI paired with molecular data from 1272 UC patients from the etrolizumab PhIII clinical trial including various cohorts, treatment arms, and timepoints. Sections were segmented using a convolutional neural network, extracting 8 cell types and their coordinates. For each WSI, ~500 interaction features from an overlaid network were engineered using our developed software, CellMaskProfiler. The topology of the cell-cell interaction networks allowed clustering of WSI with similar profiles. Cell count features and clinical data enabled the annotation of clusters. Paired molecular data was used to perform differential expression.

Results
Using the cell-cell topology, we identified 7 distinct UC subtypes characterised by specific cellular interactions, molecular profiles and clinical features resolving into, intact, and neutrophil, eosinophil, plasma, or lymphocyte dominated profiles. WSI with a high proportion of epithelial cells and more connections between epithelial cells types were strongly associated with lower Robarts Histology Index, indicating milder disease or intact epithelium, while strong interaction with neutrophils showed the opposite effect. Looking at different treatment arms allowed to relate baseline biopsy WSI characteristics with probability of treatment response highlighting the probability of response based on initial WSI subtype. Using the cellular topology allowed to characterise the transition between diseased and healthier clusters. Adjusting for cellularity effects and comparing baseline data for response at induction revealed genes characterising response. Looking at transitions between clusters revealed similar genes.

Conclusion
This study introduces a novel feature engineering approach to unravel the cellular and molecular complexity of WSI in UC. The findings underscore the significance of cellular interactions in UC pathology and provide new insights into the molecular mechanisms underlying different disease states and demonstrates that the structural topology (form) derived from WSI can be effectively linked to the transcriptomic profiles (function) to define probability of remission.
OP10 Efficacy and safety of subcutaneous guselkumab induction therapy in patients with Ulcerative Colitis: Results through week 12 from the phase 3 ASTRO study
Authors: Peyrin-Biroulet L , Allegretti J R , Danese S , Germinaro M , Baker T , Alvarez Y , Jörgens S , Jiang L , Zhang H , Hisamatsu T , Rubin D T , Long M 
Published: January 2025

Abstract

Background
Guselkumab (GUS) is a selective dual-acting IL-23p19 subunit inhibitor that potently blocks IL-23 and binds to CD64, a receptor on cells that produce IL-23. GUS demonstrated efficacy in patients (pts) with ulcerative colitis (UC) who received GUS intravenous (IV) induction and subcutaneous (SC) maintenance (QUASAR). We evaluated the efficacy and safety of GUS SC induction in ASTRO, a phase 3, randomised, double-blind, placebo (PBO)-controlled, parallel-group, multicenter trial in pts with moderately to severely active UC.

Methods
Eligible pts had a history of inadequate response or intolerance to corticosteroids, immunosuppressants, biologics, Janus kinase inhibitors, and/or sphingosine 1-phosphate inhibitors (BIO/JAKi/S1Pi-IR) or were BIO/JAKi/S1Pi naïve. Randomisation was stratified by baseline (BL) BIO/JAKi/S1Pi status and Mayo endoscopic subscore (MES) with 418 pts allocated 1:1:1 to GUS 400 mg SC q4w (x3)→GUS 200 mg SC q4w (N=140), GUS 400 mg SC q4w (x3)→GUS 100 mg SC q8w (N=139), or PBO (N=139). The primary endpoint was clinical remission (Mayo stool frequency subscore 0/1 not increased from BL, rectal bleeding subscore 0, MES 0/1 with no friability) at week (W) 12. Multiplicity-controlled W12 secondary endpoints are clinical response, symptomatic remission, endoscopic improvement, and histo-endoscopic mucosal improvement (HEMI). The prespecified analysis plan compared the combined GUS 400 mg SC treatment group to PBO at W12, and safety was assessed throughout.

Results
BL characteristics were similar across treatment groups (overall mean age, 41.7 years; mean UC duration, 7.6 years; mean modified Mayo score, 6.7; MES=3, 56.0%; BIO/JAKi/S1Pi-IR, 40.2%). The primary endpoint and all secondary endpoints were met. At W12, significantly greater proportions of pts treated with GUS 400 mg SC induction than PBO achieved clinical remission (27.6% vs 6.5%, respectively; adj Δ: 21.1%; P&lt;0.001), clinical response (65.6% vs 34.5%; adj Δ: 31.0%; P&lt;0.001), symptomatic remission (51.3% vs 20.9%; adj Δ: 30.4%; P&lt;0.001), endoscopic improvement (37.3% vs 12.9%; adj Δ: 24.3%; P&lt;0.001), and HEMI (30.5% vs 10.8%; adj Δ: 19.6%; P&lt;0.001). In prespecified analyses of subpopulations defined by prior BIO/JAKi/S1Pi history, greater proportions of GUS-treated versus PBO-treated pts achieved the endpoints (Figure). The proportions of GUS-treated pts with ≥1 adverse event (AE), serious AE, or AE leading to treatment discontinuation were not greater than PBO (Table).

Conclusion
ASTRO established the efficacy of GUS SC induction in UC, with no new safety concerns identified. These results build on the QUASAR IV induction data, demonstrating that both GUS IV and SC induction are highly efficacious in pts with moderately to severely active UC.
OP12 Therapeutic antibody clearance better predicts endoscopic outcomes than trough concentrations in patients with Crohn’s disease
Authors: Wang Z , Hoffert Y , Zhang W , Kantasiripitak W , Verstockt B , Sabino J , Ferrante M , Declerck P , D’Haens G , Laharie D , Vermeire S , Dreesen E 
Published: January 2025

Abstract

Background
Monitoring of monoclonal antibody (mAb) clearance has been suggested for prediction and follow-up of treatment outcomes in patients with inflammatory bowel diseases. We investigated clearance monitoring in patients with Crohn’s disease (CD) using data from clinical trials.

Methods
Data from patients with moderate-to-severe CD starting infliximab (n=108; TAILORIX trial [1]) and ustekinumab (n=80; a real-life cohort study [2]) therapy were repurposed. Endoscopic remission (CD Endoscopic Index of Severity &lt;3) was assessed at week (w)12 and w54 of infliximab therapy. Endoscopic response (≥50% reduction in Simple Endoscopic Score for CD) was assessed at w24 of ustekinumab therapy. We performed Bayesian forecasting to estimate time-varying mAb clearance using measured drug concentrations, covariates, and population pharmacokinetics models (NONMEM 7.5). A novel software tool for clearance monitoring of infliximab and ustekinumab was developed using the Shiny and mapbayr packages in R.

Results
Baseline demographics and clinical characteristics of the patients are summarized in Table 1.
Patients achieving endoscopic remission at w12 had significantly lower infliximab clearance and higher infliximab serum trough concentrations (Ctrough) at w2 and w6 of standard 5 mg/kg infliximab induction therapy, than patients without endoscopic remission (p&lt;0.05). During infliximab maintenance therapy (with eventual dose optimisations), patients achieving endoscopic remission at w54 had significantly lower infliximab clearance (p&lt;0.001) but not higher infliximab Ctrough (p=0.92) than patients without endoscopic remission. Moreover, infliximab clearance during maintenance had similar discriminative ability as faecal calprotectin (area under the receiver operating characteristics curve 0.63 [95% confidence interval 0.57–0.69] vs. 0.67 [0.61–0.73], respectively) (Figure 1).
Ustekinumab clearance (p&lt;0.05), but not Ctrough, was significantly different between endoscopic responders and non-responders during standard ustekinumab induction and maintenance therapy.
We developed an evidence-based interactive software tool that can predict the probability of achieving endoscopic outcomes in a clinical setting based on the estimated clearance of infliximab and ustekinumab (https://lpmx.shinyapps.io/clearance_monitoring/).

Conclusion
While Ctrough loses its ability to predict treatment response when doses are optimised or not administered by bodyweight, mAb clearance remains a reliable predictor. Our interactive clearance monitoring tool can forecast the chance of achieving endoscopic outcomes and distinguish between exposure-driven and mechanistic failure when patients with CD are dose-optimised.

References
[1]. D'Haens et al. Gastroenterology. 2018;154(5):1343-1351.e1.
[2]. Verstockt et al. J Crohns Colitis. 2019;25;13(7):864-872.
OP18 Multi-analytical Approaches Reveal Robust Gut Microbial Biomarkers for Inflammatory Bowel Disease Diagnosis: A Large-scale Cohort Study
Authors: Choi J W , Kim J E , Lee J Y , Yoo J H , Oh S J , Park S K , Park D I , Bae J W , Lee C K 
Published: January 2025

Abstract

Background
Inflammatory bowel disease (IBD), encompassing Crohn's disease (CD) and ulcerative colitis (UC), is strongly associated with gut microbiota dysbiosis. While numerous association studies have identified potential diagnostic gut microbial markers, their clinical utility remains limited due to substantial variability across studies and lack of robust validation. Furthermore, despite the availability of multiple analytical approaches for identifying microbial biomarkers, their relative effectiveness remains unclear, and definitive biomarkers for IBD diagnosis are still lacking. This study aims to identify robust gut microbial biomarkers for IBD diagnosis through multiple analytical approaches.

Methods
We analysed 3,762 participants, including healthy controls (HC, n = 2,467) and patients with IBD (n = 1,293), stratified into CD (n = 879) and UC (n = 414). Gut microbiota profiles were analysed from stool samples using 16S rRNA gene sequencing. Four analytical approaches were employed: (1) differential abundance analyses (DA: LEfSe, ANCOM-BC, and MaAsLin2), (2) supervised random forest machine learning (ML), (3) unsupervised network analysis (NW), and (4) literature-based curation (LC). Biomarker candidates generated by these methods were compared for diagnostic performance using an ensemble ML model.

Results
Diversity analysis revealed distinct gut microbial community structures among HC, UC, and CD groups (unweighted UniFrac distance, PERMANOVA, p &lt; 0.001, Fig. 1A). Dysbiosis scores, calculated based on these structural differences, were significantly higher in IBD groups compared to HC (Fig. 1B). Each analytical approach identified distinct microbial biomarkers associated with IBD and its subtypes. Supervised ML produced the most effective biomarker sets, achieving the highest diagnostic performance for distinguishing IBD from HC (AUC = 0.971), surpassing LC (AUC = 0.938), DA (AUC = 0.928), and NW (AUC = 0.912), Fig. 2. ML biomarker sets also demonstrated superior accuracy in distinguishing CD from HC (AUC = 0.933) and UC from CD (AUC = 0.892). These results highlight the superiority of ML in selecting robust biomarkers for IBD diagnostics across multiple classification tasks.

Conclusion
This study identifies robust gut microbial biomarkers for IBD diagnosis through multiple analytical approaches. The biomarker panel demonstrates high diagnostic accuracy in distinguishing both IBD from healthy controls and CD from UC. External validation of these findings is currently ongoing in an independent cohort. These findings provide a foundation for developing reliable microbiome-based diagnostic tools for IBD, potentially enabling more precise disease diagnosis and improved patient care.
OP32 Identifying clusters of antibiotic use patterns after the first episode of pouchitis in a population-based cohort
Authors: Barnes E , Karachalia Sandri A , Jess T 
Published: January 2025

Abstract

Background
An estimated 17% of patients will develop chronic pouchitis after ileal pouch-anal anastomosis (IPAA) for ulcerative colitis (UC), however little is known about antibiotic prescribing patterns in the immediate period after an initial episode of pouchitis and the risk factors for recurrent or chronic pouchitis. We evaluated antibiotic prescribing patterns in the 12 months after an initial episode of pouchitis and clinical factors associated with specific antibiotic prescription patterns.

Methods
We established a population-based cohort of all adult persons in Denmark undergoing proctocolectomy with IPAA for UC between January 1, 1996 and May 31, 2020. We identified the first episode of pouchitis in the 12 months after the final stage of IPAA surgery and then partitioned the year following an initial episode of pouchitis into 12 intervals of equal length. We assessed for at least one prescription for ciprofloxacin and/or metronidazole within each of those intervals. Sequence analysis was employed to identify the most representative sequences observed and, thereafter, the person-specific trajectories were grouped into clusters using optimal matching.1 Finally, multivariate logistic regression was used to investigate for any associations between the identified clusters and patient characteristics.

Results
Among 662 patients with an initial diagnosis of pouchitis, we identified 4 clusters of treatment sequences over the subsequent 12 months (Figure 1). Based on the timing of antibiotic prescriptions in a 12-month period after an initial episode of pouchitis, these 4 clusters correspond to clinical patterns seen in practice (rare intermittent pouchitis, intermittent pouchitis, chronic antibiotic-responsive pouchitis, and chronic antibiotic-dependent pouchitis). When analyzed in 2 categories (intermittent pouchitis and chronic pouchitis), patients with chronic pouchitis were more likely to have antibiotic exposure in the 12 months prior to the final stage of IPAA surgery (adjusted odds ratio [aOR] 1.62, 95% CI 1.10-2.38) and anti-TNF exposure prior to colectomy (aOR 2.05, 95% CI 1.41-2.99) when compared to patients with intermittent pouchitis (Table 1).

Conclusion
In a population-based cohort, we identified distinct antibiotic prescription patterns after an initial episode of pouchitis that align with diagnostic categories previously identified in clinical practice and recently published society guidelines. Antibiotic exposure prior to the final stage of IPAA increases the risk for chronic pouchitis and may indicate a high-risk phenotype in the immediate period after IPAA.

References
1. Studer, M., & Ritschard, G. (2016). What matters in differences between life trajectories: A comparative review of sequence dissimilarity measures. Journal of the Royal Statistical Society Series A: Statistics in Society, 179(2), 481-511.