bluuebunny/crossref_metadata_2025 huggingface dataset:
Terahertz tuning by core-shell nanoparticles irradiated by skew-cosh Gaussian lasers
Authors: Punia Tamanna , Malik Hitendra K
Published: January 2024

Choosing two skew-cosh Gaussian beams, an analytical investigation of a medium having spherical and cylindrical core–shell nanoparticles (NPs) is performed for the generation of tunable terahertz (THz) radiation. The core of the NPs is considered to be made up of silica which is concentrically wrapped by the graphite shell. The basal planes of NPs / graphite are taken to be in parallel or perpendicular direction with the lasers electric field. In this phenomenon, the incident beams provide nonlinear velocity to the electron cloud of the NPs, leading to a nonlinear current and hence the THz emission. After obtaining an expression of nonlinear current, the THz field is calculated making use of Maxwell’s equations along with the effective permittivity governed by the radii of core and shell of the NPs. Tunable THz radiations are obtained by judiciously varying the radii of core and shell. In order to tune the focus of radiation, the resonance peaks can be made to shift towards higher frequencies, i.e., 10.4 THz and 49.4 THz, depending on the longitudinal and transverse plasmon resonances, respectively. The parameters of laser beams and NPs can be exploited for achieving efficient THz radiation.
Quantum secure ranking based on quantum walks
Authors: Joseph Justin , Ali Syed Taqi
Published: January 2024

We propose a quantum secure multiparty multidata ranking (QSMMR) protocol based on quantum walks. Our protocol improves the traditional anonymous ranking protocol to secure ranking, where we ensure the confidentiality of the data. A quantum anonymous ranking protocol exposes all participants’ data, which is not ideal for practical scenarios such as personal wealth and health indexes. Hence, we propose the first quantum secure ranking protocol with semi-honest TP, that generates ranking for multiple data of multiple participants by keeping data completely secure. We use quantum resources to assign a random address to all participants, to perform comparison, and for the eavesdropper detection. Finally, we analyze and prove the security of the protocol.
Study of polarization for even-denominator fractional quantum Hall states in SU(4) Graphene
Authors: Indra Moumita , Majumder Dwipesh
Published: January 2024

We have focused on studying the even-denominator fractional quantum Hall (EDFQH) states observed in monolayer graphene. In this article, we have studied polarization mainly for the two EDFQH states at filling fractions ν = 1/2, 1/4, which are observed in an experimental study [Nat. Phys. 14, 930 (2018)] a few years ago. We have applied Chern-Simon’s gauge field theory to explain the possible variational wave functions for different polarized states and calculated their ground state energies using the Coulomb potential. We have chosen the lowest energy states using suitable combinations of attached flux quanta to the electrons for different polarized states of those EDFQH states.
On the solution of multi-term time fractional diffusion-wave equation involving ultra-hyperbolic operator
Authors: Javed Sehrish , Malik Salman A
Published: January 2024

A diffusion-wave equation with multi-term Hilfer fractional derivatives (HFDs) in time and ultra-hyperbolic operator (UHO) in space has been considered. Fundamental solution of the fractional diffusion-wave equation is obtained by using Laplace and Fourier transform with Mellin-Barnes integral representation. The solution obtained involved the Fox H-function. In addition, we provide some special cases of diffusion-wave equation.
TCAS-PINN: Physics-informed neural networks with a novel temporal causality-based adaptive sampling method
Authors: Guo 郭 Jia 嘉 , Wang 王 Haifeng 海峰 , Gu 古 Shilin 仕林 , Hou 侯 Chenping 臣平
Published: January 2024

Physics-informed neural networks (PINNs) have become an attractive machine learning framework for obtaining solutions to partial differential equations (PDEs). PINNs embed initial, boundary, and PDE constraints into the loss function. The performance of PINNs is generally affected by both training and sampling. Specifically, training methods focus on how to overcome the training difficulties caused by the special PDE residual loss of PINNs, and sampling methods are concerned with the location and distribution of the sampling points upon which evaluations of PDE residual loss are accomplished. However, a common problem among these original PINNs is that they omit special temporal information utilization during the training or sampling stages when dealing with an important PDE category, namely, time-dependent PDEs, where temporal information plays a key role in the algorithms used. There is one method, called Causal PINN, that considers temporal causality at the training level but not special temporal utilization at the sampling level. Incorporating temporal knowledge into sampling remains to be studied. To fill this gap, we propose a novel temporal causality-based adaptive sampling method that dynamically determines the sampling ratio according to both PDE residual and temporal causality. By designing a sampling ratio determined by both residual loss and temporal causality to control the number and location of sampled points in each temporal sub-domain, we provide a practical solution by incorporating temporal information into sampling. Numerical experiments of several nonlinear time-dependent PDEs, including the Cahn–Hilliard, Korteweg–de Vries, Allen–Cahn and wave equations, show that our proposed sampling method can improve the performance. We demonstrate that using such a relatively simple sampling method can improve prediction performance by up to two orders of magnitude compared with the results from other methods, especially when points are limited.
Infrared plasmonic refractive index sensor utilizing 2D grating of nano-bowtie particles for both gas and liquid
Authors: Wang Xiangxian , Rao Xijun , Zhu Jiankai , Chen Yizhen , Qi Yunping , Tang Chaojun , Yang Hua
Published: January 2024

We propose a plasmonic structure that can be used for refractive index sensing with different analytes in the same wavelength-domain. A two-dimensional (2D) grating composed of nano-bowtie particles is used as the optical momentum coupling structure. The double-period feature of the 2D grating makes the structure have two excitation approaches with different polarization directions of incident light. The physical mechanisms of the plasmonic structure are revealed in detail by theoretical analysis and finite-difference time-domain method. The simulation results show that the structure can achieve a gas sensing sensitivity of 1235 nm/RIU and a liquid sensing sensitivity of 950 nm/RIU in the same wavelength-domain from 1200 nm to 1400 nm. This structure can be widely used in the field of gas or liquid biochemistry due to its simple geometry and competitive sensing performance.
Structure-preserving algorithms for guiding center dynamics based on the slow manifold of classical Pauli particle
Authors: ZHANG 张 Ruohan 若涵 , WANG 王 Zhengxiong 正汹 , XIAO 肖 Jianyuan 建元 , WANG 王 Feng 丰
Published: January 2024

The classical Pauli particle (CPP) serves as a slow manifold, substituting the conventional guiding center dynamics. Based on the CPP, we utilize the averaged vector field (AVF) method in the computations of drift orbits. Demonstrating significantly higher efficiency, this advanced method is capable of accomplishing the simulation in less than one-third of the time of directly computing the guiding center motion. In contrast to the CPP-based Boris algorithm, this approach inherits the advantages of the AVF method, yielding stable trajectories even achieved with a tenfold time step and reducing the energy error by two orders of magnitude. By comparing these two CPP algorithms with the traditional RK4 method, the numerical results indicate a remarkable performance in terms of both the computational efficiency and error elimination. Moreover, we verify the properties of slow manifold integrators and successfully observe the bounce on both sides of the limiting slow manifold with deliberately chosen perturbed initial conditions. To evaluate the practical value of the methods, we conduct simulations in non-axisymmetric perturbation magnetic fields as part of the experiments, demonstrating that our CPP-based AVF method can handle simulations under complex magnetic field configurations with high accuracy, which the CPP-based Boris algorithm lacks. Through numerical experiments, we demonstrate that the CPP can replace guiding center dynamics in using energy-preserving algorithms for computations, providing a new, efficient, as well as stable approach for applying structure-preserving algorithms in plasma simulations.
Clinical value of 18F-PSMA-1007 PET/MRI in primary staging of patients with intermediate- to high-risk prostate cancer
Authors: Ali Ismail , Rezk Mahmoud , Hamouda Dalia , Talaat Omnia , Omar Yehia , Abdel Tawab Mohamed , Nasr Ibrahim
Published: January 2024

Objective

To assess the utility of 18F-PSMA-1007 PET/MRI in initial staging of intermediate- to high-risk prostate cancer (HRPCa).

Methods

A total of 46 patients with pathologically verified intermediate and/or HRPCa who underwent 18F-PSMA-1007 PET/MRI with dedicated pelvic high-resolution multiparametric MRI (mpMRI) were included.

Results

PET/MRI showed 100% sensitivity (SN), specificity (SP), positive predictive value (PPV), negative predictive value (NPV), and accuracy in detecting seminal vesicle (SV) and rectal invasion, versus 87.5%, 100%, 100% 93.8%, 95.7% and 50%, 100%,100%, 95.5%, and 95.7% for mpMRI respectively. However, PET/MRI had poor SN (40% and 0%) but high SP (94.4% and 100%) in detection of UB and neurovascular bundle (NV) invasion compared to 100% SN and SP for mpMRI. PET/MRI demonstrated stronger TNM staging agreement with the gold standard than mpMRI-WBMRI. It demonstrated concordance with T, N, and M stages in 40, 41, and 36 patients (k 0.84, 0.60, and 0.68, respectively) versus 29, 33, and 31 patients (k 0.54, 0.22, and 0.50) with accurate over all staging of 38/46 patients versus 30/46 patients (K 0.52 versus 0.22).

Conclusion

18F-PSMA-1007 PET/MRI is a promising imaging modality with high diagnostic accuracy in staging intermediate- and HRPCa; it improves local tumour evaluation and provides precise TNM staging.

Advances in knowledge

18F-PSMA-1007 PET/MRI could have high diagnostic accuracy as shown in the current study for staging HRPCa patients that is crucial for treatment selection. We think that our study will contribute to the body of knowledge and improve the literature surrounding the clinical uses of integrated 18F-PSMA-1007 PET/MRI.
The effect of Huntington’s disease on cognitive and physical motivation
Authors: Atkins Kelly J , Andrews Sophie C , Stout Julie C , Chong Trevor T J
Published: January 2024

Apathy is one of the most common neuropsychiatric features of Huntington’s disease. A hallmark of apathy is diminished goal-directed behaviour, which is characterized by a lower motivation to engage in cognitively or physically effortful actions. However, it remains unclear whether this reduction in goal-directed behaviour is driven primarily by a motivational deficit and/or is secondary to the progressive cognitive and physical deficits that accompany more advanced disease.

We addressed this question by testing 17 individuals with manifest Huntington’s disease and 22 age-matched controls on an effort-based decision-making paradigm. Participants were first trained on separate cognitively and physically effortful tasks and provided explicit feedback about their performance. Next, they chose on separate trials how much effort they were willing to exert in each domain in return for varying reward. At the conclusion of the experiment, participants were asked to rate their subjective perception of task load.

In the cognitive task, the Huntington’s disease group were more averse to cognitive effort than controls. Although the Huntington’s disease group were more impaired than controls on the task itself, their greater aversion to cognitive effort persisted even after controlling for task performance. This suggests that the lower levels of cognitive motivation in the Huntington’s disease group relative to controls was most likely driven by a primary motivational deficit. In contrast, both groups expressed a similar preference for physical effort. Importantly, the similar levels of physical motivation across both groups occurred even though participants with Huntington’s disease performed objectively worse than controls on the physical effort task, and were aware of their performance through explicit feedback on each trial. This indicates that the seemingly preserved level of physical motivation in Huntington’s disease was driven by a willingness to engage in physically effortful actions despite a reduced capacity to do so. Finally, the Huntington’s disease group provided higher ratings of subjective task demand than controls for the cognitive (but not physical) effort task and when assessing the mental (but not the physical) load of each task.

Together, these results revealed a dissociation in cognitive and physical motivation deficits between Huntington’s disease and controls, which were accompanied by differences in how effort was subjectively perceived by the two groups. This highlights that motivation is the final manifestation of a complex set of mechanisms involved in effort processing, which are separable across different domains of behaviour. These findings have important clinical implications for the day-to-day management of apathy in Huntington’s disease.
Long-term outcomes after non-curative endoscopic resection for esophageal squamous cell carcinoma followed by additional chemoradiotherapy
Authors: Cho Hourin , Abe Seiichiro , Nonaka Satoru , Suzuki Haruhisa , Yoshinaga Shigetaka , Okuma Kae , Yamamoto Shun , Daiko Hiroyuki , Kato Ken , Sekine Shigeki , Boku Narikazu , Saito Yutaka
Published: January 2024

Endoscopic resection (ER) of esophageal squamous cell carcinoma (ESCC) is evaluated pathologically, and additional treatment is recommended for cases resulting in non-curative resection, defined as pMM with lymphovascular invasion (LVI), pSM, or positive vertical margin. This study aimed to assess long-term outcomes and risk factors for recurrence in patients with ESCC treated with non-curative ER followed by additional chemoradiotherapy (CRT). We retrospectively reviewed the clinical courses of patients who underwent non-curative ER followed by additional CRT for ESCCs between August 2007 and December 2017. Recurrence rates and risk factors for recurrence were analyzed. Among 97 patients with non-curative ER, 73 underwent additional CRT. With a median follow-up period of 71 months, recurrences were observed in 10 (14%) of 73 patients, with a median interval of 24.5 (1–59 months). The 3- and 5-year recurrence-free survival were 89 and 85%, respectively, and the 3- and 5-year overall survival rates were 96 and 91%, respectively. Multivariate analysis showed that lymphatic invasion was an independent risk factor for recurrence in patients with non-curative ESCC receiving additional CRT. Among the 10 patients with recurrence, 4, 3, 2, and 1 underwent surgery, chemotherapy, supportive care, and CRT, respectively. Notably, all four patients who underwent surgery survived, regardless of regional and/or distant lymph node metastasis. Lymphatic invasion is an independent risk factor for the recurrence of non-curative ESCCs. Careful follow-up is required for at least 5 years after ER with additional CRT.
OP23 Guselkumab induction restores intestinal immune homeostasis and promotes epithelial repair in moderately to severely active Ulcerative Colitis
Authors: Sridhar S , Hart A , Venkat S , Ruane D , Horowitz D , Lee T , Waterworth D , Huang K H G , Germinaro M , Vetter M , Cua D , Freeman T C , Sisk C , McRae B , Verstockt B , Rubin D T , Sands B E , Branigan P
Published: January 2024

Background

Selective inhibition of interleukin-23 (IL-23) through antagonism of the IL-23p19 subunit has demonstrated clinical efficacy in inflammatory bowel disease, but the mechanism of action (MoA) has not been fully defined. Here we provide a detailed evaluation of the cellular and molecular MoA of guselkumab (GUS), an IL-23p19 subunit antagonist, in patients (pts) with moderately to severely active ulcerative colitis (UC) from the QUASAR Phase 2b induction study (NCT04033445).

Methods

Serum proteins were evaluated from 302 pts treated with intravenous GUS induction therapy or placebo (PBO) who had at least one paired sample at Weeks (WK) 0 and 4 or WK12. Matched colonic biopsies at WK0 and 12 were available for 255 pts. Transcriptional profiling was performed with bulk RNA sequencing (RNAseq). Transcriptional modules derived from public UC single cell RNAseq (scRNAseq) were evaluated with differential expression in the bulk RNAseq dataset. Flow cytometry and scRNAseq were performed on a subset of matched WK0 and WK12 cryopreserved biopsies from 60 pts.

Results

Both GUS induction doses were effective vs PBO in achieving key endpoints including clinical remission, endoscopic and histologic outcomes. GUS reduced serum IL-22, IFNγ and IL-17A (p<1e-05) as early as WK4, which further declined through WK12. Unsupervised analysis of tissue transcriptomic modules (n=69) revealed 57 that were significantly changed with GUS at WK12. The top 6 downregulated modules represented Th17 cell (IL-23 pathway), neutrophil, IFNγ signaling, plasma cell and inflammatory epithelial and fibroblast cell states, while modules associated with epithelial cell populations and metabolism were upregulated (all false discovery rate [FDR]<0.05). Fc-γ receptor (CD64) expression was increased at baseline in all patients and reduced at WK12. Flow cytometry demonstrated reductions of CD45+ lymphocyte and CD66+ granulocyte populations (p<0.01). Parallel scRNAseq showed a reduction of inflammatory monocytes and fibroblasts in GUS responders at WK12 while pro-healing indicators were observed at WK12 including an increase in EpCam+ cells, BEST4+ enterocytes, and ADAMDEC1+ fibroblasts (p<0.01). Module analysis indicated an increase in goblet cells (FDR<0.05) which play a role in barrier integrity.

Conclusion

GUS induction restored intestinal immune homeostasis in pts with UC who achieved key endpoints at WK12, demonstrated by resolution of inflammation associated with the IL-23 pathway and inflammatory myeloid, epithelial and fibroblast transcriptional states. GUS also promoted epithelial repair as evidenced by increases in epithelial cell population, consistent with endoscopic and histologic outcomes at WK12.
OP35 Efficacy of mirikizumab in comparison to ustekinumab in patients with moderate to severe Crohn’s disease: Results from the phase 3 VIVID 1 study
Authors: Jairath V , Sands B E , Bossuyt P , Farraye F , Ferrante M , Hisamatsu T , Kaser A , Kierkus J , Laharie D , Reinisch W , Siegmund B , Bragg S M , Hon E , Lin Z , Ugolini Lopes M , Morris N , Protic M , Danese S
Published: January 2024

Background

The primary objective of the VIVID-1 trial (NCT03926130) was to demonstrate efficacy and safety of mirikizumab (miri), a p19-directed anti-IL-23 antibody, compared to placebo (PBO) in patients (pts) with moderate-to-severe Crohn’s disease. Miri demonstrated statistically significant improvements in co-primary and all key secondary endpoints versus (vs) PBO1. Here we present the results of secondary endpoints on the comparisons of miri to ustekinumab (uste), a p40 directed anti-IL-12/IL-23 inhibitor from the Phase 3, randomised, double-blind, double-dummy, active- and PBO-controlled, treat-through (TT) study, VIVID-1 (NCT03926130).

Methods

Adult pts (N=1065) were randomised 6:3:2 to miri (N=579) 900mg intravenously (IV) every 4 weeks (Q4W) to W12, then 300mg subcutaneously (SC) Q4W to W52, uste (N=287) one ~6 mg/kg IV dose, then 90mg SC Q8W to W52 or PBO (N=199). At W12 PBO responders continued PBO to W52; PBO non-responders received the same blinded miri regimen as described above (IV then SC). Efficacy of miri vs uste was assessed by the proportion of pts achieving endoscopic response and by the proportion of pts achieving clinical remission by Crohn’s Disease Activity Index (CDAI) at W52 (both gated). Additional non-multiplicity-adjusted endpoints included endoscopic remission, corticosteroid-free clinical remission by CDAI, and the composite of CDAI clinical remission and endoscopic response at W52. (Figure 1 for definitions).

Results

Baseline characteristics were overall balanced across the three treatment groups (table 1). Pts treated with miri achieved all key major secondary endpoints (p<.000001) compared to PBO (Figure 1). Miri achieved non-inferiority to uste for clinical remission by CDAI (p=0.113117) (Figure 1C). Although superiority to uste in endoscopic response was not achieved (p=0.51) (Figure 1A), in biologic failed pts miri demonstrated a numerical trend towards greater response rates compared to uste for endoscopic response and clinical remission by CDAI (Figure 1 B & D). The overall safety profile was consistent with the known safety profile of miri. The proportion of treatment emergent adverse events (TEAE) were similar for miri (78.6%) and uste (77.3%); most common TEAEs were COVID-19, anaemia, arthralgia, headache, upper respiratory tract infection, nasopharyngitis and injection site reaction. Instances of serious adverse events were comparable for miri (10.3%) and uste (10.7%).

Conclusion

In this phase 3 TT design study, miri achieved non-inferiority to uste for clinical remission by CDAI. In biologic failed pts miri had a numerical trend towards greater response compared to uste in clinical and endoscopic endpoints, with an acceptable safety profile.

1Ferrante et al., submitted to ECCO 2024
DOP09 Models for predicting Crohn Disease (CD) exacerbation using serum and fecal metabolomics
Authors: Levhar N , Hadar R , Braun T , Efroni G , Naamneh R , Agranovich B , Talan Asher A , Selinger L , Picard O , Lahat A , Eliakim A , Kopylov U , Ben-Horin S , Amir A , Haberman Y
Published: January 2024

Background

Metabolites, produced endogenously or derived from the gut microbiome, are key mediators and effectors of many cellular functions, but there are only scant data on their temporal changes along CD course. We analyzed the dynamics of serum and fecal metabolome in a prospective cohort of quiescent CD patients over 2 years or until the occurrence of a clinical flare, aiming to identify whether changes in the metabolome precede and predict a clinical relapse.

Methods

Untargeted metabolomics was performed using LC/MS. Multivariate analyses in MaAsLin2 were applied to identify differentially abundant metabolites between CD cases who relapsed and those who remained in remission. Our models used the "Leave-One-Out" approach to compensate for over-fitting bias.

Results

We included 110 serum samples and 232 fecal samples from 44 CD participants recruited in remission (mean age 31.73 years, 59% males; Table 1). The median follow-up time was 630 days (IQR 500-808). Demographic, biomarkers, and treatment exposures were not significantly different between the 11 that experienced flare during follow-up and the 33 that remained in remission throughout. We compared the metabolomics between relapsers and non-relapsers using only preflare samples after excluding samples from a particular subject in the "Leave-One-Out" approach. The top 3 metabolites in each direction and comparison and their abundance preflare in the non-relapsers and relapsers are shown (Fig. 1A-B). We then calculated a flare index for that excluded subject, using the sum peak area ratio of all metabolites that were increased and decreased preflare. A receiver operating characteristic (ROC) area under the curve (AUC) using the "individual" flare index after z-score normalization was able to predict a subsequent flare with AUC=0.73, 95% CI 0.52-0.93 for serum metabolomics (Fig. 1C) compared with AUC=0.62 (95% CI 0.40-0.84) for CRP and AUC=0.74 (95% CI 0.54-0.94) for FCP, in the same sampling cohort. For the stool sampling cohort, metabolomics predictive accuracy was AUC=0.75 (95% CI 0.5-0.99; Fig. 1D) compared with AUC=0.67 (95% CI 0.49-0.84) for CRP and AUC=0.71 (95% CI 0.55-0.86) for FCP. Survival plot analyses after selecting Youden point based on ROC (Fig. 1C-D) showed moderately better performance for fecal flare index with log-rank Hazard Ratio (HR) of 8.20 (95% CI 1.98-34.20), than for the serum with HR of 3.45 (95% CI 1.5-11.37).

Conclusion

In a prospective cohort of quiescent CD patients, we identified metabolites in the serum and feces that were incorporated in models that can predict CD flare. These can be used to guide personalized preemptive therapy intensification and provide insight into the underlying mechanism of CD flares.
DOP29 Capsule endoscopy-guided proactive treatment versus standard treatment of patients with quiescent Crohn’s Disease: The CURE-CD randomized controlled trial
Authors: Ben-Horin S , Lahat A , Ungar B , Ukashi O , Yablecovitch D , Amitai M M , Haberman Y , Selinger L , Talan-Asher A , Kriger-Sharabi O , Naftali T , Ron Y , Yanai H , Dotan I , Kopylov U , Eliakim R
Published: January 2024

Background

Optimal strategies for treat-to-target in Crohn’s disease (CD) are still being sought. We aimed to examine the value of capsule endoscopy (CE) to guide proactive treatment optimization in patients with CD

Methods

A prospective randomized controlled clinical trial with temporally-restricted blinding. Patients with CD involving the small bowel who were in clinical remission (CDAI<150) for over three months were enrolled. Baseline clinical, biomarker, imaging, patency capsule and CE assessments were performed. ‘High risk’ patients, defined as CE Lewis score ≥350 were randomized to either proactive treatment optimization or continued standard care for 24 months. ‘Low risk’ patients with Lewis score<350 continued their standard care. All patients repeated CE every six months for 24 months. Primary outcome was the rate of clinical exacerbation (CDAI increase>70 points and CDAI>150 or hospitalization/surgery) in the standard-care versus the proactive-care sub-groups of high-risk patients, at 24 months. Secondary outcomes included risk of flare in the low-risk versus the standard-care high-risk arms, and predictive profiles for flare of calprotectin, MRI, intestinal ultrasound and Lewis score.

Results

Out of 118 screened patients, 60 were enrolled (20 in each of the three arms). Treatment intensification in CE-determined high-risk group, who were allocated to proactive treatment, comprised biologic dose-escalation (n=11/20), starting a biologic (8/20) or swapping a biologic (1/20) at study entry. Notably, 9/20 proactive-group patients underwent a second optimization following detected inflammation on subsequent semi-annual CE studies. Clinical exacerbation by 24 months (primary outcome) occurred in 5/20 (25%) of the high-risk proactive-treatment group versus 14/20 (70%) of the high-risk standard-care group (OR=0.14, 95%CI 0.04-0.57, p=0.006). For secondary outcomes, the rate of clinical flare in the standard-care low-risk group was numerically but not significantly lower than in standard-care high-risk group (9/20 versus 14/20, respectively, OR 0.3, 0.1-1.3, P=0.11). Among all patients continuing standard care, baseline CE Lewis score was higher among relapsers versus non-relapsers (median 450, IQR [225-900] versus 225, [135-600], respectively, p=0.03). Of 251 CE ingested, there was a single (0.4%) temporarily-retained CE, which resolved spontaneously.

Conclusion

In a randomized strategy-finding controlled trial, proactive treatment optimization based on CE findings in patients with CD in remission, proved safe and superior for prevention of disease exacerbation compared with continued standard care. NCT03555058
P091 Single-cell metabolic phenotyping of monocytes and macrophages in Crohn’s disease
Authors: Haag L M , Lehmann M , Walling S , Kunkel D , Hecker J , Huck A , Glauben R , Weidinger C , Kuehl A A ,   T. TRR241 IBDome Consortium, Siegmund B
Published: January 2024

Background

Crohn’s disease (CD) is a chronic inflammatory disease, which can affect any part of the gastrointestinal tract. It is characterized by alterations in the innate and adaptive immune systems. Changes in both monocyte and macrophage (MΦ) populations have been reported in CD patients. However, the precise contribution of these cells to disease pathogenesis and progression remains unclear. Our hypothesis is that in CD, the local environment affects the metabolism of monocytes and MΦ. Furthermore, we believe that the cell’s metabolism is essential for the phenotypic and functional identity of these cells. The aim of this study is to analyze and compare the metabolic signatures of peripheral blood monocyte subsets and tissue MΦ in CD patients with ileitis (iCD), deep remission (rCD) and healthy controls (HC).

Methods

A total of 28 adults from the IBDome5 cohort were analyzed, consisting of 10 individuals with iCD, 8 with rCD and 10 HC. Suspension mass cytometry was utilized to analyze peripheral blood mononuclear cells (PBMCs) using a 34-marker panel targeting key proteins and rate-limiting enzymes across multiple metabolic pathways. In addition, we conducted further analysis on intestinal tissue obtained during ileocolonoscopy using imaging mass cytometry. This allowed for the application of a similar marker panel to compare the metabolic states of tissue-resident MΦ (ongoing analysis) with the identified signatures found in peripheral blood.

Results

Peripheral blood samples of CD patients and HC were analyzed. FlowSOM clustering of CD45+ events discriminated 11 major clusters of PBMCs. Reclustering based on CD14 and CD16 allowed the identification of 4 monocyte clusters, including classical monocytes. Classical monocytes exhibited unique metabolic signatures that distinguished them from other monocyte populations. Ongoing investigations targeting metabolic signatures in the monocyte-MΦ compartment will determine whether disease states differ significantly between the single disease entities.

Conclusion

Single-cell phenotyping using suspension and imaging mass cytometry can assess metabolic states of the monocyte-MΦ compartment in CD and HC. Such insights may provide novel markers for monitoring disease activity and reveal potential therapeutic targets.
P127 Sphingosine-1-Phosphate Receptor Blockade with Etrasimod alters Lymphocyte Trafficking in Crohn's Disease: Insights from High-Dimensional Phenotypic Mapping
Authors: Nikolakis D , Pruijt M J , Aberkrom V E R , de Voogd F A E , Branquinho D , Crosby C , Teichert C , van de Sande M G H , Grootjans J , D'Haens G R A M
Published: January 2024

Background

The blockade of lymphocyte trafficking from the lymph nodes (LNs) towards the intestinal mucosa is an effective approach for the treatment of ulcerative colitis (UC). Etrasimod is an oral, once-daily (QD), selective sphingosine 1-phosphate (S1P)1,4,5 receptor (S1PR) modulator, which is currently also under investigation for Crohn’s disease (CD).

The therapeutic mechanism of action of S1PR modulators in the context of inflammatory bowel disease (IBD) is not completely understood. It is hypothesized that both B and T- cell populations are affected by this treatment and are retained in the peripheral LNs, reducing circulating lymphocytes and resulting in fewer immune cells available to traffic in the gastrointestinal tract. Etrasimod has been reported to induce a partial and selective reduction of lymphocyte subsets in the blood of healthy subjects, but the direct effect of S1PR modulators on LN leukocytes has not been evaluated. The aim of this study was to investigate changes in leukocyte subpopulations in peripheral LNs and peripheral blood (PB) in response to S1PR inhibition with etrasimod in patients with CD.

Methods

CD patients with moderate to severe disease activity, participating in the Phase 2, double-blinded, non-placebo-controlled portion of the CULTIVATE trial, were eligible for this sub-study. At baseline and after 14 weeks of etrasimod induction treatment (2 or 3 mg/day), 10cc of PB and 4 ultrasound guided biopsy samples of an inguinal LN were obtained. The isolated peripheral blood mononuclear cells (PBMCs) and LN leukocyte populations, were analyzed at single cell level via high-dimensional immunophenotyping through mass cytometry (CyTOF) at both timepoints.

Results

We observed that in the LNs, the numbers/percentages of naïve, central and effector memory T-helper cells, as well as, of CD8+ naïve T-cells were increased after treatment with etrasimod. There was a decrease in the proportion of these cell populations in peripheral blood. Circulating naïve and memory B-cells were reduced, while these subsets where also slightly reduced in the LN compartment. Innate immune cell populations were not significantly altered.

Conclusion

Etrasimod induction treatment resulted in an increase of both naïve and central memory T-lymphocyte subsets in inguinal LNs, with a corresponding decrease in the periphery. The effect on the frequency of B-cells was not consistent in the LNs and PB, while innate immunotypes and T-regs, were not significantly affected. Despite the limited sample size, these selective effects were consistent with previously published PB immunophenotyping studies with etrasimod.

This study was conducted as a collaboration between Amsterdam UMC and Pfizer.
P193 Fatigued patients with Inflammatory Bowel Disease exhibit distinct systemic antibody epitope repertoires
Authors: Griesbaum M G , Vogl T , Andreu-Sánchez S , Klompus S , Kalka I N , Leviatan S , van Dullemen H M , Visschedijk M C , Festen E A M , Faber K N , Dijkstra G , Weinberger A , Segal E , Weersma R K , Bourgonje A R
Published: January 2024

Background

Patients with inflammatory bowel diseases (IBD) frequently experience fatigue, affecting up to 80% of those with active disease and approximately 50% with quiescent disease. The exact cause of IBD-associated fatigue is often unknown, making clinical management very challenging. In this study we aimed to explore whether patients with quiescent IBD reporting fatigue exhibit specific systemic antibody responses, which could provide insight into immune reactivities underlying fatigue.

Methods

Systemic antibody epitope repertoires were profiled in 327 patients with IBD (156 Crohn’s disease [CD]; 171 ulcerative colitis [UC]) leveraging phage-display immunoprecipitation sequencing (PhIP-Seq) against 344,000 rationally selected peptide antigens. Fatigue severity was assessed on a 10-point Likert scale, ranging from 1 (no fatigue) to 10 (highest fatigue severity). Quiescent IBD was defined as clinical (Harvey-Bradshaw Index [HBI] <5 or Simple Clinical Colitis Activity Index [SCCAI] <2.5) and biochemical remission (C-reactive protein [CRP] <5 mg/L) at time of sampling. Multivariable logistic regression analyses, allowing adjustment for potential confounding factors e.g. age, sex, and smoking, were performed to identify associations between fatigue and systemic antibody responses.

Results

A total of 105 different antibody-bound peptides were associated with fatigue (nominal P-value<0.05), albeit none passed adjustment for multiple comparisons. Among these antibodies, 50 (47.6%) were found to be less frequent in highly fatigued patients (fourth quartile, Q4), while 55 (52.4%) were identified as more frequent in highly fatigued patients compared to those with low fatigue scores (first quartile, Q1). Among highly fatigued patients, antibody responses were primarily directed towards viral antigens, notably several antigens from Epstein-Barr virus (EBV), as well as bacterial antigens, including functional proteins from Streptococcus and Staphylococcus species. Fatigued patients with CD exhibited elevated systemic antibody responses against allergens, Staphylococcus, Pseudomonas aeruginosa, and Shigella spp. Fatigued patients with UC showed higher frequencies of antibody responses against herpes simplex virus (HSV), influenza viruses, and few responses against allergens and Streptococcus bacteria. These results remained materially unchanged when repeating analyses in patients with quiescent IBD.

Conclusion

This study may suggest a potential role of viral antigens, particularly EBV, in the pathophysiology of fatigue in patients with IBD. However, larger confirmatory studies are needed to validate these findings. PhIP-Seq may represent a valuable strategy to approach the investigation of immune responses underlying complex symptoms such as fatigue.
P280 Comparative responsiveness of disease activity indices in moderately-to-severely active Ulcerative Colitis: a post-hoc analysis of the UNIFI trial
Authors: Solitano V , Panaccione R , Sands B E , Wang Z , Zou G , Peyrin-Biroulet L , Danese S , Cornfield L J , Feagan B G , Singh S , Jairath V , Ma C
Published: January 2024

Background

Clinical, endoscopic, histological, and composite instruments are used to measure disease activity in ulcerative colitis (UC). We compared responsiveness of the Mayo Clinic Score (MCS), modified Mayo Clinic Score (mMS), partial Mayo Clinic Score (pMS), Robarts Histopathology Index (RHI), and UC-100 score after treatment with ustekinumab in patients with moderately-to-severely active UC.

Methods

Publicly available data from the phase 3 UNIFI induction trial (NCT02407236) comparing the efficacy and safety of ustekinumab versus placebo in patients with moderate-to-severe UC were obtained from Vivli (Vivli ID #7549) and Yale University Open Data Access Project (#2021-4848). Post-hoc analyses were performed on patient level data to ascertain outcomes of interest. Treatment assignment was the criterion for change in evaluation of responsiveness, which was quantified using the probability of a treated patient having a larger change than a placebo patient (win probability [WinP]) and estimated using nonparametric methods. Extent of responsiveness was interpreted according to Cohen’s benchmarks as very small (WinP<0.56); small (0.56≤ WinP<0.64); medium (0.64≤ WinP<0.71); and large (WinP≥0.71).

Results

Data from 961 patients with moderately-to-severely active UC randomised in UNIFI were included. At baseline, 319 patients received placebo and 624 patients received ustekinumab. A total of 912 (94.9%) patients completed the induction trial. Overall mean baseline index scores were: MCS 8.9 (±1.6), mMS 6.6 (±1.3), pMS 6.2 (±1.4), RHI 16.6 (±8.1), and UC-100 score 71.4 (±16.5) (Table). The UC-100 demonstrated a large degree of responsiveness (WinP 0.72 [95% CI: 0.66, 0.78]). The MCS (0.68 [0.62, 0.73]), mMS (0.69 [0.63, 0.75]), and pMS (0.65 [0.59, 0.71]) demonstrated similar, medium effect sizes (all comparisons p>0.05) (Figure). The RHI alone had a relatively small effect size (WinP 0.63 [0.56-0.70]). Among individual UC-100 components (Mayo Clinic stool frequency subscore, Mayo Clinic endoscopic subscore, and RHI), the endoscopic score was most responsive (WinP 0.59 [0.36-0.82]). The combination of endoscopy and RHI was associated with a medium degree of responsiveness (WinP 0.69 ([0.34, 1.00]).

Conclusion

UC disease activity indices are similarly responsive to change. Depending on trial design and measurement feasibility, different instruments can be considered optimal for evaluation of efficacy. The mMS is similarly responsive to the MCS without including the physician global assessment and may be more appropriate for determining trial eligibility and defining primary endpoint, whereas the UC-100 may be more appropriate for measuring treatment effect when an objective continuous measure is needed.
P346 Assessing Brain Morphology in Functional Gastrointestinal and Inflammatory Bowel Disorders Using Functional Magnetic Resonance Imaging (fMRI)
Authors: Piotrowicz G , Skrobisz K , Naumczyk P , Markiet K , Sabisz A , Rydzewska G , Szurowska E
Published: January 2024

Background

Functional gastrointestinal disorders (FGIDs) and non-specific inflammatory bowel diseases (IBD) are increasingly common in young adults. Studies have shown abnormal interhemispheric interactions in FGIDs and altered Default Mode Network (DMN) connectivity in brain regions linked to gastric sensations and emotional regulation. This study explores these neural mechanisms in FGIDs and IBDs, focusing on chronic visceral pain and its association with DMN reorganization.

Methods

The study included patients with functional dyspepsia (FD), N=18; irritable bowel syndrome (IBS), N=20 and IBD, N=18 alongside a control group of 18 healthy volunteers. Selection criteria included the Rome III Criteria for FGIDs and various diagnostic tests for IBDs. MRI scans were conducted using a 3T Achieva TX Scanner, applying standard T1 and T2 sequences without contrast agents. Functional imaging utilized T2 Gradient Echo-Planar Imaging.

Results

DMN analysis showed no anterior-posterior split. Significant differences were observed in the IBD group compared to controls, particularly in the left superior frontal gyrus. When comparing all patient groups with controls, increased DMN connectivity was noted in the left cingulum and supplementary motor area. These areas were also significant when comparing only FGIDs patients with controls, indicating altered DMN connectivity in these disorders. Please see: Figure 1 and Table 1.

Conclusion

The study highlights differences in DMNs between patient and control groups, especially in the left superior frontal gyrus, left cingulum, and left supplementary motor area. All disease groups showed variations from controls in the DMN pattern within the left cingulum. Significant differences in the DMN of the supplementary motor area were observed in functional gastric disease groups compared to controls. These findings suggest a link between brain areas involved in sensorimotor processes and symptoms of FD and IBS, providing insights into the neural basis of these conditions. Despite varied changes, common features differentiating the entire study group from healthy controls were identified. This condensed version focuses on the key aspects of your original text, ensuring that the main findings and methodology are clearly presented within the character limit.
P360 Prevalence and risk factors for fatigue in patients with inflammatory bowel disease and endoscopic healing
Authors: Yzet C , Brazier F , Meudjo E , Robert C , Moreau C , Derval E , Richard N , Fumery M
Published: January 2024

Background

Fatigue is a frequent symptom among patients with inflammatory bowel disease (IBD). While the recent STRIDE II international guidelines consider disability-free and normal quality of life as therapeutic targets, the degree of endoscopic healing required to limit fatigue is unknown. The aim of this study was to investigate the prevalence of fatigue and its determinants in a cohort of IBD patients with endoscopic healing.

Methods

We conducted a single-center cross-sectional study between January 2019 and June 2023. All consecutive IBD patients with endoscopic healing Crohn's disease (CD, CDEIS <4) and ulcerative colitis (UC, Mayo ≤ 1) were assessed for disability (IBD-disk) the day of the colonoscopy. Fatigue and severe fatigue were defined by an IBD-Disk energy subscore >5 and >7, respectively.

Results

166 patients were included, of whom 64% (107/166) had CD. The majority of patients were treated with anti-TNF (91/166, 55%), half of them in combination therapy (44/166). The prevalence of fatigue and severe fatigue were 39% (65/166) and 23.5% (39/166) respectively, with no significant difference between CD and UC (p=0.59). The prevalence of fatigue in patient with partial endoscopic healing (Mayo 1 and CDEIS>0 and <4)) and with complete healing (Mayo 0, CDEIS 0) was 44.4% (24/54) and 36.6% (41/112) p =0.424.In multivariate analysis, factors associated with fatigue were female gender (OR=4.2, [1.1; 16.5], p= 0.040), presence of joint pain (OR=4.36, [1.0; 18.2], p= 0.04), sleep disturbance (OR =26.2, [5.5; 124.4], p <0.0001). Younger age (OR=0.95, [0.9; 0.99], p= 0.023) was associated with a significantly lower risk of fatigue. In multivariate analysis, severe fatigue was associated with female gender (OR=3.2, [1.1; 9.2], p= 0.026), the presence of joint pain (OR=2.9, [1.1; 8.1], p= 0.037) or sleep disorders (OR =11.3, [3.6; 35.9], p <0.0001).

Conclusion

One third of IBD patients with endoscopic healing suffer from fatigue. Female gender, arthralgia and especially sleep disorders are risk factors for fatigue. These results argue in favor of a holistic management of IBD patients.
P385 Epithelial neutrophil localization and Claudin-2 immunohistochemical "leaky gut" expression are innovative predictors of outcomes in Ulcerative Colitis patients in endoscopic remission
Authors: Zammarchi I , Santacroce G , Hayes B , Crotty R , O’Driscoll E , Kaczmarczyk W , Maeda Y , McCarthy J , Sugrue K , O’Sullivan C , Burke L , Ghosh S , Iacucci M
Published: January 2024

Background

Patients with Ulcerative Colitis (UC) in clinical and endoscopic remission (ER) may still experience disease relapse, emphasizing the need to identify reliable predictors of outcome in clinical practice. Recently, neutrophil-based histological scores have highlighted the pivotal role of neutrophils in predicting disease outcome. Furthermore, the impairment of the intestinal barrier has been proposed as a crucial element in forecasting disease outcomes. Hence, this study aims to assess the predictive role of epithelial versus lamina propria neutrophil localization and barrier proteins expression in UC patients in ER.

Methods

UC patients in clinical remission who underwent colonoscopy between January 2020 and June 2022 at two tertiary referral centres were retrospectively enrolled. Patients in ER, defined by Mayo Endoscopic Score (MES) ≤1 and UC Endoscopic Index of Severity (UCEIS) ≤1 were included. Histological activity was assessed with Robarts Histopathology Index (RHI), Nancy Histological Index (NHI) and PICaSSO Histological Remission Index (PHRI). Neutrophil localization in the epithelium and lamina propria was accurately evaluated. Additionally, immunohistochemical expression of epithelial barrier proteins, namely Claudin-2 and JAM-A, was assessed to evaluate the integrity of intestinal barrier. Two pathologists experienced in IBD independently analysed all histological slides to ensure reliability. Kaplan-Meier were plotted to analyse survival free from adverse events such as flare-up, change/optimization of medication or hospitalization over a 12-month follow-up period.

Results

Out of 60 UC patients in ER (58.3% males, mean age 44.2±13.6 years), 36.7%, 38.3% and 36.7% were in histological remission according to RHI, NHI and PHRI, respectively. 25% of patients developed an adverse outcome within 12 months. Neutrophils in the epithelium significantly correlated with adverse outcomes compared with lamina propria localization (p=0.03) or their absence altogether (p<0.01). Claudin-2 showed significantly higher expression according to endoscopic and histological activity (Table 1), while no significant difference was found for JAM-A. Notably, strong and diffuse claudin-2 expression was associated with a higher rate of adverse outcomes (p<0.01), as well as the simultaneous presence of epithelial neutrophils and Claudin-2 (p=0.04). Substantial agreement between pathologists was found (K=0.67).

Conclusion

This multicentre retrospective study highlights the potential role of epithelial neutrophils localization and claudin-2 ‘leaky gut’ protein expression as practical clinical tools to predict outcomes in UC patients. These findings hold promise in guiding patient-tailored therapy in IBD.