bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of two wet exfoliation strategies on the yield and colloidal behavior of 2D hexagonal boron nitride nanosheets
Authors: Azme Anika , Escobar Isabel C , Tsyusko Olga , Aich Nirupam
Published: January 2025

We report the exfoliation process optimization, physicochemical characterizations, and comparative aggregation behavior of the inorganic 2D nanomaterial hexagonal Boron Nitride (h-BN) produced from two repetitive sonication-centrifugation processes with varying centrifugation speeds and recycle frequency: Continuous and Segmented protocols. Enhancing exfoliation efficiency and understanding aqueous stability are essential for sustainable design and environmental applications. Results showed that the Segmented protocol outperformed the Continuous protocol by having a six-fold increase in the exfoliated h-BN nanosheet yield by reusing the unexfoliated bulk h-BN and decreasing centrifugation speeds. Centrifugation speeds of 1880 and 950 rpm produced nanosheets of similar sizes due to the slight difference in the centrifugal force generated in both protocols. Moreover, nanosheets from both protocols had enhanced polarity due to the higher amounts of −OH bonds attached to the exposed edges of the nanosheets. However, the hydroxylation percentage of the nanosheets decreased with centrifugation speed. Both protocols produced h-BN nanosheets that were stable in DI water dispersion. The comparatively lower initial aggregation rate at all centrifugation speeds supported the fact that the Segmented protocol nanosheets were more stable than the Continuous ones. The Segmented protocol h-BN nanosheets showed better overall stability at lower speeds than the other centrifugation speeds. Segmented protocol nanosheets from 3750 rpm had the lowest aggregation rate than the other centrifugation speed. These findings assist in finding the balance between exfoliation protocol, environmental application, and implication of h-BN nanosheets.
Towards neuromorphic compression based neural sensing for next-generation wireless implantable brain machine interface
Authors: Mohan Vivek , Tay Wee Peng , Basu Arindam
Published: January 2025

This work introduces a neuromorphic compression based neural sensing architecture with address-event representation inspired readout protocol for massively parallel, next-gen wireless implantable brain machine interface (iBMI). The architectural trade-offs and implications of the proposed method are quantitatively analyzed in terms of compression ratio (CR) and spike information preservation. For the latter, we used metrics such as root-mean-square error and correlation coefficient (CC) between the original and recovered signals to assess the effect of neuromorphic compression on the spike shape. Furthermore, we use accuracy, sensitivity, and false detection rate to understand the effect of compression on downstream iBMI tasks, specifically, spike detection. We demonstrate that a data CR of 15–265 per channel can be achieved by transmitting address-event pulses for two different biological datasets. The CR further increases to 200–

50

K

per channel, 50 × more than in prior works, by the selective transmission of event pulses corresponding to neural spikes. A CC of ≈0.9 and spike detection accuracy of over 90% were obtained for the worst-case analysis involving

10

K

-channel simulated recording and typical analysis using 100 or 384-channel real neural recordings. We also analyzed the collision handling capability for up to 10K channels and observed no significant error, indicating the scalability of the proposed pipeline. We also present initial results to show the ability of intention decoders to work directly on the events generated by the neuromorphic front-end.
Ensemble modeling of the climate-energy nexus for renewable energy generation across multiple US states
Authors: Adul Joy , Kumar Rohini , Obringer Renee
Published: January 2025

The effects of climate change on renewable energy generation are of growing concern, as shifts in weather patterns and extreme events can significantly impact energy production. This study aims to leverage machine learning models to predict renewable energy generation based on the surrounding climate. We analyze data from four key states: California, New York, Florida, and Georgia, and focus on three critical renewable energy sources: hydroelectric, solar, and wind power. To determine the optimal model, we test six primary machine learning techniques, as well as an ensemble and a mean-only baseline. The results indicate that the ensemble approach improves the predictive accuracy of the model. Using this ensemble, we projected the changes to climate-sensitive portion of the renewable energy generation under climate change. Our results indicated that there was a wide variation of possible futures, depending on the state, source, and season. For example, the model projected a reduction in California’s monthly total renewable energy generation in the summer by 0.5%, or about 30 000 MWh, under SSP5-8.5, the worst-case scenario, but an increase of 0.5%, or about 25 000 MWh, in New York’s monthly total summer renewable energy generation under the same scenario. The modeling techniques detailed in this study can be applied across new regions, sources, or time periods. Ultimately, by understanding the influence of climate on renewable energy generation, we can improve the long-term planning process for the electricity grid, while building resilience and ensuring sustainable climate change mitigation and adaptation.
Submanifolds with boundary and Stokes’ Theorem in Heisenberg groups
Authors: Di Marco Marco , Julia Antoine , Nicolussi Golo Sebastiano , Vittone Davide
Published: January 2025

We introduce and study the notion of

C

H

1

C^1_\mathbb {H}

-regular submanifold with boundary in sub-Riemannian Heisenberg groups. As an application, we prove a version of Stokes’ Theorem for

C

H

1

C^1_\mathbb {H}

-regular submanifolds with boundary that takes into account Rumin’s complex of differential forms in Heisenberg groups.
Roles for the canonical polarity machinery in the de novo establishment of polarity in budding yeast spores
Authors: Cooperman  Benjamin , McMurray Michael
Published: January 2025

The yeast Saccharomyces cerevisiae buds at sites predetermined by cortical landmarks deposited during prior budding. During mating between haploid cells in the lab, external pheromone cues override the cortical landmarks to drive polarization and cell fusion. By contrast, in haploid gametes (called spores) produced by meiosis, a predetermined polarity site drives initial polarized morphogenesis independent of mating partner location. Spore membranes are made de novo so existing cortical landmarks were unknown, as were the mechanisms by which the spore polarity site is made and how it works. We find that the landmark canonically required for distal budding, Bud8, stably marks the spore polarity site along with Bud5, a GEF for the GTPase Rsr1 that canonically links cortical landmarks to the conserved Cdc42 polarity machinery. Cdc42 and other GTPase regulators arrive at the site during its biogenesis, after spore membrane closure but apparently at the site where membrane synthesis began, and then these factors leave, pointing to the presence of discrete phases of maturation. Filamentous actin may be required for initial establishment of the site, but thereafter Bud8 accumulates independent of actin filaments. These results suggest a distinct polarization mechanism that may provide insights into gamete polarization in other organisms.
The kinesin Kar3 is required for endoplasmic reticulum–associated degradation
Authors: Akoto Emmanuel , Doss Ellen M. , Claypool Kieran P. , Owutey Sophia L. , Richards Kyle A. , Lehman Katie M. , Daraghmi Mahmoud M. , Turk Samantha M. , Indovina Christopher J. , Avaala James A. , Evans Melissa D. , Scott Abigail R. , Schneider Hayden O. , Rogers Evan M. , True Jason D. , Smaldino Philip J. , Rubenstein Eric M.
Published: January 2025

Degradation of aberrant, excess, and regulatory proteins at the endoplasmic reticulum (ER) is a conserved feature of eukaryotic cells, disruption of which contributes to disease. While remarkable progress has been made in recent years, mechanisms and genetic requirements for ER-associated degradation (ERAD) remain incompletely understood. We recently conducted a screen for genes required for turnover of a model ER translocon-associated substrate of the Hrd1 ubiquitin ligase in Saccharomyces cerevisiae. This screen revealed loss of Kar3 impedes degradation of Deg1*-Sec62, which persistently and aberrantly engages the translocon. Kar3 is a microtubule-associated kinesin 14 family member that impacts multiple aspects of microtubule dynamics during cell division and karyogamy. We investigated involvement of Kar3 and its cofactors in ERAD. Loss of Kar3 hindered ERAD mediated by three ubiquitin ligases but did not impair turnover of a soluble nuclear protein. Further, KAR3 deletion caused hypersensitivity to conditions associated with proteotoxic stress. Kar3’s cytoplasmic cofactor Vik1 was also required for efficient degradation of Deg1*-Sec62. Our results reveal a profound and underappreciated role for microtubule-associated proteins in ERAD.
GRASP55 regulates sorting and maturation of the lysosomal enzyme β-hexosaminidase A
Authors: Akaaboune Sarah Reem , Javed Aadil , Bui Sarah , Wierenga Alissa , Wang Yanzhuang
Published: January 2025

The Golgi apparatus plays a crucial role in the delivery of lysosomal enzymes. Golgi reassembly stacking proteins, GRASP55 and GRASP65, are vital for maintaining Golgi structure and function. GRASP55 depletion results in the missorting and secretion of the lysosomal enzyme cathepsin D, though the mechanisms remain unclear. In this study, we conducted secretomic analyses of GRASP55 knockout cells and found a significant increase in lysosome-associated proteins in the extracellular medium. Using the lysosomal beta-hexosaminidase subunit alpha (HEXA) as a model, we found that GRASP55 depletion disrupted normal trafficking and processing of HEXA, resulting in increased secretion of the immature (pro-form) HEXA into the extracellular milieu, along with decreased levels of the mature form and enzymatic activity within the cell. GRASP55 depletion significantly reduced the complex formation between HEXA and mannose 6-phosphate (M6P) receptors (MPR), despite no overall change in MPR expression. Finally, we found there was a notable reduction in the expression of GNPTAB, leading to a reduction in M6P modification of HEXA, hindering its efficient targeting to lysosomes. These findings reveal the role of GRASP55 in regulating lysosomal enzyme dynamics, emphasizing its role in the sorting and trafficking of lysosomal proteins.
Combining experimental and observational data through a power likelihood
Authors: Lin Xi , Tarp Jens Magelund , Evans Robin J
Published: January 2025

Randomized controlled trials are the gold standard for causal inference and play a pivotal role in modern evidence-based medicine. However, the sample sizes they use are often too limited to provide adequate power for drawing causal conclusions. In contrast, observational data are becoming increasingly accessible in large volumes but can be subject to bias as a result of hidden confounding. Given these complementary features, we propose a power likelihood approach to augmenting randomized controlled trials with observational data to improve the efficiency of treatment effect estimation. We provide a data-adaptive procedure for maximizing the expected log predictive density (ELPD) to select the learning rate that best regulates the information from the observational data. We validate our method through a simulation study that shows increased power while maintaining an approximate nominal coverage rate. Finally, we apply our method in a real-world data fusion study augmenting the PIONEER 6 clinical trial with a US health claims dataset, demonstrating the effectiveness of our method and providing detailed guidance on how to address practical considerations in its application.
Causal relationships between hippocampal volumetric traits and the risk of Alzheimer’s disease: a Mendelian randomization study
Authors: Guo Lining , Chen Yayuan , Sun Zuhao , Zhao Jiaxuan , Yao Jia , Zhang Zhihui , Lei Minghuan , Zhai Ying , Xu Jinglei , Jiang Yurong , Wang Ying , Xue Hui , Liu Mengge , Liu Feng
Published: January 2025

Alzheimer’s disease, a common and progressive neurodegenerative disorder, is associated with alterations in hippocampal volume, as revealed by neuroimaging research. However, the causal links between the volumes of the hippocampus and its subfield structures with Alzheimer’s disease remain unknown. A genetic correlation analysis using linkage disequilibrium score regression was conducted to identify hippocampal volumetric traits linked to Alzheimer’s disease. Following this, to examine the causal links between Alzheimer’s disease and hippocampal volumetric traits, we applied a two-sample Mendelian randomization approach, utilizing a bidirectional framework. Seven hippocampal volumetric traits were found as genetically correlated with Alzheimer’s disease in the genetic correlation analysis and were then included in the Mendelian randomization analyses. Inverse variance weighted Mendelian randomization analyses revealed that increased volumes in the left whole hippocampus, left hippocampal body, right presubiculum head and right cornu ammonis 1 head were causally related to higher risks of Alzheimer’s disease. Conversely, a higher risk of Alzheimer’s disease was causally associated with decreased volumes of the left hippocampal body and left whole hippocampus. These results were validated through other Mendelian randomization approaches and sensitivity analysis. Our findings uncover bidirectional causal relationships between Alzheimer’s disease and hippocampal volumetric traits, suggesting not only the potential significance of these traits in predicting Alzheimer’s disease but also the reciprocal influence of Alzheimer’s disease on hippocampal volumes.
Safety design of the piston rod seal structure for submerged high-pressure liquid hydrogen pump
Authors: Zhang Feng , Li Xuan , Zhang Xin , Xiong Xue , Cui Xin , Cai Xingye , He Guangli
Published: January 2025

For the submerged high-pressure liquid hydrogen pump, a core piece of equipment of liquid hydrogen transportation, extensive analysis, and research were conducted on its components and structure during the development process. By referencing typical failure probabilities in the energy industry and statistical data from prototype pump development and testing, a list of failure probabilities for each part of the liquid hydrogen pump was compiled, and the consequences of those failures were deduced. The nitrogen liquid test experiment verified the possibility of pump seal failure and identified the fault modes. It confirmed that the piston rod seal is one of the critical components prone to failure in the liquid hydrogen pump. Subsequently, six important technical optimization measures for the piston rod seal pair have been carried out, reducing the probability of failure. Moreover, based on the concept of inherent safety, the sealing structure of the piston rod was innovatively designed, transforming hidden failures into visible ones, facilitating timely detection and monitoring of failures, and greatly reducing the safety risks caused by piston rod seal failure. The improved liquid hydrogen pump successfully passed subsequent tests, ensuring its long-term safe operation.
MDD-SSTNet: detecting major depressive disorder by exploring spectral-spatial-temporal information on resting-state electroencephalography data based on deep neural network
Authors: Chen Qiurong , Xia Min , Li Jinfei , Luo Yiqian , Wang Xiuzhu , Li Fali , Liang Yi , Zhang Yangsong
Published: January 2025

Major depressive disorder (MDD) is a psychiatric disorder characterized by persistent lethargy that can lead to suicide in severe cases. Hence, timely and accurate diagnosis and treatment are crucial. Previous neuroscience studies have demonstrated that major depressive disorder subjects exhibit topological brain network changes and different temporal electroencephalography (EEG) characteristics compared to healthy controls. Based on these phenomena, we proposed a novel model, termed as MDD-SSTNet, for detecting major depressive disorder by exploring spectral-spatial-temporal information from resting-state EEG with deep convolutional neural network. Firstly, MDD-SSTNet used the Sinc filter to obtain specific frequency band features from pre-processed EEG data. Secondly, two parallel branches were used to extract temporal and spatial features through convolution and other operations. Finally, the model was trained with a combined loss function of center loss and Binary Cross-Entropy Loss. Using leave-one-subject-out cross-validation on the HUSM dataset and MODMA dataset, the MDD-SSTNet model outperformed six baseline models, achieving average classification accuracies of 93.85% and 65.08%, respectively. These results indicate that MDD-SSTNet could effectively mine spatial-temporal difference information between major depressive disorder subjects and healthy control subjects, and it holds promise to provide an efficient approach for MDD detection with EEG data.
Amygdala-centered fusional connections characterized nonmotor symptoms in Parkinson’s disease
Authors: Zhang Yi , Li Sixiu , Yu Jiali , Li Rong , Liao Wei , Chen Qin , Xing Haoyang , Lu Fengmei , Hu Xiaofei , Chen Huafu , Gao Qing
Published: January 2025

The importance of nonmotor symptoms in understanding the pathogenesis of the heterogeneity of Parkinson’s disease has been highlighted. However, the validation of specific brain network biomarkers in nonmotor symptom subtypes is currently lacking. By performing a new approach to compute functional connectivity with structural prior using magnetic resonance imaging, the present study computed both functional connectivity and fusional connectivity features in the nonmotor symptom subtypes of Parkinson’s disease, one characterized by cognitive impairment with late onset and the other depression with early onset. The functional connectivity and fusional connectivity features centered at the left amygdala were both detected. The fusional features significantly enhanced the classification performance. The amygdala-postcentral and amygdala-orbital frontal features were critical for cognitive impairment with late onset detection, while the amygdala-temporooccipital features were crucial for depression with early onset detection. Additionally, the fusional connectivity features between the amygdala and the junction sulcus of parietooccipital and temporooccipital regions contributed significantly to differentiating cognitive impairment with late onset and depression with early onset. The within-subtype correlation analysis revealed that age at onset and cognitive scores were associated with features of amygdala-somatosensory/visual-motor processing areas in cognitive impairment with late onset, while related to features of amygdala-emotional processing areas in depression with early onset. Our findings highlighted distinct amygdala-centered fusional connectivity features related to diverse nonmotor symptoms in Parkinson’s disease, offering new insights for pathogenesis-targeted treatments for specific Parkinson’s disease subtypes.
A New Headspace Gas Chromatography Method for Determination of Ethylene Oxide and Dioxane in Polyethylene Glycols
Authors: Premaratne Gayan , McAdoo Andrew , Tian Jingzhi , Rustum Abu
Published: January 2025

In this paper, a new headspace gas chromatography (HSGC) method has been developed for the determination of ethylene oxide (EO) and 1,4-Dioxane (Dioxane) in bulk lots of polyethylene glycols (PEG). PEG samples are dissolved in dimethyl sulfoxide, heated in a headspace oven maintained at 90°C for 10 min and then injected into the GC system for analysis. Analytes are separated through a thermal gradient elution from 36 to 240°C on an Agilent DB-624 column (60 m × 0.53 mm diameter, film thickness 3.00 μm). The carrier gas is helium and detector is flame ionization detector. Total run time of the new HSGC method is about 18 min. In the new HSGC method, other common residual solvents present in PEGs such as methanol (MeOH), methyl formate (MF) and acetyl aldehyde (Acetal) are also sufficiently separated from EO and Dioxane peaks. In the HSGC methods prescribed in USP monograph <228> and EP monograph <2.4.25>, EO co-elutes with MF. The new HSGC method was successfully validated according to current ICH/VICH guidelines and was found to be specific, linear, accurate, precise, robust and sensitive. This HSGC method is fast and quality control (QC) friendly and suitable for routine analysis for the determination of EO and Dioxane in bulk batches of PEGs in QC laboratories.
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

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

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<0.05) and pre-UC (P<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<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

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 (<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<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<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 <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<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

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

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<0.001), clinical response (65.6% vs 34.5%; adj Δ: 31.0%; P<0.001), symptomatic remission (51.3% vs 20.9%; adj Δ: 30.4%; P<0.001), endoscopic improvement (37.3% vs 12.9%; adj Δ: 24.3%; P<0.001), and HEMI (30.5% vs 10.8%; adj Δ: 19.6%; P<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

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 <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<0.05). During infliximab maintenance therapy (with eventual dose optimisations), patients achieving endoscopic remission at w54 had significantly lower infliximab clearance (p<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<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

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 < 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

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.
OP34 Mirikizumab demonstrates rapid improvements in bowel urgency severity, bowel urgency frequency, and stool deferral time in patients with moderately-to-severely active Ulcerative Colitis: 12-week interim results from the phase 3b LUCENT-URGE trial
Authors: Danese S , Dignass A , Laharie D , Limdi J K , Kempinski R , Lewis J D , Younes Z , Cohen E , Alaka K , Eastman W J , Tian T , Kayhan C , Rubin D , Dubinsky M
Published: January 2025

Background

Bowel urgency (BU) is a common, under-recognized and debilitating symptom among patients with ulcerative colitis (UC). LUCENT-URGE is a Phase 3b, open-label, single-arm 28-week (W) study in adults with moderately-to-severely active UC and BU (Urgency Numeric Rating Scale [UNRS] ≥3) at baseline treated with mirikizumab (MIRI) (NCT05767021). BU was assessed using the validated UNRS1 and 2 new BU assessments: BU Frequency (BUF) and Stool Deferral Time (SDT). These 3 BU measures (UNRS, BUF, SDT) and clinical endpoints provide a more comprehensive understanding of BU and the impact of MIRI treatment. Here, we report W12 interim analysis results.

Methods

Patients were treated with intravenous (IV) MIRI 300 mg at W 0, 4 and 8, followed by 200 mg subcutaneous at W12 and every 4 weeks up to W28. The primary endpoint, BU severity (UNRS) at W12, was assessed by change from baseline. BUF improvement was assessed by change from baseline at W12. SDT was reported in minutes and categorized as (4) Severe: <1 min; (3) Moderate-Severe: 1-2 min: (2) Moderate: 2-5 min; (1) Mild: 5-15 min; (0) None: ≥15 minutes.

Results

172 patients were enrolled from 8 countries. At baseline, mean (± standard deviation [SD]) modified Mayo score [MMS]) was 6.8±1.3; 64% of patients had severe disease activity (MMS 7-9), mean duration of UC was 8.0±8.2 years, mean UNRS score was 6.9 ±1.6, mean BUF was 6.9±3.7. UNRS, BUF, and SDT improved from baseline to W12 (Figure 1). At W12, 63% patients achieved clinical response and 44% achieved both clinical response and UNRS clinically meaningful improvement (≥3 point decrease). Correlations between UNRS and BUF, and between UNRS and SDT at baseline, W12, and W12 change from baseline were of similar magnitude (Spearman correlation coefficient range: 0.43-0.68). The safety profile of MIRI observed in LUCENT-URGE was consistent with the profile previously reported.

Conclusion

In patients with moderately-to severely active UC and BU, MIRI demonstrated improvement in BU measures with a decrease by more than 50% in BUF after 12W of treatment. Selecting patients with urgency and targeting BU improvement is a novel strategy to assess response to therapy for UC. Broader associations between BU and quality of life, UC symptoms, histopathologic findings, and gene expression data will be explored upon completion of the W28 LUCENT-URGE study.

References

1.Dubinsky MC, Shan M, Delbecque L, et al. Psychometric evaluation of the Urgency NRS as a new patient-reported outcome measure for patients with ulcerative colitis. J Patient Rep Outcomes 2022; 6(1): 114.