bluuebunny/crossref_metadata_2025 huggingface dataset:
Structural health dynamic monitoring for gear transmission based on guided waves
Authors: Chai Yuan , Wang Yihan , Liu Qijian , Qing Xinlin
Published: January 2023

The rotating machinery has a wide range of applications in many fields. The gear transmission system is one of the key structures of rotating machinery. Once the failure occurs to the gear system, it will destroy the equipment itself and lead the whole industrial production to break. Thus, it is necessary to directly monitor the health condition of the gear system under static and running working conditions. Guided waves method is a technology which has been widely used in the field of structural health monitoring. In this paper, guided waves technology is innovatively applied to the condition monitoring of gear system, which realizes the gear structure direct monitoring for low speed rotating machinery. The piezoelectric transducers integrated with the SMART Layer were placed near the gear mesh region for the direct health monitoring. The feasibility was verified by the guided waves monitoring experiments in a fixed-axis spur gear transmission system. The tooth wear and gear crack were monitored by guided waves under a single working condition. In addition, the stability verification experiment of guided waves was also performed under various low-speed working conditions. To characterize the propagation of gear faults, considering the characteristics of guided waves, a modified health indicator extraction methodology is proposed based on permutation entropy. The results indicated that the guided waves technology has fantastic potential applications in gear transmission system dynamic direct health monitoring.
Effect of ultraviolet post-curing, laser power, and layer thickness on the mechanical properties of acrylate used in stereolithography 3D printing
Authors: Zeng Yu-Shan , Hsueh Ming-Hsien , Hsiao Te-Ching
Published: January 2023

Three-dimensional (3D) printing technology has developed rapidly in the past few years. This technology is widely used in houses, workpieces, artworks, organs, and even the food industry. Among the multiple 3D printing methods, the stereolithography appearance (SLA) technique is well known for its high printing speed and considerable accuracy. In this research, the optimization parameters of the laser curing technology were applied by changing laser power and molding thickness. The mechanical properties were tested using a tensile test and a compression test of photosensitive resin materials after ultraviolet (UV) curing. The experimental results revealed that increasing the laser power or reducing the molding thickness increased the ultimate tensile strength, tensile Young’s modulus, and compressive strength of the material. However, when the stretch was decreased after UV curing, the strength of the material effectively improved, but the toughness of the material decreased. The abovementioned experimental results will be helpful to researchers for further studies on SLA.
Investigating defects in InGaN based optoelectronics: from material and device perspective
Authors: Nag Dhiman , Bhunia Swagata , Sarkar Ritam , Chatterjee Soumyadip , Laha Apurba
Published: January 2023

III-nitride optoelectronics have revolutionized solid-state lighting technology. However, non-radiative defects play a major bottleneck in determining the performance of InGaN-based optoelectronics devices. It becomes especially challenging when high indium is required to be incorporated to obtain emission at higher wavelength (>500 nm). In this research article, we are going to discuss our investigation on the origin of defects in InGaN-based optoelectronics devices from the material and device perspective and characterize them through various techniques. This article broadly consists of two parts. In the first part, we investigate defects in InGaN based optoelectronics from a material point of view. Here, we discuss the challenges in the growth of InGaN planar (2-dimensional) and nanowires (1-dimensional) with high indium (≥20%) incorporation using the plasma-assisted molecular beam epitaxy (PA-MBE) technique. Photoluminescence spectroscopy (PL) has been performed to characterize these grown samples to assess their optical quality. Atomic force microscopy (AFM) has been employed to characterize the surface morphology of grown InGaN layers. High-resolution transmission electron microscopy (HRTEM) and scanning electron microcopy (SEM) are also used to characterize InGaN planar and nanowire samples grown under various process conditions. In the second part, we investigate the role of defects on InGaN optoelectronics from a device point of view. Here, we discuss the fabrication of InGaN multi-quantum well-based light emitting diodes (LEDs). Temperature-dependent current versus voltage measurements are carried out to investigate the role of defects on carrier dynamics under forward and reverse bias conditions. Frequency-dependent capacitance versus voltage (CV) and conductance versus voltage (GV) techniques are employed extensively to characterize defects in fabricated InGaN LEDs.
Classification of breast microcalcifications with GaAs photon-counting spectral mammography using an inverse problem approach
Authors: Ghammraoui Bahaa , Bader Shahed , Thuering Thomas , Glick Stephen J
Published: January 2023

The purpose of this study was to investigate the use of a Gallium Arsenide (GaAs) photon-counting spectral mammography system to differentiate between Type I and Type II calcifications. Type I calcifications, consisting of calcium oxalate dihydrate (CO) or weddellite compounds are more often associated with benign lesions in the breast, and Type II calcifications containing hydroxyapatite (HA) are associated with both benign and malignant lesions in the breast. To be able to differentiate between these two calcification types, it is necessary to be able to estimate the full spectrum of the x-ray beam transmitted through the breast. We propose a novel method for estimating the energy-dependent x-ray transmission fraction of a beam using a photon counting detector with a limited number of energy bins. Using the estimated x-ray transmission through microcalcifications, it was observed that calcification type can be accurately estimated with machine learning. The study was carried out on a custom-built laboratory benchtop system using the SANTIS 0804 GaAs detector prototype system from DECTRIS Ltd with two energy thresholds enabled. Four energy thresholds detector was simulated by taking two separate acquisitions in which two energy thresholds were enabled for each acquisition and set at (12 keV, 21 keV) and then (29 keV, 36 keV). Measurements were performed using BR3D (CIRS, Norfolk, VA) breast imaging phantoms mimicking 100% adipose and 100% glandular tissues swirled together in an approximate 50/50 ratio by weight with the addition of in-house-developed synthetic microcalcifications. First, an inverse problem-based approach was used to estimate the full energy x-ray transmission fraction factor using known basis transmission factors from varying thicknesses of aluminum and polymethyl methacrylate (PMMA). Second, the classification of Type I and Type II calcifications was performed using the estimated energy-dependent transmission fraction factors for the pixels containing calcifications. The results were analyzed using receiver operating characteristic (ROC) analysis and demonstrated good discrimination performance with the area under the ROC curve greater than 84%. They indicated that GaAs photon-counting spectral mammography has potential use as a non-invasive method for discrimination between Type I and Type II calcifications. Results from this study suggested that GaAs-based spectral mammography could serve as a non-invasive measure for ruling out malignancy of calcifications found in the breast. Additional studies in more clinically realistic conditions involving breast tissues samples with smaller microcalcification specks should be performed to further explore the feasibility of this approach.
Hybrid and heterogeneous photonic integrated near-infrared InGaAs/InAlAs single-photon avalanche diode
Authors: Zhang Jishen , Xu Haiwen , Zhang Gong , Chen Yue , Wang Haibo , Tan Kian Hua , Wicaksono Satrio , Sun Chen , Kong Qiwen , Wang Chao , Ci Wen Lim Charles , Yoon Soon-Fatt , Gong Xiao
Published: January 2023

We have demonstrated the integrated indium gallium arsenide/indium aluminum arsenide (InGaAs/InAlAs) single-photon avalanche diodes (SPAD) with silicon (Si) waveguides and grating couplers on the Silicon-on-insulator substrate. A vertical coupling scheme is adopted which allows the use of a thick bonding interlayer for high yield. The epoxy ‘SU-8’ is selected to be the adhesion layer with a low transmission loss, low volumetric shrinkage, and low curing temperature. In addition, both hybrid and heterogeneous integration schemes are realized which are compatible with the current multi-project wafer process. Extensive performance characterization is carried out while the results are compared. Our hybrid integrated SPAD exhibits high photon detection efficiency (PDE) of ∼21% and a relatively low dark count rate (DCR) of 8.6 × 105 Hz, which are among the best performance reported for InGaAs/InAlAs SPADs while the heterogeneous integrated SPAD shows a decent PDE of 6% with a DCR of 2 × 107 Hz. Combined with the inherent wide applicability of the bonding using the SU-8 layer, this photonic integration provides a promising solution for large-scale quantum information with various material systems.
Constructing free products of cyclic subgroups inside the group of units of integral group rings
Authors: Marciniak Zbigniew , Sehgal Sudarshan
Published: January 2023

It has been proved in Janssens, Jespers, and Temmerman [Proc. Amer. Math. Soc. 145 (2017), pp. 2771–2783] that if

h
h

is an element of prime order

p
p

in a finite nilpotent group

G
G

and

u
=
h
+
(
h
−
1
)
g

h
^

∈

Z

G

u=h+(h-1)g\widehat {h}\in \mathbb {Z}G

,

u
∉
G

u\not \in G

, then

⟨

u
∗

,
u
⟩
≈

C
p

∗

C
p

\langle u^*,u\rangle \approx C_p\ast C_p

. We offer a simple geometric approach to generalize this result.
Proof of two conjectures on Askey-Wilson polynomials
Authors: Castillo K. , Mbouna D.
Published: January 2023

We give positive answer to two conjectures posed by M. E. H Ismail in his monograph [Classical and quantum orthogonal polynomials in one variable, Cambridge University Press, Cambridge, 2005]. These results generalize the classical problems of Sonine and Hahn.
Probabilistic intuition holds for a class of small subgraph games
Authors: Nenadov Rajko
Published: January 2023

Consider the following two-player game on the edges of

K
n

K_n

, the complete graph with

n
n

vertices: Starting with an empty graph

G
G

on the vertex set of

K
n

K_n

, in each round the first player chooses

b
∈

N

b \in \mathbb {N}

edges from

K
n

K_n

which have not previously been chosen, and the second player immediately and irrevocably picks one of these edges and adds it to

G
G

. We show that for any graph

H
H

with at least one edge, if

b
>
c

n

1

/

m
(
H
)

b > c n^{1/m(H)}

, where

c
=
c
(
H
)
>
0

c = c(H) > 0

only depends on

H
H

and

m
(
H
)

m(H)

is the usual density function, then the first player can ensure the resulting graph

G
G

contains

Ω
(

n

v
(
H
)

/

b

e
(
H
)

)

\Omega (n^{v(H)} / b^{e(H)})

copies of

H
H

. The bound on

b
b

is the best possible apart from the constant

c
c

and shows that the density of the resulting graph for which it is possible to enforce the appearance of

H
H

coincides with a threshold for the appearance in the Erdős-Rényi random graph. This resolves a conjecture by Bednarska-Bzdȩga, Hefetz, and Łuczak [J. Combin. Theory Ser. B 119 (2016), pp. 122–154] and provides a prominent class of games for which probabilistic intuition accurately predicts the outcome. The strategy of the first player is deterministic with polynomial running time, with the degree depending on the size of

H
H

.
A partial converse ghost lemma for the derived category of a commutative Noetherian ring
Authors: Liu Jian , Pollitz Josh
Published: January 2023

In this article a condition is given to detect the containment among thick subcategories of the bounded derived category of a commutative noetherian ring. More precisely, for a commutative noetherian ring

R
R

and complexes of

R
R

-modules with finitely generated homology

M
M

and

N
N

, we show

N
N

is in the thick subcategory generated by

M
M

if and only if the ghost index of

N

p

N_\mathfrak {p}

with respect to

M

p

M_\mathfrak {p}

is finite for each prime

p

\mathfrak {p}

of

R
R

. To do so, we establish a “converse coghost lemma” for the bounded derived category of a non-negatively graded DG algebra with noetherian homology.
Heritage Language Instruction to Young Immigrants: An In-depth Look at the Psycholinguistic Effects During the Simultaneous Acquisition of Two Second Languages
Authors: Senar Fernando , Serrat Elisabet , Janés Judit , Huguet Àngel
Published: January 2023

Heritage Language Instruction (HLI) is a resource used in many immigration-receiving countries that allows students with an immigrant background to continue to be in contact with their Heritage Language (HL). However, many of the psycholinguistic effects of this instruction are still unknown. This study aims to provide an in-depth view of the effects of HLI on the development of the HL and the languages of the host country. For this purpose, the sample consisted of 108 students (20 HL learners, 88 controls) of Romanian origin who had emigrated to Catalonia. Their language skills in the phonetic, orthographic, morphosyntactic, lexical, and semantic domains were analysed using linear regression statistics and covariance analysis. The results showed that HLI exerted a mitigating effect on HL attrition, as well as a significant improvement of the linguistic competencies in the autochthonous languages. These results indicate that HLI is an effective tool in the psycholinguistic development of immigrant students, capable of facilitating their academic and social performance.
Predicting microbe–drug associations with structure-enhanced contrastive learning and self-paced negative sampling strategy
Authors: Tian Zhen , Yu Yue , Fang Haichuan , Xie Weixin , Guo Maozu
Published: January 2023

Motivation

Predicting the associations between human microbes and drugs (MDAs) is one critical step in drug development and precision medicine areas. Since discovering these associations through wet experiments is time-consuming and labor-intensive, computational methods have already been an effective way to tackle this problem. Recently, graph contrastive learning (GCL) approaches have shown great advantages in learning the embeddings of nodes from heterogeneous biological graphs (HBGs). However, most GCL-based approaches don’t fully capture the rich structure information in HBGs. Besides, fewer MDA prediction methods could screen out the most informative negative samples for effectively training the classifier. Therefore, it still needs to improve the accuracy of MDA predictions.

Results

In this study, we propose a novel approach that employs the Structure-enhanced Contrastive learning and Self-paced negative sampling strategy for Microbe-Drug Association predictions (SCSMDA). Firstly, SCSMDA constructs the similarity networks of microbes and drugs, as well as their different meta-path-induced networks. Then SCSMDA employs the representations of microbes and drugs learned from meta-path-induced networks to enhance their embeddings learned from the similarity networks by the contrastive learning strategy. After that, we adopt the self-paced negative sampling strategy to select the most informative negative samples to train the MLP classifier. Lastly, SCSMDA predicts the potential microbe–drug associations with the trained MLP classifier. The embeddings of microbes and drugs learning from the similarity networks are enhanced with the contrastive learning strategy, which could obtain their discriminative representations. Extensive results on three public datasets indicate that SCSMDA significantly outperforms other baseline methods on the MDA prediction task. Case studies for two common drugs could further demonstrate the effectiveness of SCSMDA in finding novel MDA associations.

Availability

The source code is publicly available on GitHub https://github.com/Yue-Yuu/SCSMDA-master.
The epidemiology, healthcare and societal burden of basal cell carcinoma in Wales 2000–2018: a retrospective nationwide analysis
Authors: Ibrahim Nader , Jovic Matthew , Ali Stephen , Williams Namor , Gibson John A G , Griffiths Rowena , Dobbs Thomas D , Akbari Ashley , Lyons Ronan A , Hutchings Hayley A , Whitaker Iain S
Published: January 2023

Background

Basal cell carcinoma (BCC) represents the most commonly occurring cancer worldwide within the white population. Reports predict 298 308 cases of BCC in the UK by 2025, at a cost of £265–366 million to the National Health Service (NHS). Despite the morbidity, societal and healthcare pressures brought about by BCC, routinely collected healthcare data and global registration remain limited.

Objectives

To calculate the incidence of BCC in Wales between 2000 and 2018 and to establish the related healthcare utilization and estimated cost of care.

Methods

The Secure Anonymised Information Linkage (SAIL) databank is one of the largest and most robust health and social care data repositories in the UK. Cancer registry data were linked to routinely collected healthcare databases between 2000 and 2018. Pathological data from Swansea Bay University Health Board (SBUHB) were used for internal validation.

Results

A total of 61 404 histologically proven BCCs were identified within the SAIL Databank during the study period. The European age-standardized incidence for BCC in 2018 was 224.6 per 100 000 person-years. Based on validated regional data, a 45% greater incidence was noted within SBUHB pathology vs. matched regions within SAIL between 2016 and 2018. A negative association between deprivation and incidence was noted with a higher incidence in the least socially deprived and rural dwellers. Approximately 2% travelled 25–50 miles for dermatological services compared with 37% for plastic surgery. Estimated NHS costs of surgically managed lesions for 2002–2019 equated to £119.2–164.4 million.

Conclusions

Robust epidemiological data that are internationally comparable and representative are scarce for nonmelanoma skin cancer. The rising global incidence coupled with struggling healthcare systems in the post-COVID-19 recovery period serve to intensify the societal and healthcare impact. This study is the first to demonstrate the incidence of BCC in Wales and is one of a small number in the UK using internally validated large cohort datasets. Furthermore, our findings demonstrate one of the highest published incidences within the UK and Europe.
DOP04 Single cell RNA sequencing reveals a potential role for IFNγ in priming circulating monocytes for intestinal inflammatory function in Crohn’s Disease.
Authors: Hornsby E , Gadhok R , Yadon A N , Lindsay J O , Stagg A J
Published: January 2023

Background

Hyper-inflammatory monocyte-derived cells accumulate in the intestine and contribute to pathology in inflammatory bowel disease (IBD). Our previous work has shown that intestinal monocyte-derived cells from Crohn’s Disease patients have a reduced response to the immunoregulatory cytokine IL-10 and that this property is already established in circulating monocytes prior to their arrival in the intestine. Here, we have used scRNAseq and functional experiments to define the scope of IBD-associated changes in blood monocytes and explore the role of inflammatory cytokines in shaping these.

Methods

Total monocytes were isolated from the peripheral blood of 12 newly diagnosed, treatment naive IBD patients with active endoscopic disease (6 Crohn’s Disease [CD] and 6 Ulcerative Colitis [UC]) and 10 healthy controls (HC) by negative magnetic selection. scRNAseq was performed using the 10x Genomics Chromium 3’ assay at a target capture rate of 1000 cells/sample and sequencing at ~50,000 reads/cell. Data were analysed using Cell Ranger, Seurat, Metascape and Gene Set Enrichment Analysis. Blood CD14+ monocytes from healthy donors were pre-incubated in medium alone or with IFNγ (100U/ml) for 24 hours. Inhibition of LPS-induced TNFα production by IL-10 was measured by intracellular cytokine staining and flow cytometry.

Results

UMAP clustering identified six transcriptionally distinct monocyte clusters: clusters 0, 1 and 2 mapped to classical monocytes; cluster 3 to non-classical monocytes; cluster 4 to intermediate monocytes; and cluster 5 contained platelet signals. The proportion of cluster 4 was increased in CD patients compared to HC. Differential gene expression analysis of CD and UC monocyte clusters compared to healthy controls identified a total of 246 differentially expressed genes (DEGs) in CD and 149 in UC. Only 39 of these DEGs were significantly affected in both diseases. Both CD and UC DEGs were significantly enriched for pathways related to cytokine signalling and inflammation (Figure 1).

IFNγ and TNFα -response gene sets were positively enriched in CD, but negatively enriched in UC (Figure 2).

Pre-treatment of healthy monocytes with IFNγ in vitro reduced their response to IL-10 as measured by inhibition of LPS-induced TNFα (Figure 3).

Conclusion

Expression of genes associated with inflammation and cytokine signaling are altered in blood monocytes from IBD patients implying their modification by systemic signals prior to arrival in the intestinal mucosa. Cytokine- (IFNγ and TNFα) stimulated genes are differentially affected in CD and UC monocytes. In CD, systemic IFNγ may reduce the responsiveness of monocytes to IL-10 to prime them for inflammatory function.
DOP31 Gut metabolomic and compositional signatures predict response to treatment with exclusive enteral nutrition in children with active Crohn’s disease
Authors: Gerasimidis K , Nichols B , Briola A , Havlik J , Mascellani A , Milling S , Ijaz U , Quince C , Svolos V , Russell R K , Hansen R
Published: January 2023

Background

Predicting response to treatment with exclusive enteral nutrition (EEN) in paediatric Crohn’s disease (CD) can lead to more personalised, cost-effective, and efficacious therapy. We explored the ability of pre-treatment clinical and multi-omics parameters to predict faecal calprotectin (FCal) levels at EEN completion.

Methods

In 37 children [median (IQR), 12.4y (10.1, 15.0)] with active CD, disease parameters, dietary intake, 19 inflammatory cytokines, and 92 plasma inflammation-related proteomic markers in plasma, diet-related bacterial metabolites and 1H NMR metabolomics in faeces, as well as the faecal, duodenal, ileal, ascending and descending colon microbiome (16S rRNA sequencing), and dietary intake were measured prior to EEN initiation. Fifteen children responded to EEN (RS) and 12 not (non-RS) using a FCal cut-off <300.

Results

Disease and host immunological parameters did not predict FCal levels at EEN completion. Responders had lower fibre intake, half the concentration of butyrate, acetate, phenylacetate and higher bacterial richness, in faeces, than non-RS. A model trained with the discriminant duodenal operational taxonomic units (OTUs) demonstrated a sensitivity of 67%, specificity of 90% and positive predictive value of 80% to differentiate RS from non-RS. The predictive ability of the faecal and the microbiomes of other mucosal sites was inferior to that of the duodenum. In multicomponent prediction including all datasets and faecal microbiome, higher levels of phenylacetate and relative abundance of OTU of Bacteroides, were predictive of non-RS with a sensitivity of 73%, specificity of 81% and positive predictive value of 73%. Replacing the faecal with the duodenal microbiome in a subset of participants (n=14), produced a model with 100% accuracy to predict RS from non-RS. The single most important variable in this model was a Lachnospira OTU which was absent in all RS but highly abundant in non-RS.

Conclusion

We identified pre-treatment microbial signals and diet-related metabolites which may comprise targets for pre-treatment optimisation and personalised nutritional therapy in CD.
DOP40 Corticosteroid discontinuation and clinical outcomes in patients with moderately to severely active Crohn’s disease treated with upadacitinib
Authors: Dubinsky M C , D’Haens G , Dewit O , Juillerat P , Panaccione R , Fujii T , Lacerda A P , Dubcenco E , Anyanwu S , Doshi C , Mallick M , Garrison A , Liu J , Loftus Jr E V
Published: January 2023

Background

Corticosteroids (CS) may be used for induction of remission in Crohn’s disease (CD); however, side effects, toxicities, and low rates of mucosal healing may limit their long-term use. Safety and efficacy of upadacitinib (UPA), an oral selective Janus kinase inhibitor, were evaluated among patients with CD receiving UPA with CS at baseline in phase 3 clinical trials.

Methods

In 2 phase 3 studies (U-EXCEL, NCT03345849; U-EXCEED, NCT03345836), patients with moderate-to-severe CD were randomized to 12-week induction with UPA 45 mg once daily (QD) or placebo (PBO). Patients who achieved clinical response to UPA 45 mg were rerandomized in U-ENDURE (NCT03345823) to UPA 30 mg QD, UPA 15 mg QD, or PBO for a 52-week maintenance period. Patients taking CS at baseline or week 0 of maintenance (end of induction) were included. A CS taper began at induction week 4 and continued during maintenance. Endpoints included the proportion of patients who discontinued CS use (CS-free) at week 12 or for ≥ 90 days prior to week 52, and achieved clinical remission by stool frequency/abdominal pain score or by Crohn’s Disease Activity Index (CDAI), enhanced clinical response, decrease of at least 100 points in CDAI from baseline, endoscopic remission, and endoscopic response at week 12 and week 52. CS daily dose (in prednisone equivalent doses) was recorded. Safety was assessed through induction and maintenance.

Results

Of 1021 patients evaluated, 358 (35.1%) were taking CS at baseline (mean daily prednisone equivalent dose, 23.0 mg). Greater changes from baseline in mean CS daily dose were observed with UPA vs PBO at induction week 12 (−17.3 mg vs −10.7 mg); these changes were sustained at maintenance week 52 (UPA 30 mg, −16.4 mg; UPA 15 mg, −17.4 mg; PBO, −14.7 mg). The proportion of patients who achieved a ≥ 50% reduction in CS daily dose was higher with UPA vs PBO at induction week 12 among patients taking CS at baseline (72.6% vs 48.4%) and at week 52 among patients taking CS at baseline or week 0 of maintenance (UPA 30 mg, 49.2%; UPA 15 mg, 44.4%; PBO, 11.1%). A significantly higher proportion of patients taking UPA vs PBO were CS-free and achieved clinical remission, clinical response, endoscopic response, and endoscopic remission at week 12 (Fig 1A) and week 52 (Fig 1B). Rates of adverse events (AEs), serious AEs, and discontinuation were comparable between groups (Table 1). Serious infections, opportunistic infections, and herpes zoster events were numerically higher with UPA vs PBO (Table 1).

Conclusion

Patients with CD taking CS were able to taper and discontinue their CS regimen and experience clinical and endoscopic improvements with UPA treatment during the induction and maintenance periods.
DOP56 Long-term disease progression and resective surgery rates in Crohn’s disease over different therapeutic eras – a population-based study from western Hungary between 1977–2020, data from the Veszprem county cohort
Authors: Gonczi L , Lakatos L , Golovics P A , Pandur T , David G , Erdélyi Z , Szita I , Lakatos P L
Published: January 2023

Background

Few population-based studies have investigated the long-term surgery rates of Crohn’s disease (CD). The present study is a continuation of the Veszprem IBD population based cohort with a follow-up since 1977. Our aim was to analyze the long-term disease course and surgery rates over different therapeutic eras in a prospective population-based database from Veszprem Province, including incident CD patients.

Methods

Patient inclusion was between January 1, 1977 and December 31, 2018; follow-up ended December 31, 2020. Both in-hospital and outpatient records were collected and comprehensively reviewed at diagnosis and during clinical follow-up. Surgery rates were examined in three different eras based on time of diagnosis: cohort-A, 1977-1995; cohort-B, 1996-2008; and cohort-C, 2009-2018.

Results

Data of 946 incident CD patients were analyzed (male/female: 496/450; median age at diagnosis:28 years(y) [IQR: 22-40]), with a median of 15y(IQR 9-21) follow-up.Table 1. Overall immunosuppressive therapy use was increasing by time (48.0%/62.4%/65.5%), as well as the probability of biological therapy initiation within 5 years of diagnosis (0.0±0%/7.3±1.2%/22.7±2.2%) in cohorts A/B/C. Figure 1. The cumulative probability of disease behavior progression in patients with luminal (B1) behavior into stenosing or penetrating phenotype (B2/B3) was 27.1±5.3%/ 21.5±2.5%/ 11.3±2.2% in cohorts A/B/C after 5 years (pLogRank<0.001). Figure 2. The cumulative probability of resective surgery in the total population was 34.2±1.6% after 10 years, 44.9±2.0% after 20 years, and 61.9±4.2% after 30 years. The cumulative probability of first resective surgery between cohorts A/B/C were as follows: 28.7±3.7%/ 26.3±2.1%/ 28.1±2.4% after 5 years; 39.4±4.0%/ 32.6±2.2%/ 33.0±2.7% after 10 years; and 54.5±4.1%/ 41.4±2.6% (cohorts A/B) after 20 years. There were no statistically significant differences in surgery rates between the cohorts overall [pLogRank=0.055], however a notable decrease in long-term (20y) surgery rates was observed comparing cohorts B and C vs. cohort A.Figure 3. A cox-regression multivariate analysis showed that stenosing or penetrating disease (B2/B3) behavior (HR 4.52; 95%CI 3.60-5.68; p<0.001) and ileal (L1) location at diagnosis (HR 1.30; 95%CI 1.05-1.61; p=0.016) were independent predictors of resective surgery.Table 2.

Conclusion

Disease behavior progression decreased, however no differences in resective surgery risk at 5 and 10 years from diagnosis have been observed in incident CD patients despite the increasing use of immunosuppressives and biologicals in this population based cohort. However, a decrease is shown in long term (20y) surgery risk comparing the earliest cohort to latter ones with higher immunosuppressive and biological use.
DOP66 Ileal resections from fibrotic-CD patients present microbiota dysbiosis, altered metabolomic profiles and metabolite-sensing GPCRs expression
Authors: Bauset C , Carda-Diéguez M , Buetas E , Lis-López L , Seco-Cervera M , Coll S , Ortiz-Masiá D , Calatayud S , Barrachina M D , Mira Á , Cosín-Roger J
Published: January 2023

Background

Crohn’s Disease (CD) is a subtype of IBD characterized by a chronic transmural inflammation of the gastrointestinal tract associated with several complications being intestinal fibrosis the most frequent. CD patients present microbiota dysbiosis and altered metabolomic profiles. GPCRs constitute a family of receptors which could be involved in inflammatory and fibrotic processes associated to CD. We aim to characterize microbiota composition, tissue metabolomic profile and metabolite-sensing GPCRs expression in ileal resections from fibrotic CD patients.

Methods

Ileal resections from B2-CD (n=21) and non-IBD (n=13) patients were obtained. Microbiota characterization was performed by 16S rRNA gene Illumina Miseq sequencing. Bioinformatic analysis of sequencing data was performed using constrained correspondence analysis and non-parametric Wilcoxon test to compare species proportions. Bacterial load was estimated by qPCR. Metabolomic analysis was performed by NMR. Results are expressed as μg metabolite/g tissue. Murine intestinal fibrosis was induced in C67BL/6 mice by: a) the heterotopic intestinal transplant model and b) chronic administration of 4 cycles of increasing DSS percentages. Gene expression of GPCRs was analyzed by qPCR. Data were expressed as fold induction vs control (mean±SEM) and compared by a t-test. Correlations were analyzed with the Spearman coefficient.

Results

First, microbiota analysis revealed a reduction in bacterial diversity and load in fibrotic CD patients. Then, in B2-CD samples we found at genus level Enterococcus genera significantly decreased and at species level Ruminococcus bromii and Faecalibacterium prausnitzii also reduced compared to controls.

From the metabolomic analysis, altered levels of metabolites were found in ileal resections from fibrotic CD patients as summarized in Table 1.

Next, B2-CD patients exhibited differential expression of metabolite-sensing GPCRs vs non-IBD as shown in Table 2.

Moreover, gene expression of fibrotic markers was analyzed in B2-CD patients and significantly increased levels of COL1A1 (13.22±4.38), COL3A1 (1.84±0.52), and COL4A1(7.75±2.19), were found vs controls. Of interest, GPR81, GPR84, GPR4 and GPR68 positively correlated with profibrotic markers, specifically with COL1A1 and COL4A1.

Finally, in line with human results, we also analyzed the expression of metabolite-sensing GPCRs in two different murine colitis models and results obtained are represented in Table 3.

Conclusion

Fibrotic CD patients exhibit microbial dysbiosis, joined with altered levels of metabolites and gene expression of metabolite-sensing GPCRs, which are also affected in murine colitis models. Their correlation with profibrotic markers points them as protagonists of intestinal fibrosis.
DOP72 HLA-DQA1*05 associates with immunogenicity and loss of response to anti-TNF therapy in the IBD population: A meta-analysis
Authors: Bergstein S , Spencer E A
Published: January 2023

Background

The human leukocyte antigen (HLA) allele group HLA-DQA1*05 has been associated with the development of antidrug antibodies (ADA) to tumor necrosis factor antagonists (anti-TNF)1 in the inflammatory bowel disease (IBD) population, except in the setting of proactive optimization2. We performed a meta-analysis to determine the prevalence of HLADQA1*05 carriage, to define the association of HLA-DQA1*05 on immunogenicity and loss of response (LOR) to anti-TNF, and to explore the impact of therapeutic drug monitoring (TDM) on this association.

Methods

A systematic search of EMBASE, MEDLINE, Web of Science, and SCOPUS was conducted and identified 49 studies. Fourteen studies were included in the meta-analysis according to our inclusion and exclusion criteria. Two reviewers independently assessed eligibility and extracted data. Data extraction focused on the prevalence of HLADQA1*05 carriage, management style of the subjects (proactive TDM vs not), use of combination therapy with immunomodulators (IMM), and association of the variant with ADA and LOR. To examine the potential mitigating effect of management style, three forest plots were generated for each outcome including: 1. all studies, 2. studies using solely proactive TDM, and 3. studies where TDM was either not defined or not performed.

Results

The prevalence of HLADQA1*05 carriage was 43.3% across the 14 manuscripts (Table 1). Ten studies used data from adult populations, 2 reported on pediatrics only, and 2 reported on a mix of pediatrics and adults. Nine studies took place in Europe, and 5 occurred in North America. A little over half (57%) were abstracts. All studies included some patients on combination therapy with IMM. Data analysis confirmed that possessing the HLADQA1*05 variant leads to an increased ADA risk (OR 1.63 [95% CI: 1.35 - 1.98]). When focusing on the studies that used proactive optimization of anti-TNF therapy, the variant was no longer a risk factor for developing ADA (OR 0.37 [95% CI: 0.19 - 0.70]). Without proactive optimization, the carriage of HLADQA1*05 appears to consistently be associated with a higher risk of immunogenicity (OR 1.93 [95% CI: 1.58 - 2.36]) (Figure 1). HLADQA1*05 was also found to be a risk factor for LOR (HR 1.84 [95% CI: 1.53 - 2.22]) (Figure 2); insufficient data were available for the studies with proactive TDM on LOR.

Conclusion

Prevalence of HLADQA1*05 carriage is consistent across studies from both North America and Europe. This variant increases the risk of ADA and LOR to anti-TNF. However, in studies that used solely proactive TDM, variant carriage no longer conferred a risk for ADA.

1. Sazonovs A, et al. Gastro. 2020;158(1):189-199.

2. Spencer EA, et al. Gastro. 2022;162(6):1746-1748.e1743.
DOP76 Comparison of healing of complex perianal Crohn′s disease fistulas by advancement flap and mesenchymal stem cell therapy
Authors: Serclova Z , Tremerova A , Lengalova M , Petra Z
Published: January 2023

Background

The combination of surgical approach and biologic treatment is the most successful approach to achieve healing of perianal Crohn′s disease (CD) fistulas. Alongside conventional surgical methods (advancememt flap AF), a new method of fistula closure - allogeneic mesenchymal stem cell (MSC) therapy found its way to clinical practice.

Methods

The aim of a single centre prospective observational study was to compare the healing results of complex perianal CD fistulas by advancement flap and mesenchymal stem cell therapy (by darvadstrosel). 119 consecutive CD patients with complex fistula (95 with anorectal and 24 anovaginal); treated by MSC-darvastrocel in between 2018 to 3/2022. All patients had a long term loose seton drainage and optimized conventional therapy with luminal remission confirmed by colonoscopy.

Complete healing was clinically assessed (no visible external opening or a scar without secretion, no inflammation, no subsequent perianal surgery needed within 3 months post index surgery).

Results

AF group: Duration of luminal CD was 8,84 years (1-38) and perianal CD 4,74 years (0,5-17). Patients underwent 4,22 (1-23) previous perianal surgeries. The follow up was 11,47 months (0,5-48,9). Conservative therapy (biologics and immunosuppressants) was stable for 23,1 months (1-137). Patients did not suffer from anorectal stenosis or rectal inflammation.

MSC group: (60 pp. 36F/24M): Duration of luminal CD was 13 years (2-43 years), of perianal CD 7 years (2-23 years). Number of previous perianal surgeries was 8 (3-25). Conservative therapy was stable for 19 months (1-120). Follow up was 12,5 months (5-34). 38,3% (23) of patients had anorectal stenosis, 38,3% patients underwent advancement flap procedure prior, and 62% suffered from chronic inflammation in rectum.

Complete healing was achieved in 86,5 % pts in the AF group and 74.1% of those were healed even with vaginal fistulas.

Conclusion

There was no significant difference in the healing rate of both methods (p= 0,202).

AF procedure could be beneficial in vaginal fistulas, where MSC therapy is contraindicated.

MSC therapy is useful in the case of chronic changes of rectal mucosa, anorectal stenosis and the presence of 2 internal openings, where AF procedure is not performable.

High success rate in both groups may be conditioned by good preparation of patients (multiple previous drainages) and stable luminal disease (stable conservative treatment).
DOP83 Proactive dosing is superior to clinically based dosing in terms of endoscopic healing in paediatric patients with Crohn’s disease receiving maintenance infliximab: A randomized controlled trial
Authors: Kang B , Moon J S , Lee Y J , Kim M J , Choe B H , Ko J S , Park J H , Choe Y H
Published: January 2023

Background

Proactive dosing based on drug monitoring of adalimumab has been reported to be associated with higher rates of clinical remission in children with Crohn’s disease (CD). We aimed to investigate whether proactive drug monitoring of infliximab (IFX) is associated with higher rates of endoscopic healing (EH) in paediatric patients with CD.

Methods

We conducted a nonblinded, randomized controlled trial of 112 children with CD who were biologic naïve and had responded to induction treatment with IFX at 4 centers in South Korea from July 2017 to November 2020. Patients were randomly assigned to groups that received dosing based on proactive monitoring or clinically based dosing. The primary endpoint was EH at 1 year treatment.

Results

The primary endpoint was achieved in 80.0% (40/50) of the proactive dosing group and 57.1% (28/49) of the clinically based dosing group (P = 0.025). Transmural healing was achieved in 37.8% (17/45) of the proactive dosing group and 30.8% (12/39) of the clinically based dosing group (P = 0.657). Sustained corticosteroid-free clinical remission was achieved in 89.5% (51/57) of the proactive dosing group and 70.9% (39/55) of the clinically based dosing group (P = 0.025). Sustained durability of infliximab was observed in 94.7% (54/57) of the proactive dosing group and 92.7% (51/55) of the clinically based dosing group (P = 0.714).

Conclusion

Dosing based on proactive monitoring was superior to clinically based dosing in terms of endoscopic healing in a randomized controlled trial of paediatric CD.
P002 Exclusive Enteral Nutrition, the gut microbiome and corticosteroid response in patients with acute severe colitis
Authors: Bajaj A , Markandey M , Vuyyuru S , Mohta S , Singh M , Verma M , Kumar S , Kante B , Kumar P , Makharia G , Kedia S , Travis S , Ahuja V
Published: January 2023

Background

Supplementation with exclusive enteral nutrition (EEN) in addition to standard of care with intravenous corticosteroids (SOC) augments the steroid response in patients with acute severe ulcerative colitis (ASUC). EEN is known to alter gut microbial composition. The present study identifies changes in gut microbiota driven by EEN in patients with ASUC receiving standard steroid therapy and examines correlations between EEN-associated bacteria and response to corticosteroid therapy.

Methods

Stool samples were collected at baseline (Day0) and post-therapy (Day 7) from 44 patients with ASUC who received either SOC (n=24) or SOC supplemented with EEN (n=20) for a period of 7 days, at baseline (Day 0) and post-therapy (Day-7). Microbiome characterization was carried out using 16S rRNA gene sequencing followed by data processing using QIIME2 and R packages to analyze diversity and differentially abundant taxa.

Results

Seven-day EEN supplementation of SOC in patients with ASUC resulted in enhanced proportions of Methylobacterium, Sphingomonas, Limosilactobacillus, Megamonas, Thermus, Viellonella, with a reduction in Ruminococcus gnavus, Gemmiger, Pseudomonas, and Enterococcus. EEN-mediated enhancement in specific taxa correlated positively with patients’ day-7 serum albumin levels and negatively with day-3 faecal calprotectin levels (FCal) (Fig.1). Gut microbial composition of patients who responded to EEN-augmented SOC showed an enhanced abundance of Coprococcus, Megamonas, Oribacterium, Sediminibacterium, Acidibacter, and Thermus, and reduction in Sutterella, R. gnavus, Collinsella, Dorea, and Morganella, when compared to non-responders (Fig.2). Baseline gut microbiome signature in patients with ASUC predicts a potential response to both SOC and EEN-supplemented SOC in patients with ASUC (Fig.3).

Conclusion

Augmentation of clinical response by EEN-conjugated corticosteroid therapy is accompanied by specific gut microbial changes in patients with ASUC.
P038 Notch pathway in fibrosis: a new anti-fibrotic therapy in Crohn's disease?
Authors: Marti-Chafer S , Jimenez-Mallen E , Mendoza T , Macias-Ceja D C , Bauset C , Seco-Cervera M , Calatayud S , Cosin-Roger J , Barrachina M D , Ortiz-Masiá D
Published: January 2023

Background

Fibrosis represent the main complications related to Crohn's disease (CD). Notch signalling mediate fibrogenic process, including epithelial-mesenchymal transition (EMT) and fibroblast senescence but its role in CD fibrosis is currently unknown. Previous studies have shown a high expression of NOTCH4, NOTCH3, DLL3 and DLL4 in CD fibrotic tissue. DLL4 mainly activates transcription factors involved in EMT, and macrophages could act as a possible source of DLL4 (Edo, et al., 2022. JCC (i200)).The general aim of the present study is to determine the possible potential of Notch pathway as a therapeutic target in intestinal fibrosis associated with CD. Specifically, we pretend: to analyze the localization of NOTCH3/4 receptors in the intestinal tissue of patients with CD complicated; to study the relevance of NOTCH3/4 receptors in the EMT; to study the relevance of Notch pathway in the senescence of intestinal fibroblast.

Methods

We have analyzed in intestinal samples from CD patients with complicated lesions: the localization of NOTCH3/4 receptors by IH and the protein expression of senescence markers (BCL2 and P53) by WB. We carry out in vitro studies and analyze: the protein expression of HES1 (effector Notch pathway) and EMT markers in DLL4-HT29 treated cells transfected with miNOTCH3 or miNOTCH4; and the protein expression of senescence proteins in HSIF fibroblasts treated with DLL4 or DLL3.

Results

NOTCH3 was located preferentially in muscular areas -muscularis mucosa, endothelium and muscularis externa- with a striking staining of infiltrated cells in the mucosa of the unaffected area. NOTCH4 is found more specifically in the crypts of the mucosa, as well as in cells of the lamina propria of the unaffected mucosa. The expression of senescence proteins in the tissue showed elevated levels of BCL2 and P53, compared to the unaffected tissue of the same patient. DLL4 increased the protein expression of EMT markers in HT29 cells, and NOTCH4 silencing significantly reverted the expression of these EMT markers. NOTCH3 silencing produced no significant changes after DLL4-HT29 treatment. DLL3, and not DLL4, produced in intestinal fibroblasts a significant increase in the protein expression levels of BCL2, and P53, compared to the vehicle (Figure).

Conclusion

NOTCH pathway is involved in the regulation of key cellular functions and processes essential for the pathogenesis of intestinal fibrosis in CD patients. DLL4-NOTCH4 interaction triggers transcription factors involved in mesenchymal epithelial transition in colonic epithelial cells, while DLL3 seems to have a more relevant role in activation of senescence in fibroblasts.
P066 ON104, a novel bioengineered antibody targeting oxidized Macrophage Migration Inhibitory Factor (oxMIF) shows efficacy in two distinct models of experimental colitis
Authors: Ferhat M , Mangano K , Nicoletti F , Landlinger C , Michael T
Published: January 2023

Background

Macrophage Migration Inhibitory Factor (MIF) is a pleiotropic inflammatory cytokine and a primary counter-regulator of glucocorticoids (GCs) that emerged as a pivotal regulator of chronic inflammation including inflammatory bowel diseases (IBD). MIF occurs in two immunologically distinct, conformational isoforms: reduced MIF, ubiquitously present in various tissues and the circulation of healthy subjects, and oxidized MIF (oxMIF), described as the pathogenic and druggable isoform of MIF. In this study we evaluated the anti-inflammatory effects of the anti-oxMIF antibody ON104 in two different mouse models of colitis.

Methods

The fully human antibody ON104, which specifically targets oxMIF, was generated by advanced antibody engineering technology. The therapeutic potential of the Fc-silenced ON104 antibody was tested in two different models of colitis in mice: the acute model of DSS-induced colitis in C57BL/6 mice and the chronic model of adoptive T-cell transfer in SCID mice. At disease induction, ON104 was given twice a week for 8 weeks (chronic colitis) or three times for 1 week (acute colitis). Body weight, stool consistency, and rectal bleeding were assessed to evaluate colitis severity. At the end of the DSS-induced colitis model, colons were dissected for immuno-histological examinations.

Results

ON104 antibody, specifically directed against oxMIF, was completely devoid of Fcγ receptors binding and cytokine triggering in the presence of immune cells. Treatment with ON104 in the chronic colitis model substantially attenuated clinical signs of colitis by thwarting body weight loss and restoring stool consistency. In the acute DSS colitis model, oxMIF neutralization was able to reduce mucosal thickness and colonic immune cell infiltration compared to vehicle-treated mice.

Conclusion

Our findings substantiate the role of oxMIF in the pathogenesis of experimental colitis. Thus, targeting oxMIF may represent a new and promising treatment option for IBD.