bluuebunny/crossref_metadata_2025 huggingface dataset:
Enhancing quantum features and teleportation fidelity of two-mode non-Gaussian states using conditional measurements
Authors: Truong Minh Duc , Tran Quang Dat
Published: January 2024

The family of two-mode non-Gaussian entangled states, including the pair coherent states (PCSs) and their genealogies, has been extensively investigated regarding their quantum properties and their practical applications in quantum information. Specifically, certain states, such as the multiphoton catalytic pair coherent states (MCPCSs), have been newly introduced under specific experimental conditions. For a more feasible approach, in this paper, we introduce novel nonclassical states obtained by subtracting photons through conditional measurements using beam splitters applied to the two modes of the PCSs. These states are called pair coherent states with conditional measurements (PCSCMs). Our purpose is to demonstrate that the quantum features, such as entanglement, Einstein–Podolsky–Rosen (EPR) correlation, EPR steering, and the average fidelity in teleportation can be enhanced in comparison with both the original PCSs and the MCPCSs. In specific cases, several characteristics are observed in PCSCMs but not inspected in both PCSs and MCPCSs. In our findings, we prove that the quantum characteristics within the PCSCMs are influenced not just by the number of detected photons, denoted by variables k and l, but also by the discrepancy in photon numbers, especially by the difference of k − l.
From kesterite 2D nanosheets to wurtzite 1D nanorods: controllable synthesis of Cu−Zn−Sn−S and their application in electrocatalytic hydrogen evolution
Authors: Li Yu , Wang Shuaibing , Chen Jie , Lin Ouyang , Yin Zhe , Yang Chunhe , Tang Aiwei
Published: January 2024

As typical quarternary copper-based chalcogenides, Cu–Zn–Sn–S nanocrystals (CZTS NCs) have emerged as a new-fashioned electrocatalyst in hydrogen evolution reactions (HERs). Oleylamine (OM), a reducing surfactant and solvent, plays a significant role in the assisting synthesis of CZTS NCs due to the ligand effect. Herein, we adopted a facile one-pot colloidal method for achieving the structure evolution of CZTS NCs from 2D nanosheets to 1D nanorods assisted through the continuous addition of OM. During the process, the mechanism of OM-induced morphology evolution was further discussed. When merely adding pure 1-dodecanethiol (DDT) as the solvent, the CZTS nanosheets were obtained. As OM was gradually added to the reaction, the CZTS NCs began to grow along the sides of the nanosheets and gradually shrink at the top, followed by the formation of stable nanorods. In acidic electrolytic conditions, the CZTS NCs with 1.0 OM addition display the optimal HER activity with a low overpotential of 561 mV at 10 mA/cm2 and a small Tafel slope of 157.6 mV/dec compared with other CZTS samples. The enhancement of HER activity could be attributed to the contribution of the synergistic effect of the diverse crystal facets to the reaction.
Green synthesis of three-dimensional magnesium ferrite/titanium dioxide/reduced graphene from Garcinia mangostana extract for crystal violet photodegradation and antibacterial activity
Authors: Lin Tong Hoang , Cong Che Quang , Nam Nguyen Thanh Hoai , An Hoang , Hai Nguyen Duy , Buu Ton That , Binh Thoi Le Nhat , Minh Hoang Le , Ngan Lam Thanh , Ngan Hoang Thuy Kim , Vi Du Chi , Khoa Ta Dang , Hieu Nguyen Huu
Published: January 2024

In this study, three-dimensional porous magnesium ferrite/titanium dioxide/reduced graphene oxide (MgFe2O4-GM/TiO2/rGO (MGTG)) was successfully synthesized via green and hydrothermal-supported co-precipitation methods using the extract of Garcinia mangostana (G. mangostana) as a reducing agent. The characterization results indicate the successful formation of the nano/micro MgFe2O4 (MFO) and TiO2 on the structure of the reduced graphene oxide (rGO), which can also act as efficient support, alleviating the agglomeration of the nano/micro MFO and TiO2. The synergic effects of the adsorption and photodegradation activity of the material were investigated according to the removal of crystal violet (CV) under ultraviolet light. The effects of catalyst dosage, CV concentration, and pH on the CV removal efficiency of the MGTG were also investigated. According to the results, the CV photodegradation of the MGTG-200 corresponded to the pseudo-first-order kinetic model. The reusability of the material after 10 cycles also showed a removal efficiency of 92%. This happened because the materials can easily be recollected using external magnets. In addition, according to the effects of different free radicals ·O2
−, h+, and ·OH on the photodegradation process, the photocatalysis mechanism of the MGTG was also thoroughly suggested. The antibacterial efficiency of the MGTG was also evaluated according to the inhibition of the Gram-positive bacteria strain Staphylococcus aureus (S. aureus). Concurrently, the antibacterial mechanism of the fabricated material was also proposed. These results confirm that the prepared material can be potentially employed in a wide range of applications, including wastewater treatment and antibacterial activity.
Assessing the effective settling of mineral particles in the ocean with application to ocean-based carbon-dioxide removal
Authors: Yang Adam J K , Timmermans Mary-Louise
Published: January 2024

Ocean alkalinity enhancement (OAE), a potential approach for atmospheric carbon dioxide removal (CDR), can involve introducing milled mineral particles into the ocean to promote carbon dioxide uptake. The effectiveness of this method relies on particles remaining in the ocean mixed layer while dissolution takes place, which depends on particle settling rates. Conventionally, particle settling rates are assessed using the Stokes settling velocity in stagnant conditions. However, recent numerical modeling reveals that in dynamic, stratified ocean environments, sediment vertical transport can be up to an order of magnitude faster than Stokes settling because of two types of fluid instabilities that can take place at the mixed layer base. Here, we estimate effective settling velocities in the presence of these instabilities and assess the implications for the efficacy of this particular OAE approach for CDR. The new effective settling rate estimates are sufficiently rapid that there is negligible particle dissolution before particles settle out of the mixed layer. This result is independent of initial particle size for the range of sizes considered here. Findings underscore the importance of considering ocean dynamics and stratification in assessing particle settling rates and provide valuable insights for optimizing OAE applications in diverse marine settings.
The spindle index from localization
Authors: Inglese Matteo , Martelli Dario , Pittelli Antonio
Published: January 2024

We present a new supersymmetric index for three-dimensional

N

=
2

gauge theories defined on

Σ

×

S
1

, where

Σ

is a spindle, with twist or anti-twist for the R-symmetry background gauge field. We start examining general supersymmetric backgrounds of Euclidean new minimal supergravity admitting two Killing spinors of opposite R-charges. We then focus on

Σ

×

S
1

and demostrate how to realise twist and anti-twist. We compute the supersymmetric partition functions on such backgrounds via localization and show that these are captured by a general formula, depending on the type of twist, which unifies and generalises the superconformal and topologically twisted indices.
Cancer-mediated axonal guidance of sensory neurons in a microelectrode-based innervation MPS
Authors: van der Moolen Matthijs , Lovera Andrea , Ersoy Fulya , Mommo Sacha , Loskill Peter , Cesare Paolo
Published: January 2024

Despite recent advances in the field of microphysiological systems (MPSs), availability of models capable of mimicking the interactions between the nervous system and innervated tissues is still limited. This represents a significant challenge in identifying the underlying processes of various pathological conditions, including neuropathic, cardiovascular and metabolic disorders. In this novel study, we introduce a compartmentalized three-dimensional (3D) coculture system that enables physiologically relevant tissue innervation while recording neuronal excitability. By integrating custom microelectrode arrays into tailored glass chips microfabricated via selective laser-etching, we developed an entirely novel class of innervation MPSs (INV-MPS). This INV-MPS allows for manipulation, visualization, and electrophysiological analysis of individual axons innervating complex 3D tissues. Here, we focused on sensory innervation of 3D tumor tissue as a model case study since cancer-induced pain represents a major unmet medical need. The system was compared with existing nociception models and successfully replicated axonal chemoattraction mediated by nerve growth factor (NGF). Remarkably, in the absence of NGF, 3D cancer spheroids cocultured in the adjacent compartment induced sensory neurons to consistently cross the separating barrier and establish fine innervation. Moreover, we observed that crossing sensory fibers could be chemically excited by distal application of known pain-inducing agonists only when cocultured with cancer cells. To our knowledge, this is the first system showcasing morphological and electrophysiological analysis of 3D-innervated tumor tissue in vitro, paving the way for a plethora of studies into innervation-related diseases and improving our understanding of underlying pathophysiology.
Fast generation of spin squeezing via resonant spin-boson coupling
Authors: Barberena Diego , Muleady Sean R , Bollinger John J , Lewis-Swan Robert J , Rey Ana Maria
Published: January 2024

We propose protocols for the creation of useful entangled states in a system of spins collectively coupled to a bosonic mode, directly applicable to trapped-ion and cavity QED setups. The protocols use coherent manipulations of the resonant spin-boson interactions naturally arising in these systems to prepare spin squeezed states exponentially fast in time. The resonance condition harnesses the full spin-boson coupling and thus avoids the slower timescales when operating in the off-resonance regime. We demonstrate the robustness of the protocols by analyzing the effects of natural sources of decoherence in these systems and show their advantage compared to more standard slower approaches where entanglement is generated with off-resonant spin-boson interactions.
Theoretical, numerical, and experimental investigation on second-order Bezier curve flexure hinges
Authors: Wang Qiliang , Hong Yongfeng , Xu Meijuan , Xia Shitian , Li Yongqi , Liu Tong
Published: January 2024

This paper proposes the second-order Bezier curve flexure hinge. The flexure hinge can obtain different notch profiles by changing the position of the control points. Firstly, the compliance and precision of the flexure hinge are modeled based on the force deformation formula of the cantilever beam in material mechanics. Compared with the simulation data of ANSYS Workbench, the modeling error is less than 7%. Secondly, the influence of geometric parameters on compliance and precision is analyzed. The flexure hinge is compared with circular, elliptical, and parabolic hinges. The results show that the second-order Bezier curve flexure hinges have a higher compliance precision ratio. In addition, the use of second-order Bezier curve flexure hinges provides better performance than the use of traditional circular and elliptical flexure hinges in bridge amplification mechanisms. Finally, a flexure hinge was manufactured and measured. The experimental results show that the error between the experimental and modeling values is 8.76%. Both the simulation and experimental results verified the effectiveness of the model.
Risk of bleeding with concomitant use of oral anticoagulants and aspirin: A systematic review and meta-analysis
Authors: Ghule Priyanka , Panic Jennifer , Malone Daniel C
Published: January 2024

Purpose

Oral anticoagulants (OACs) and aspirin can trigger bleeding events when used alone or in combination. The purpose of this study was to compare the risk of any type of bleeding in individuals exposed to a combination of OAC and aspirin with the risk in those taking an OAC or aspirin alone.

Methods

MEDLINE and Web of Science were queried in January 2021 for eligible articles. Studies were included if they were either randomized controlled trials (RCTs) or observational studies and evaluated the number of any bleeding events in two groups, one with exposure to both OAC and aspirin and one with exposure to OAC alone or aspirin alone. Pooled odds ratios were calculated using a random-effects model.

Results

Forty-two studies were included. In an analysis of 15 RCTs and 19 observational studies evaluating OAC plus aspirin versus OAC alone, a significant difference in the risk of bleeding was observed in the combination groups, with an odds ratio [OR] of, 1.36 (95% CI, 1.15-1.59) for RCTs and an OR of 1.42 (95% CI-, 1.09-1.87) for observational studies. When OAC plus aspirin was compared to aspirin alone, a higher rate of bleeding was found in the combination group (OR, 2.36; 95%CI, 1.91-2.92) in the analysis of 15 RCTs, but no significant difference was found among 10 observational studies (OR, 1.93; 95% Cl, 0.99-3.75).

Conclusion

The risk of any type of bleeding was significantly increased among patients taking aspirin plus OAC compared to those taking OAC alone in both RCTs and observational studies. Evaluation of RCTs comparing OAC plus aspirin to aspirin alone suggests increased bleeding risk as well.
Text mining for contexts and relationships in cancer genomics literature
Authors: Collins Charlotte , Baker Simon , Brown Jason , Zheng Huiyuan , Chan Adelyne , Stenius Ulla , Narita Masashi , Korhonen Anna
Published: January 2024

Motivation

Scientific advances build on the findings of existing research. The 2001 publication of the human genome has led to the production of huge volumes of literature exploring the context-specific functions and interactions of genes. Technology is needed to perform large-scale text mining of research papers to extract the reported actions of genes in specific experimental contexts and cell states, such as cancer, thereby facilitating the design of new therapeutic strategies.

Results

We present a new corpus and Text Mining methodology that can accurately identify and extract the most important details of cancer genomics experiments from biomedical texts. We build a Named Entity Recognition model that accurately extracts relevant experiment details from PubMed abstract text, and a second model that identifies the relationships between them. This system outperforms earlier models and enables the analysis of gene function in diverse and dynamically evolving experimental contexts.

Availability and implementation

Code and data are available here: https://github.com/cambridgeltl/functional-genomics-ie.
Sixty-four-fold data reduction of chest radiographs using a super-resolution convolutional neural network
Authors: Nam Ju Gang , Kang Seung Kwan , Choi Hyewon , Hong Wonju , Park Jongsoo , Goo Jin Mo , Lee Jae Sung , Park Chang Min
Published: January 2024

Objectives

To develop and validate a super-resolution (SR) algorithm generating clinically feasible chest radiographs from 64-fold reduced data.

Methods

An SR convolutional neural network was trained to produce original-resolution images (output) from 64-fold reduced images (input) using 128 × 128 patches (n = 127 030). For validation, 112 radiographs—including those with pneumothorax (n = 17), nodules (n = 20), consolidations (n = 18), and ground-glass opacity (GGO; n = 16)—were collected. Three image sets were prepared: the original images and those reconstructed using SR and conventional linear interpolation (LI) using 64-fold reduced data. The mean-squared error (MSE) was calculated to measure similarity between the reconstructed and original images, and image noise was quantified. Three thoracic radiologists evaluated the quality of each image and decided whether any abnormalities were present.

Results

The SR-images were more similar to the original images than the LI-reconstructed images (MSE: 9269 ± 1015 vs. 9429 ± 1057; P = .02). The SR-images showed lower measured noise and scored better noise level by three radiologists than both original and LI-reconstructed images (Ps < .01). The radiologists’ pooled sensitivity with the SR-reconstructed images was not significantly different compared with the original images for detecting pneumothorax (SR vs. original, 90.2% [46/51] vs. 96.1% [49/51]; P = .19), nodule (90.0% [54/60] vs. 85.0% [51/60]; P = .26), consolidation (100% [54/54] vs. 96.3% [52/54]; P = .50), and GGO (91.7% [44/48] vs. 95.8% [46/48]; P = .69).

Conclusions

SR-reconstructed chest radiographs using 64-fold reduced data showed a lower noise level than the original images, with equivalent sensitivity for detecting major abnormalities.

Advances in knowledge

This is the first study applying super-resolution in data reduction of chest radiographs.
OP38 Should all patients with newly diagnosed inflammatory bowel diseases be screened for metabolic bone disease? Results from a Danish population-based inception cohort study
Authors: Attauabi M , Roager Madsen G , Bendtsen F , Seidelin J , Burisch J
Published: January 2024

Background

Inflammatory bowel diseases (IBD), encompassing ulcerative colitis (UC) and Crohn’s disease (CD), are associated with an increased risk of metabolic bone diseases (MBD). The aim of the current study was to evaluate for the occurrence of MBD in which all patients with newly diagnosed IBD are offered a Dual-energy X-ray absorptiometry (DXA) scan. Secondly, we aimed to identify risk factors for development of MBD.

Methods

All adult patients with newly diagnosed IBD within a catchment area corresponding to ~20% of the Danish population have since May 2021 been enrolled in an ongoing prospective population-based inception cohort, IBD Prognosis Study. Herein, all participants were, as part of the initial work-up, invited to a DXA scan at IBD diagnosis. A T-score< −2.5 standard deviations (SD) was diagnostic for osteoporosis, while a T-score between –1 and –2.5 defined osteopenia. Multivariate analyses adjusted findings for age, gender, and medication differences.

Results

A total of 316 patients with newly diagnosed IBD (UC: 178, CD: 117, unclassified IBD (IBDU): 21) received a DXA scan within 90 days (interquartile range (IQR) 51-139 days). Baseline characteristics of the population were similar to those previously described for newly diagnosed IBD.

In total, 48 (27%, females (F): 26%, males (M): 28%) and 17 (10%, F: 14%, M: 5%) patients with UC were found to have osteopenia and osteoporosis, resp. The corresponding numbers for CD were 23 (20%, F: 15%, M: 24%) and nine (8%, F: 7%, M: 9%).

Subgroup analysis showed a high occurrence of osteopenia in both UC and CD regardless of age group (Table 1). No difference between UC and CD was observed in terms of the risk of osteopenia (adjusted odds ratio (aOR)=1.86 (95% confidence interval (CI) 0.99-3.60) or osteoporosis (OR=1.42 (95% CI 0.53-4.08)).

Low albumin level (<36 g/L) was the only factor associated with osteopenia in patients with UC (aOR=2.57 (95% CI 1.05-6.53). In patients with CD, no risk factors were identified. However, the risk of osteoporosis was independently associated with age higher than 65 years in both UC (aOR=13.4 (95% CI 3.78-51.36)) and CD (aOR=6.39 (95% CI 1.09-35.47)), while female gender was not relevant (UC: aOR=2.63 (95% CI 0.75-10.98), CD: (aOR=0.47 (95% CI 0.08-2.20)).

Finally, the risk of MBD was not associated with IBD phenotype, medications, or patient-reported or endoscopic severity.

Conclusion

To our knowledge, the current study is the first evaluation of DXA scans as a screening tool for patients with newly diagnosed IBD in a population-based setting. We found a high incidence of osteopenia affecting every fourth patient at IBD diagnosis. These findings are concerning given the high risk of repeated need for systemic steroids in this patient population.
DOP01 Definitions of histological abnormalities in inflammatory bowel disease: an ECCO position paper
Authors: Rosini F , Feakins R M , Borralho Nunes P , Driessen A , Gordon I O , Zidar N , Baldin P , Christensen B , Danese S , Herlihy N , Iacucci M , Loughrey M B , Magro F , Mookhoek A , Svrcek M
Published: January 2024

Background

High quality histological examination of ileocolonic biopsies in inflammatory bowel disease (IBD) plays a critical role in optimising clinical management, investigative studies, and clinical trials. The correct assessment of histological features can confirm the diagnosis of IBD, assist with its subclassification (as ulcerative colitis or Crohn’s disease), facilitate the estimation of disease activity and disease extent, and aid the detection of mimics and complication.

However, there are surprisingly few universal definitions of each histological abnormalities and the existing definitions are often inconsistent. The main practical concern is that histological scoring schemes, or guidelines on histological diagnosis, include detailed features, and many of these features have, paradoxically, no, or vague definitions. Furthermore, interobserver variability for many histological features in IBD is significantly high, possibly reflecting lack of precision.

The aim of this paper is to review and assess any existing histologcal definitions and criteria, selecting the most appropriate where possible, and modifying them or writing new definitions where necessary.

Methods

The European Crohn's and Colitis Organisation (ECCO) and the project leaders formed a panel of experts in the IBD field, composed of pathologists and gastroenterologists to explore inconsistencies in the definitions of histological abnormalities using the best resources and evidence available. The panel examined existing definitions, peer reviews publications, scoring schemes, guidelines and textbooks. An important contribution was also given by their professional experience and knowledge.

Results

The literature review process confirmed that most current existing definitions often have no evidence base and vary between sources.

The panel of experts developed 40 statements on histological definitions in IBD with accompanying supporting text for each statement.

Conclusion

The statements represent expert consensus with the support of evidence where available. Further possible development of this process will include attempts to grade histological changes, aiming to improve the consistency of pathological diagnosis, a reduction in currently high rates of interobserver variability, more precision in clinical trial work and research, and to facilitate development of new guidelines and scoring schemes for IBD.
DOP16 Safety of long-term ozanimod treatment for up to 4 years in patients with moderately to severely active Ulcerative Colitis: an interim analysis of the True North open-label extension
Authors: Siegel C , Danese S , Rubin D T , Sabino J , Long M D , Cross R K , Armuzzi A , Blumenstein I , Kobayashi T , Lama S , Charles L , Cetin V , Petersen A , Wu H , Wang D , Jain A , D'Haens G
Published: January 2024

Background

The 52-week, phase 3 True North (TN) study (NCT02435992) demonstrated the efficacy and safety of ozanimod (OZA), a highly selective sphingosine 1-phosphate receptor 1 and 5 modulator, in patients (pts) with moderately to severely active ulcerative colitis (UC). A prior analysis reported the long-term safety of up to 3 y of OZA in the ongoing TN open-label extension (OLE; NCT02531126; from TN baseline to OLE Week [W] 94). This analysis presents the cumulative long-term safety of OZA in TN and the TN OLE for an additional year (up to OLE W142).

Methods

The TN study design has been previously described. This analysis included all TN pts who entered the OLE from TN (clinical nonresponders at W10, lost response during maintenance, or completed maintenance at W52). Safety assessments were reported from the first dose of OZA either in TN or OLE up to OLE W142. Lab abnormalities, including absolute lymphocyte count (ALC) reductions, were reported. Exposure-adjusted incidence rates (EAIRs) per 100 patient-years (PY) were calculated for all treatment-emergent adverse events (TEAEs).

Results

A total of 823 pts entered the TN OLE (average age: 41.7 y; 59% male); 62% had left-sided UC disease. Total PY exposure to OZA at OLE W142 was 2536 y. Overall, the cumulative safety assessments did not significantly change with an additional year of OZA exposure from OLE W94 to W142 (Table). A decrease in EAIRs per 100 PY was observed in overall TEAEs (85.5 vs 87.6) and serious TEAEs (7.0 vs 7.4) at OLE W142 vs OLE W94, respectively. Notably, with an additional year of OZA exposure, TEAEs leading to treatment discontinuation remained at 2.5 EAIR/100 PY, and there were no new cases of bradycardia or atrioventricular block. One new TEAE each of herpes zoster, macular oedema, cystoid macular oedema, myocardial ischaemia, pulmonary embolism, and deep vein thrombosis were noted. COVID-19 TEAEs increased at OLE W142 (n=103; EAIR: 4.3/100 PY) from OLE W94 (n=66; EAIR: 3.0/100 PY). Reductions in ALC <500 cells/mm3 were common in the OLE (OLE W94, 54.0%; OLE W142, 56.1%); few pts had ALC <200 cells/mm3 (OLE W94, 5.3%; OLE W142, 6.5%), but these pts had no serious infections. No serious hepatic safety events were observed. One new death due to adenocarcinoma, which was unrelated to OZA, was reported.

Conclusion

The ongoing safety profile of OZA is consistent with previous analyses, with no new safety signals identified compared with previous UC analyses. Long-term use of OZA representing 2536 PYs of exposure continues to be well tolerated in pts with moderately to severely active UC.
DOP18 Efficacy of risankizumab versus ustekinumab by baseline Crohn’s Disease location: post-hoc analysis of the SEQUENCE head-to-head trial
Authors: Peyrin-Biroulet L , Colombel J F , D’Haens G , Dubinsky M , Cao Q , Kligys K , Garrison A , Huang X , Neimark E , Anschutz T , Crowley J , Panaccione R
Published: January 2024

Background

In Crohn’s disease (CD), disease location may impact treatment effect. This post-hoc analysis of the SEQUENCE head-to-head trial (NCT04524611) compared the efficacy of risankizumab (RZB), an interleukin (IL)-23 p19 inhibitor, versus ustekinumab (UST), an IL-12/23 p40 inhibitor, by CD location.

Methods

SEQUENCE was an open-label, efficacy assessment-blinded, randomized controlled trial, which enrolled patients (pts) with moderate to severe CD who previously failed ≥1 anti-tumor necrosis factor (TNF) therapy. Pts included in the primary efficacy analysis were randomised 1:1 to receive RZB (selected dosing: intravenous 600 mg induction dose administered at weeks (wks) 0, 4, and 8, followed by subcutaneous 360 mg maintenance dose every 8 wks starting at wk 12) or UST (a single weight-based induction dose administered at wk 0, followed by subcutaneous 90 mg maintenance dose every 8 wks starting at wk 8. A mandatory steroid taper began at wk 2. The primary endpoints were clinical remission (CD Activity Index <150) at wk 24 and endoscopic remission (Simple Endoscopic Score for CD ≤4 and at least a 2-point reduction versus baseline and no subscore >1 in any individual variable, as scored by a central reviewer blinded to treatment allocation) at wk 48. In this post-hoc analysis, both endpoints were evaluated in 100% of pts included in the primary efficacy analysis, stratified by baseline CD location subgroups (ileal only, colonic only, ileal-colonic). Nominal P-values were reported for treatment differences within subgroups.

Results

At baseline, majority of pts had either ileal-colonic (225 [43.3%]) or colonic (208 [40%]) CD; 87 (16.7%) pts had isolated ileal disease. At wk 24, numerically greater proportions of pts achieved clinical remission with RZB versus UST, regardless of disease location (treatment difference [95% confidence interval], P-value: ileal only, Δ0.8 [-20.1, 21.7], P=0.941; colonic only, Δ22.4 [9.2, 35.5], P=0.001; ileal-colonic, Δ18.2 [5.3, 31.0], P=0.007) (Figure). Pts randomized to RZB with colonic only disease had numerically higher rates of clinical remission relative to pts with ileal only or ileo-colonic disease. At wk 48, RZB-treated pts demonstrated numerically higher rates of endoscopic remission than UST-treated pts (ileal only, Δ22.5 [4.4, 40.6], P=0.017; colonic only, Δ18.3 [6.6, 30.0], P=0.003; ileal-colonic, Δ10.3 [-0.2, 20.9], P=0.057) (Figure). Endoscopic remission rates in the RZB-treated pts were generally similar between ileal only and colonic only CD.

Conclusion

In pts who have failed ≥1 anti-TNF therapy, RZB demonstrated greater rates of endoscopic remission compared to UST regardless of CD location, and greater rates of clinical remission in ileo-colonic and colonic CD.
DOP44 Melatonin Ameliorates Colitis In DSS-fed Mice Via The SIRT1 Pathway
Authors: Lin B , Mao Q , Zhang W , Zhang Y , Cao Q , Xu M
Published: January 2024

Background

Melatonin is an amine hormone with high content in gastrointestinal tract, which plays a positive role in anti-inflammatory. Intestinal microbiota imbalance and intestinal immune damage caused by colitis are often accompanied by a decrease in endogenous melatonin. However, whether melatonin supplementation improves colitis, and the mechanism is unclear.

Methods

The study focused on melatonin treatment of colitis in dextran sodium sulfate(DSS)-fed mice and analyzed the mechanism multidimensionally by quantitative real-time PCR, western blotting, immunofluorescence, 16s-rDNA, and mRNA-seq.

Results

The weight, colon length, and microscopic structure of the colonic crypts were improved in DSS-fed mice after melatonin supplementation. Tumor necrosis factor-α(TNF-α), interleukin-1β(IL-1β), and IL-6 were significantly elevated in colon tissues of the DSS group, and this result was down-regulated in the melatonin group. Tight junction proteins(ZO-1 and occludin) in the colonic mucosa were significantly decreased in the DSS group, and improved in the melatonin group. In terms of antimicrobial peptides, melatonin supplementation significantly increased levels of defa-3, defa-4, and CRAMP. Surprisingly, our study found increased expression of SIRT1 protein in the intestinal tissues of the melatonin group. After the addition of Ex-527, a SIRT1 inhibitor, the protective effect of melatonin on DDS-fed mice disappeared, and tight junction proteins did not differ from those of the DSS group. In addition, fecal 16s-rRNA results in the control, DSS, and melatonin groups suggested some differences. The DSS group had an increase in α-diversity (Shannon's Diversity Index) and a decrease in β-diversity (PCoA) in comparison to the control group, and all of these changes were reversed in the melatonin group, but there was no significance between the three groups. At the phylum level, Firmicutes were significantly increased in the DSS-fed group, and the melatonin group reversed this change. At the genus level, the abundance of Akkermansia was decreased in the DSS group and increased with melatonin supplementation. While the abundance of Desulfovibrio, a pathogenic genus was increased in the DSS group and decreased with melatonin supplementation. Colon tissue mRNA-seq identified a number of possible pathogenic and therapeutic pathways, such as Slc7a2, a cationic amino acid transporter.

Conclusion

The study suggests that melatonin modulates the intestinal mucosal barrier through the SIRT1 pathway to alleviate colitis.
DOP47 Characterisation of endoscopic improvement in Crohn’s Disease with upadacitinib treatment
Authors: Panaccione R , Melmed G Y , Khanna R , D’Haens G , Danese S , Ford S , Anyanwu S I , Garrison A , Lacerda A P , Vermeire S
Published: January 2024

Background

Upadacitinib (UPA), an oral Janus kinase inhibitor approved for the treatment of moderately to severely active Crohn’s disease (CD), demonstrated significantly higher rates of endoscopic response and remission compared with placebo (PBO) in the phase 3 induction (U-EXCEL, U-EXCEED) and maintenance (U-ENDURE) trials.1 Improvements in the narrowing component of BL stenoses with UPA have been previously reported.2 This analysis evaluated changes in the individual components of the Simple Endoscopic Score for CD (SES-CD) among patients treated with UPA vs PBO.

Methods

Data were pooled from the two induction phase 3 studies evaluating patients who received PBO or UPA 45 mg (UPA45) once daily (QD) for 12 weeks. Patients who achieved clinical response to 12 weeks of UPA45 were re-randomised in the U-ENDURE maintenance study to receive PBO, UPA 15 mg (UPA15) QD, or UPA 30 mg (UPA30) QD for 52 weeks. This analysis evaluated the mean changes from baseline (BL) in total SES-CD and four individual components (size of ulcers, ulcerated surface, affected surface, presence of narrowing), as well as improvements by disease location and prior biologic failure (bio-failure) status.

Results

Mean [SD] total SES-CD at BL was similar across treatment groups (induction: PBO 13.9 [7.5], UPA45 14.6 [7.7]). In the overall population, mean [SD] changes from BL in total SES-CD were greater with UPA45 (–6.8 [7.6]) vs PBO (–0.5 [5.7]; P < .0001) at week 12, and at week 52 with UPA15 (–9.9 [8.6]) and UPA30 (–10.3 [8.1]) vs PBO (–2.4 [5.0]; all P < .0001; Figure 1A). Similar results were observed for patients with ileocolonic and colonic disease at week 12 and week 52 (Figure 1A). For patients with prior bio-failure, mean changes from BL in total SES-CD were greater with UPA45 (–6.6 [7.9]) vs PBO (0.0 [5.8]; P < .0001) at week 12, and with UPA15 (–10.4 [9.4]) and UPA30 (–9.7 [7.2]) vs PBO (–2.8 [4.8]; all P < .0001) at week 52; similar findings were reported for patients without prior bio-failure. At week 12 and week 52, treatment with UPA resulted in greater improvements vs PBO in the individual SES-CD components of size of ulcers, ulcerated surface, and affected surface, but not for the presence of narrowing (Figure 1B).

Conclusion

In patients with moderately to severely active CD, UPA induction and maintenance treatment vs PBO improved total SES-CD, irrespective of prior bio-failure. The changes were driven by the SES-CD components of the size of ulcers, ulcerated surface, and affected surface. When evaluated by disease location, appreciable improvements occurred in patients with ileocolonic and colonic CD, as compared to ileal disease.

References:

1. Loftus, E. V. et al. N. Engl. J. Med. 2023;388,1966–80

2. Reinisch, W. et al. UEGW 2023. MP005 [Poster]
DOP83 Intestinal epithelium-specific deletion of the Aryl hydrocarbon Receptor (AhR) reduces intestinal Tight Junction permeability thereby hindering homeostatic antigen sampling and tolerogenic immune responses
Authors: Saha K , Ganapathy A S , Arumugam P , Wang A , Harris L , Yochum G , Koltun W , Nighot M , Nighot P
Published: January 2024

Background

The Aryl Hydrocarbon Receptor (AhR) plays important functions in intestinal stem cell differentiation, intestinal homeostasis, and immune regulation, however, its role in regulating intestinal tight junction (TJ) barrier and immune tolerance remains poorly understood. In this study, we assessed the role of intestinal epithelium-specific AhR deletion on the intestinal paracellular TJ barrier and its role in homeostatic intestinal antigen sampling and immune tolerance.

Methods

Ahr fl/fl , and AhrVil-Cre mice were maintained in a specific pathogen-free area until injected with tamoxifen (i.p) to delete the Ahr gene, and then moved to the normal housing. The AhR deletion was maintained by weekly tamoxifen injections for 3 weeks. We performed physiological assessments of the gut epithelial barrier and used flow cytometry, confocal immunofluorescence imaging, and qRT-PCR analysis were also employed to assess the effects of epithelial AhR deletion.

Results

Conditional gut epithelium-specific knockout of AhR (AhrΔIEC) significantly increased the colonic transepithelial resistance (TER) and reduced the paracellular flux of urea and inulin. Assessment of transcript levels in the mouse colonic tissues, after 3 weeks of AhR deletion, showed that AhrΔIEC colonic tissues had higher transcript abundance of barrier-forming proteins like Claudin-3, -4, and occludin with reduced abundance of the pore-forming claudin-2. Ultrastructural investigation of intestinal TJs of AhrΔIEC mice showed diffused, laterally extended, and collapsed TJ architecture. AhrΔIEC did not alter the baseline levels of TNF-α, IFN-γ, and IL-4 however, the transcript levels of IL-6, IL-1β, and IL-17A showed marked elevation. The AhrΔIEC colonic tissues also showed increased infiltration by CD45+ immune cells under baseline conditions with a high abundance of inflammatory dendritic cells (DCs), macrophages (MΦs), and Th17 cells with a corresponding reduction in their tolerogenic counterparts and Treg cells. The AhrΔIEC also showed reduced colonic transcript levels of IL-10, a key anti-inflammatory cytokine, and Programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA4), the two key proteins, involved in limiting the pro-inflammatory responses in the gut mucosa. In-vitro, AHR-/- in Caco-2 cells also reduced paracellular TJ permeability, and co-culture assays with human dendritic cells showed reduced basal to apical paracellular podia formation and antigen sampling by DCs.

Conclusion

Our data show that deletion of the AhR gene in the gut epithelial cells reduces the epithelial paracellular TJ permeability in-vitro and in-vivo and also highlights the role of homeostatic paracellular TJ permeability in the development of intestinal immune homeostasis.
P021 Higher TNFα and IL-6 mucosal levels in ulcerative colitis patients with more severe endoscopic activity
Authors: Calviño Suárez C , Martinez-Rodriguez A L , Moreira-Alvarez D , Ardao-Palacios I , Duran-Rubi M , Ferreiro-Iglesias R , Baston-Rey I , Porto-Silva S , Nieto-Garcia L , Varela-Liste M J , Brea-Floriani J M , Dominguez-Munoz J E , Loza-Garcia M , Barreiro-de Acosta M
Published: January 2024

Background

Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterised by colonic mucosa inflammation. Its clinical course is marked by alternating periods of relapse and remission that impair patients' quality of life. In the last decades, novel therapies have shown to be effective for UC resulting in lower rates of colectomy. However, there is still a significant proportion of non-responding patients that change from one treatment to another, being exposed to its potential adverse events. Thus, predictive factors of response to available drugs are needed to tailor the best treatment strategy for each patient. The aim of our study was to measure TNFα and IL-6 levels in colonic biopsies from patients with UC with moderate to severe endoscopic activity.

Methods

A prospective, observational single-centre study was designed and it is currently on going. Adult UC patients with moderate to severe endoscopic activity (Mayo Endoscopic Score (MES) > 1) in a routine colonoscopy were included. Biopsies from inflamed (MES>1) and non-inflamed (MES=0) colon of each patient were homogenised and processed by using RIPA buffer and ultrasounds to obtain cell lysates. Human Luminex Discovery Assay (2 plex) was used for the simultaneous detection and quantitation of IL-6 and TNFα. Data are shown as percentage, median, interquartile range (IQR) and mean ± standard deviation (SD) as appropriate.

Results

So far, 21 patients were consecutively included (mean age 53.8 years (SD 17.0), 52.4% female). About 43% of patients had left-sided UC, 28.5% extensive UC and 28.5% proctitis. Regarding endoscopic activity, 61.9% of patients showed MES=2 and 38.1% were MES=3. Fourteen patients (66.6%) were bio-naïve and 7 (33.3%) had been exposed to anti-TNFα. IL-6 was detected in biopsies from colon with MES ≥ 2 of 18 (85.7%) patients, of which 10 (55.6%) patients also TNFα was found. Neither IL-6 nor TNFα were detected in biopsies from non-inflamed colon (p=0.00). Median IL-6 in inflamed colonic samples from patients with MES-2 was 25.6pg/ml (IQR 0.2-74.3) and 92.2pg/ml (IQR 16.9-314.3) in those with MES-3 (p=0.09). Median TNFα in inflamed colonic biopsies from patients with MES-2 was 0.0pg/ml (IQR 0.0-20.0) and 22.2pg/ml (IQR 0.0-34.3) in patients with MES-3 (p=0.12) (Figure 1). No differences were found in TNFα levels between anti-TNFα naïve patients and those patients previously exposed to anti-TNFα (p=0.96).

Conclusion

IL-6 and TNFα are elevated in inflamed colonic mucosa, particularly in those patients with more severe endoscopic activity, while they are not found in non-inflamed colonic mucosa. The correlation between cytokine levels and endoscopic severity suggests their potential as biomarkers for treatment response.
P032 Exploring the genetic sequence of action across the natural history of IBD
Authors: Mateos B , Gaite-Reguero A , Rodríguez-Lago I , Marigorta U M
Published: January 2024

Background

We have been very successful at identifying genetic variants associated with inflammatory bowel disease (IBD). From a single locus by the early 2000s, we now know about over 300 regions involved in IBD susceptibility. However, we face two main gaps of knowledge. First, we ignore the mechanisms by which they lead to disease. Second, we ignore their role through the natural history of the disease (e.g., prognosis). To address these gaps, we must integrate inferences from other omic techniques and characterize the genetic sequence of action that takes place across the distinct stages of the disease.

Methods

We have processed publicly available important studies of the genomics and transcriptomics of IBD to make inferences about the sequence of action of genes involved. In total, we processed the large IBDGC GWAS, five transcriptomics and two proteomic datasets (Table 1). We studied different phases of the disease: preclinical, debut and remission, both in Crohn’s disease and ulcerative colitis. We selected sets of genes associated with stages of IBD by the mentioned omics and looked for the overlaps. Last, we performed transcriptome-wide association studies (TWAS) to study the gene expression levels determined genetically in each individual.

Results

We report three main observations from this omic-wide exploration on the genetic sequence of action in IBD. First, we observed a lack of overlap in the gene lists that are relevant in each stage (Figure 1). For instance, just 6.4% of genes discovered by GWAS are differentially expressed at the time of diagnosis and/or remission e.g., NOD2, C2, CCL2, IL27, CSF2, CCL11 and BACH2. In turn, gene signatures discovered through transcriptomics are not particularly enriched for GWAS signals. Second, the genetic risk of each individual, measured through polygenic risk scores, does not correlate with the clustering of patients detected molecularly using gene expression. Third, TWAS analysis reveals an intriguing twist, since we observe large differences between the genetically determined component and the actual gene expression observed in each stage.

Conclusion

Although the genetic makeup of an individual influences expression of key genes involved in IBD, many other genes not detected in genetic studies (GWAS) conform the backbone of molecular alterations present at the time of diagnosis. This global observation challenges the conventional assumption, implying that different actors play a leading role in each stage. Moreover, genetic predisposition is not a strong determinant of the molecular heterogeneity observed in patients across stages. We conclude that the gene regulation dynamics across the natural history of IBD are more intricate than usually assumed.
P033 Unrevealing new potential key mechanisms implicated in inflammatory bowel disease by multiomic approach
Authors: Baldan-Martin M , Azkargorta M , Aransay A M , Gil-Redondo R , Moreno-Indias I , Iloro I , Soleto I , Orejudo M , Ramírez C , Lucendo A J , Rodríguez Gutiérrez C , Gutiérrez A , Martín Arranz E , Bujanda L , Rodríguez-Lago I , Riestra S , Iglesias-Flores E , Bermejo F , Van Domselaar M , García M J , Fernández Salazar L , Barrio Andrés J , Calvet X , Torrealba L , Bastón Rey I , Pallarés H , Ber Y , Carnerero E L , Casanova M J , Casals F , Mendoza J , Moreno Monteagudo J A , Millet Ó , Elortza F , Mato J M , Tinahones F J , Chaparro M , Gisbert J P
Published: January 2024

Background

Inflammatory bowel diseases (IBD), comprising Crohn´s disease (CD) and ulcerative colitis (UC), are characterised by chronic, relapsing and remitting inflammation of the gastrointestinal tract. Despite significant efforts to understand the pathogenetic mechanisms of IBD, the elucidation of its etiopathology and progression remains incomplete. This study aimed to clarify IBD pathogenesis using a multiomic approach in serum, urine, intestinal tissue and stool samples.

Methods

We performed a multiomic analysis (transcriptomic, proteomic, metabolomic and metagenomic) in a discovery cohort of 53 patients with active CD, 50 patients with active UC, and 33 healthy controls (HC). Proteomic analysis of intestinal tissue was performed by liquid chromatography-mass spectrometry, serum and urine samples were used for metabolome study using nuclear magnetic resonance spectroscopy, and metagenomic analysis of stool samples was performed by 16rRNA gene sequencing.

Results

Gene expression profiles showed a detailed transcriptome landscape of intestinal tissue in patients with CD and UC. A total of 4,105 proteins were identified in mucosal biopsies, of which 2,128 were differentially expressed (DE) between CD and HC, 2,715 proteins DE in UC compared with HC, and 1,653 proteins DE between CD and UC. Metabolomic analyses revealed metabolites and pathways related to ketone, amino sugar and methyl histidine metabolism, Warburg effect, and ammonia recycling deregulated in IBD patients. Moreover, metagenomic results indicated that CD and UC differ in their microbial populations according to beta diversity. In comparison to HC, the microbial population in CD was different, and its alpha diversity was significantly lower (Figure 1).

Conclusion

The results showed that some analytes identified could play essential roles in the pathogenesis of CD and UC. New potential key mechanisms that could help to understand the information of omics layers that underlies the pathogenesis of IBD have been outlined.