bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

.
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

Abstract
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

AbstractMotivationPredicting 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.ResultsIn 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.AvailabilityThe 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

Abstract

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

Abstract

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

Abstract

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 &lt;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

Abstract

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

Abstract

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&lt;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&lt;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

Abstract

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.