bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of engagement, persistence and adherence on cognitive training outcomes in older adults with and without cognitive impairment: a systematic review and meta-analysis of randomised controlled trials
Authors: Li Zhen , He Hao , Chen Yiqi , Guan Qing
Published: January 2024

Background

Limited understanding exists regarding the influences of engagement, persistence and adherence on the efficacy of cognitive training for age-related cognitive decline and neurodegenerative cognitive impairment.

Methods

This study conducted a meta-analysis of randomised controlled trials (RCTs). We systematically searched MEDLINE, PubMed, Web of Science, Embase and CINAHL databases from 1 January 2012 to 13 June 2023, and included RCTs assessing the effects of cognitive training in older adults, both with and without cognitive impairment. Hedges’ g with a 95% confidence interval (CI) was used to synthesise cognitive training effect sizes on various neuropsychological tests. Subgroup analyses were conducted based on variables including engagement, persistence, adherence and cognitive conditions of normal cognition, mild cognitive impairment (MCI) or neurodegenerative dementia.

Results

This meta-analysis included 55 RCTs with 4,455 participants with cognitive conditions spanning normal cognition, MCI and neurodegenerative dementia. The mean age of participants was 73.9 (range: 65.7–84.5) years. Overall, cognitive training showed a significant cross-domain effect (Hedges’ g = 0.286, 95% CI: 0.224–0.348). Training effects are significant when engagement or persistence rates exceed 60% or when adherence rates exceed 80%. Higher levels of persistence are required to achieve significant training effects in memory, visuospatial ability and reasoning than in executive function and attention and language. Higher persistence is also required for older adults with normal cognition to achieve significant training gains compared to those with cognitive impairment.

Conclusions

This systematic review highlights the critical roles of engagement, persistence and adherence in augmenting the efficacy of cognitive training.
Evaluation of disposable protective garments against epoxy resin permeation and penetration from anti-corrosion coatings
Authors: Mellette Michael P , Bello Dhimiter , Bello Anila , Xue Yalong , Yost Michael , Woskie Susan
Published: January 2024

Introduction

Epoxy-based resin formulations are a frequent cause of allergic and irritant contact dermatitis in the construction and painting industries. Cases of epoxy resin contact dermatitis continue to persist across many sectors and are likely attributable to the growing use of epoxy products, including epoxy-based anti-corrosion coatings and inadequate skin protection. There are no published performance data against epoxy resins for garment materials and gloves to guide proper material selection in the workplace.

Objectives

The objective of this study was to evaluate the resistance of 5 protective garment materials against permeation and penetration by bisphenol A diglycidyl ether and its higher oligomers found commonly in epoxy-based anti-corrosion coatings.

Methods

Five disposable garment materials were evaluated for resistance to bisphenol A diglycidyl ether monomers and oligomers during contact with epoxy-based anti-corrosion coatings, including latex gloves, nitrile gloves, Tyvek coveralls, polypropylene/polyethylene (PP/PE) coveralls, and a cotton T-shirt. A permeation test cell system was used to evaluate each garment material against an epoxy-based zinc-rich primer and an epoxy-based intermediate coating using a realistic application method. Glass fiber filters were used to collect permeating and penetrating epoxy resin during a 120-min test period. Bisphenol A diglycidyl ether quantification was performed with high-performance liquid chromatography–electrospray ionization-tandem mass spectrometry. Paint loading, coating thickness, and homogeneity were assessed on polytetrafluoroethylene filters sprayed in series in permeation test cells.

Results

Latex gloves provided the least resistance to permeation by BADGE in coating formulations, with a maximum cumulative permeation over the 2-h test interval of 21.7 ng cm−2 with the primer and 513.8 ng cm−2 with the intermediate coating product. Nitrile gloves were not permeated by either coating formulation. The Tyvek coveralls provided greater protection as compared to the PP/PE coveralls. The cotton T-shirt was penetrated by bisphenol A diglycidyl ether more frequently than any of the tested garment materials and resulted in a maximum cumulative penetration of 128 ng cm−2 with the primer and 28.0 ng cm−2 with the intermediate coating.

Conclusion

Although all the garment materials evaluated during this study provided sufficient protection to prevent cumulative permeation in excess of the established acceptable permeation thresholds, the use of nitrile gloves and Tyvek coverall is highly recommended to minimize skin exposure to bisphenol A diglycidyl ether. We recommend cotton T-shirts to be used under Tyvek coveralls as a secondary layer of skin protection and for added comfort, but not as a primary protection layer.
Non-Negative matrix factorization combined with kernel regression for the prediction of adverse drug reaction profiles
Authors: Zhong Yezhao , Seoighe Cathal , Yang Haixuan
Published: January 2024

Motivation

Post-market unexpected Adverse Drug Reactions (ADRs) are associated with significant costs, in both financial burden and human health. Due to the high cost and time required to run clinical trials, there is significant interest in accurate computational methods that can aid in the prediction of ADRs for new drugs. As a machine learning task, ADR prediction is made more challenging due to a high degree of class imbalance and existing methods do not successfully balance the requirement to detect the minority cases (true positives for ADR), as measured by the Area Under the Precision-Recall (AUPR) curve with the ability to separate true positives from true negatives [as measured by the Area Under the Receiver Operating Characteristic (AUROC) curve]. Surprisingly, the performance of most existing methods is worse than a naïve method that attributes ADRs to drugs according to the frequency with which the ADR has been observed over all other drugs. The existing advanced methods applied do not lead to substantial gains in predictive performance.

Results

We designed a rigorous evaluation to provide an unbiased estimate of the performance of ADR prediction methods: Nested Cross-Validation and a hold-out set were adopted. Among the existing methods, Kernel Regression (KR) performed best in AUPR but had a disadvantage in AUROC, relative to other methods, including the naïve method. We proposed a novel method that combines non-negative matrix factorization with kernel regression, called VKR. This novel approach matched or exceeded the performance of existing methods, overcoming the weakness of the existing methods.

Availability

Code and data are available on https://github.com/YezhaoZhong/VKR.
Exact global alignment using A* with chaining seed heuristic and match pruning
Authors: Groot Koerkamp Ragnar , Ivanov Pesho
Published: January 2024

Motivation

Sequence alignment has been at the core of computational biology for half a century. Still, it is an open problem to design a practical algorithm for exact alignment of a pair of related sequences in linear-like time.

Results

We solve exact global pairwise alignment with respect to edit distance by using the A* shortest path algorithm. In order to efficiently align long sequences with high divergence, we extend the recently proposed seed heuristic with match chaining, gap costs, and inexact matches. We additionally integrate the novel match pruning technique and diagonal transition to improve the A* search. We prove the correctness of our algorithm, implement it in the A*PA aligner, and justify our extensions intuitively and empirically.

 

On random sequences of divergence d=4% and length n, the empirical runtime of A*PA scales near-linearly with length (best fit n1.06, n≤107 bp). A similar scaling remains up to d=12% (best fit n1.24, n≤107 bp). For n=107 bp and d=4%, A*PA reaches >500× speedup compared to the leading exact aligners Edlib and BiWFA. The performance of A*PA is highly influenced by long gaps. On long (n>500kb) ONT reads of a human sample it efficiently aligns sequences with d<10%, leading to 3× median speedup compared to Edlib and BiWFA. When the sequences come from different human samples, A*PA performs 1.7× faster than Edlib and BiWFA.

Availability and implementation

github.com/RagnarGrootKoerkamp/astar-pairwise-aligner.
Severity, impact on quality of life and mental health burden of pruritus in prurigo nodularis: a cross-sectional study of a diverse patient cohort
Authors: Cornman Hannah L , Whang Katherine A , Ma Emily , Aggarwal Prachi , Kambala Anusha , Reddy Sriya V , Gabriel Sylvie , Kwatra Shawn G
Published: January 2024

We performed a cross-sectional study using validated survey instruments, finding severe pruritus, reduced quality of life (QoL) and a significant mental health burden in a diverse cohort of patients with prurigo nodularis (PN) from the USA. Itch severity and QoL scores were comparable to those found in European populations, aside from ItchyQoL scores (higher scores in this US cohort). Black patients reported higher itch intensity scores than White patients. More than 37% of patients met the cutoff for severe depression, but only 26% had a clinical diagnosis of depression. Dermatologists should be aware that PN extends beyond severe pruritus, consider screening for psychiatric comorbidities and address other concerns that affect QoL as needed.
Surgeon views regarding the adoption of a novel surgical innovation into clinical practice: systematic review
Authors: Konda Nagarjun N , Lewis Thomas L , Furness Hugh N , Miller George W , Metcalfe Andrew J , Ellard David R
Published: January 2024

Background

The haphazard adoption of new surgical technologies into practice has the potential to cause patient harm and there are many misconceptions in the decision-making behind the adoption of new innovations. The aim of this study was to synthesize factors affecting a surgeon’s decision to adopt a novel surgical innovation into clinical practice.

Methods

A systematic literature search was performed to obtain all studies where surgeon views on the adoption of a novel surgical innovation into clinical practice have been collected. The databases screened were MEDLINE, Embase, Science Direct, Scopus, the Web of Science, and the Cochrane Library of Systematic Reviews (last accessed October 2022). Innovations covered multiple specialties, including cardiac, general, urology, and orthopaedics. The quality of the papers was assessed using a 10-question Critical Appraisal Skills Programme (CASP) tool for qualitative research.

Results

A total of 26 studies (including 1112 participants, of which 694 were surgeons) from nine countries satisfied the inclusion and exclusion criteria. Types of study included semi-structured interviews and focus groups, for example. Themes and sub-themes that emerged after a thematic synthesis were categorized using five causal factors (structural, organizational, patient-level, provider-level, and innovation-based). These themes were further split into facilitators and barriers. Key facilitators to adoption of an innovation include improved clinical outcomes, cost-effectiveness, and support from internal and external stakeholders. Barriers to adoption include lack of organizational support and views of senior surgeons.

Conclusion

There are multiple complex factors that dynamically interact, affecting the adoption of a novel surgical innovation into clinical practice. There is a need to further investigate surgeon and other stakeholder views regarding the strength of clinical evidence required to support the widespread adoption of a surgical innovation into clinical practice.
The use of CBCT in orthodontics with special focus on upper airway analysis in patients with sleep-disordered breathing
Authors: Savoldi Fabio , Dagassan-Berndt Dorothea , Patcas Raphael , Mak Wing-Sze , Kanavakis Georgios , Verna Carlalberta , Gu Min , Bornstein Michael M
Published: January 2024

Applications of cone-beam CT (CBCT) in orthodontics have been increasingly discussed and evaluated in science and practice over the last two decades. The present work provides a comprehensive summary of current consolidated practice guidelines, cutting-edge innovative applications, and future outlooks about potential use of CBCT in orthodontics with a special focus on upper airway analysis in patients with sleep-disordered breathing. The present scoping review reveals that clinical applications of CBCT in orthodontics are broadly supported by evidence for the diagnosis of dental anomalies, temporomandibular joint disorders, and craniofacial malformations. On the other hand, CBCT imaging for upper airway analysis—including soft tissue diagnosis and airway morphology—needs further validation in order to provide better understanding regarding which diagnostic questions it can be expected to answer. Internationally recognized guidelines for CBCT use in orthodontics are existent, and similar ones should be developed to provide clear indications about the appropriate use of CBCT for upper airway assessment, including a list of specific clinical questions justifying its prescription.
Nature, severity, and impact of chronic oropharyngeal dysphagia following curative resection for esophageal cancer: a cross-sectional study
Authors: Gillman Anna , Kenny Ciaran , Hayes Michelle , Walshe Margaret , Reynolds John V , Regan Julie
Published: January 2024

Chronic oropharyngeal dysphagia (COD) and aspiration after esophageal cancer surgery may have clinical significance; however, it is a rarely studied topic. In a prospective cross-sectional observational study we comprehensively evaluated the nature, severity, and impact of COD, its predictors, and the impact of the surgical approach and site of anastomosis. Forty participants were recruited via purposive sampling from the (Irish) National Center between November 2021 and August 2022. Swallow evaluations included videofluoroscopy [Dynamic Imaging Grade of Swallowing Toxicity v2 (DIGESTv2), MBS Impairment Profile, Penetration-Aspiration Scale)]. Functional Oral Intake Scale (FOIS) identified oral intake status. The patient reported outcome measures of swallowing, and Quality of Life (QL) included EAT-10 and MD Anderson Dysphagia Inventory (MDADI). Fourteen (35%) participants presented with COD on DIGESTv2 and 10% had uncleared penetration/aspiration. Avoidance or modification of diet on FOIS was observed in 17 (42.5%). FOIS was associated with pharyngeal dysphagia (OR = 4.05, P = 0.046). Median (range) EAT-10 and MDADI Composite results were 3(0–30) and 77.9(60–92.6), respectively. Aspiration rates significantly differed across surgical groups (P = 0.029); only patients undergoing transhiatal surgery aspirated. Survivors of esophageal cancer surgery may have COD that is undiagnosed, potentially impacting swallow-related QL. Given the small number of aspirators, further research is required to determine whether aspiration risk is associated with surgical approach. A FOIS score below 7 may be a clinically useful prompt for the MDT to refer for evaluation of COD following curative intent surgery. These data present findings that may guide preventive and rehabilitative strategies toward optimizing survivorship.
OP24 SPP1 in colitis-associated colon cancer
Authors: Manna S , Cardoso da Silva D , Sehn M , Wiese J , Heldt C , Plumbom I , Conrad T , Schallenberg S , Dony V , Farahani S K , Weiss F , Branchi F , Elezkurtaj S , Siegmund B , Weixler B , Hummel M , Gröne J , Schumann M
Published: January 2024

Background

Patients with ulcerative colitis (UC) and Crohn’s disease (CD) face a lifelong risk of developing colitis-associated carcinoma (CAC). Current insights into CAC development originate from murine CAC models, while human CAC studies primarily focus on mutational analyses. Although the mutational landscape reveals distinct patterns and frequencies compared to colorectal cancer, it falls short in elucidating the inflammatory mechanisms of CAC development. Consequently, we adopted a multi-omics approach to unravel CAC carcinogenesis, utilizing human samples from patients with CD, CD-associated CAC (CD-CAC), UC, and UC-associated CAC (UC-CAC). Findings were further validated in vitro using human colon organoids.

Methods

A Nanostring Immunology v2 panel was employed on RNA (archival FFPE sections) from 40 patients suffering from either IBD or CAC, alongside inflammation-free healthy controls (n=10 per group). Our data revealed a robust upregulation of the SPP1 (Secreted Phosphoprotein 1) gene encoding osteopontin (OPN) in CAC patients. Prospectively, we extended our methodology to an unbiased imaging-based spatial RNA in situ sequencing (ISS) approach (477 genes, Xenium, 10X Genomics) using FFPE sections from CAC and UC patients (n=3 per group). This provided insights into the spatial expression of SPP1 and its target receptors at a subcellular resolution. Findings were validated using whole FFPE section confocal microscopy. In addition, in vitro models, including human UC organoids, were analyzed by bulk RNA-Seq, RT-qPCR, and downstream functional assays.

Results

Nanostring Immunology v2 gene expression data revealed upregulation of the SPP1 gene encoding OPN (Fig 1A) and EMT transcription factors FN1 and ZEB1 in CAC patients. Xenium RNA in situ sequencing (ISS) unveiled the spatial heterogeneity of SPP1 expression in CAC (Fig 1B). Unsupervised graph-based clustering identified an SPP1+CD68+ macrophage cluster exclusively in CAC (Fig 1C), validated through OPN/CD68 immunostainings (Fig 1D). In vitro OPN stimulation across multiple human and mice colon organoid models excluded OPN as the trigger of EMT. Interestingly, Xenium ISS and immunostainings revealed a mutually exclusive spatial location of SPP1/OPN+ macrophages and CD8+ T cells (Fig 1E, F and G).

Conclusion

SPP1 is significantly upregulated in CAC (RNA and protein), expressed by CD68+ macrophages. In vitro OPN stimulation demonstrated no direct effect on intestinal epithelial organoids. The mutually exclusive spatial locations of SPP1/OPN+ macrophages and CD8+ T cells suggests a crucial role of SPP1/OPN in modulating the immunosurveillance of CAC cells by CD8+ tumour lymphocytes.
OP27 Oxalyl-CoA decarboxylase is a major and specific virulence factor for Adherent Invasive Escherichia coli
Authors: Toumi E , Orianne G , Reisacher C , Rolhion N , Sokol H , Skurnik D
Published: January 2024

Background

Adherent Invasive E. coli (AIEC) strains are found in one-third of patients with ileal Crohn’s disease (CD). To date, the bacterial genes involved in AIEC survival in the inflammatory environment are still unclear. Here, we systematically identify the genes of AIEC required for gut colonization and survival under the inflammatory conditions present in a mouse model of IBD.

Methods

We performed a transposon sequencing (TnSeq) approach using the laboratory strain E. coli K12 MG1655 and the AIEC strain LF82. We created two saturated Tn mutant libraries (3x105 mutant per bank) and gavaged them to mice with and without dextran-sodium sulfate (DSS)-induced colitis. We screened for essential genes for each bacterium in both conditions in the Cecum, Colon, Ileum and Jejunum.

Results

After High-throughput sequencing, we identified oxc gene, encoding for the oxalyl-CoA decarboxylase enzyme, as crucial for the survival of LF82 but not MG1655 in the whole gastrointestinal tract in colitis setting. To confirm our TnSeq results, the effect of oxc isogenic mutant (∆oxc) and complemented strains of LF82 and MG1655 was tested.

The inflammation severity was exacerbated in mice colonized with LF82WT or the complemented strain compared to LF82∆oxc. LF82∆oxc strain load decreased after colitis induction while the LF82WT and the complemented strain persisted. In a competition between LF82 WT and ∆oxc, the WT strain was able to outcompete the ∆oxc strain. This altered ability of LF82∆oxc to colonize the gut was associated with decreased bacterial motility and flagella expression.

In vitro, we found a decreased resistance of different AIEC strains to oxidative stress and acidic pH compared to a collection of commensal E. coli strains. This difference was abolished in all the ∆oxc AIEC strains we built and tested, demonstrating a crucial role for this gene in the tolerance to oxidative and acidic stress. Finally, lack of oxc also caused a reduction in survival into RAW264.7 macrophages, and an altered pro-inflammatory response of the macrophage, with a significant reduction of TNF-α levels.

Conclusion

oxc plays a major role in vitro and in vivo for AIEC strains but not for laboratory or commensal strains. Further studies to (i) fully explore this role and (ii) evaluate Oxc as a therapeutic target are currently under investigation.
OP40 Transcriptomic signature of response to vedolizumab in patients with moderate-to-severe ulcerative colitis: Results from an international, multicentre, retrospective cohort study
Authors: Linggi B , Salas A , Veny M , Borowski K , Silverberg M S , Milgrom R , Stempak J , Boland B , Eckmann L , Smith M I , Parker C E , Jairath V , Teft W , Vande Casteele N
Published: January 2024

Background

Transcriptomic analysis has the potential to facilitate drug development and clinical decision making in inflammatory bowel disease. Current understanding of pharmacodynamic response to vedolizumab is limited by a lack of publicly available mucosal biopsy RNA samples/sequencing data and corresponding clinical information. We aimed to identify gene signatures associated with response to vedolizumab in ulcerative colitis (UC) patients by pooling data from 3 international sites.

Methods

Patients receiving vedolizumab for the treatment of moderate-to-severe UC at Hospital Clínic de Barcelona (IDIBAPS), Mount Sinai Hospital (MSH), and University of California, San Diego (UCSD) with baseline and post-treatment (week 14 [± 4 weeks]) mucosal biopsy RNA-sequencing data and Mayo Clinic endoscopic subscores (MCES) were eligible for inclusion. Endoscopic response was defined as an MCES <1. Demographic and clinical data were collected. Differential expressed genes (DEGs) between baseline and week 14 were identified using linear mixed models with a >1.5 or <-1.5-fold change (adjusted P-value <.05). Enrichment was performed using Reactome pathway analysis and a previously published UC gene signature (adjusted P-value <.05).1 Analyses were performed using R version 4.3.0.

Results

Twenty-three patients were included (IDIBAPS: n=12; MSH: n=8; UCSD: n=3). Site-specific differences in sex, surgical history, and corticosteroid use were observed (Table). Analysing data by site yielded a relatively small number of DEGs between baseline and week 14 (IDIBAPS=57 [27 up-regulated, 30 down-regulated]; MSH=0; UCSD=0) among endoscopic responders (IDIBAPS: n=5; MSH: n=7; UCSD: n=2). Combining data from the 3 sites increased the number of DEGs among endoscopic responders at week 14 (n=14) to 1162 (662 up-regulated and 500 down-regulated). The down-regulated DEGs were enriched for genes involved in 37 of 103 up-regulated Reactome pathways in UC, including neutrophil degranulation, interleukin-4 and interleukin-13 signalling, interleukin-10 signalling, and integrin cell surface interactions. The up-regulated DEGs were enriched for genes involved in 1 of 39 down-regulated Reactome pathways in UC (Drug ADME).

Conclusion

We defined a pharmacodynamic signature using mucosal biopsies from UC patients who had endoscopic response to vedolizumab at week 14. The signature was enriched for several, but not all, pathways involved in UC. In addition to providing insight into vedolizumab’s mechanism of action, we underscored the utility of multi-site collaboration to access data, increase statistical power, and enhance the generalizability of research findings. Reference: 1. Linggi et al. Sci Rep 2021;11:18243.
DOP12 Efficacy and safety of obefazimod in UC patients at weeks 48 and 96 of an open-label maintenance study among clinical responders at week 8 of the Phase 2b induction trial
Authors: Vermeire S , Peyrin-Biroulet L , Danese S , Dubinsky M , Dulai P , Tilg H , Siegmund B , Gineste P , Sloan S , Rabbat C , Sands B E
Published: January 2024

Background

Obefazimod is an investigational, oral, once-daily, small molecule which enhances expression of microRNA-124 and is currently in phase 3 clinical trials for the treatment of patients with moderately to severely active ulcerative colitis (UC) [1]. Obefazimod demonstrated efficacy and safety in patients with UC at week-8 in a placebo-controlled, Phase 2b induction trial and in the subsequent open-label maintenance (OLM) study [2]. Here we report efficacy and safety at weeks 48 and 96 among patients who achieved clinical response at week 8 of the double-blind induction trial and compared efficacy to the overall study population.

Methods

Patients received placebo or obefazimod 25mg, 50mg or 100mg once daily (od) during the Phase 2b, induction trial and, irrespective of their clinical response, could enter the optional 96-week OLM study with obefazimod 50mg od. Patients were followed monthly for safety and efficacy. This analysis focuses on efficacy and safety among patients who reached clinical response (decrease from baseline in the Modified Mayo score (MMS) ≥ 2 points and ≥30% from baseline, plus a decrease in rectal bleeding sub-score (RBS) ≥ 1 or an absolute RBS ≤ 1) at week 8 of double-blind induction and continued treatment in the OLM.

Results

Among the 217 patients who participated in the OLM, 57% (124/217) achieved clinical response at week 8 of the induction trial. Within this subgroup, 66% (82/124) and 60% (74/124) achieved clinical remission at weeks 48 and 96, respectively. Clinical response was achieved by 86% (107/124) and 77% (95/124), endoscopic improvement was achieved by 70% (87/124) and 64% (79/124), and endoscopic remission was achieved by 38% (47/124) and 42% (52/124) at weeks 48 and 96, respectively. The proportions of patients achieving these efficacy endpoints in this subpopulation were numerically higher than those observed in the overall study population (Table 1). No new safety findings were observed in this sub-population during the OLM.

Conclusion

A substantial proportion of patients who reached clinical response at week 8 of the induction study achieved clinical efficacy endpoints at week 48 and 96 of the open-label maintenance study. Among these patients, nearly 8 out of 10 maintained clinical response, and 6 of 10 achieved durable clinical remission for up to 96 weeks of treatment with 50 mg of once-daily obefazimod.

References

1. Vermeire S, et al. J Crohns Colitis. 2023; doi: 10.1093/ecco-jcc/jjad067;

2. Vermeire S, et al. The Lancet Gastroenterology & Hepatology. 2022.
DOP14 Proctocolectomy is associated with improved transplant-free survival in patients with primary sclerosing cholangitis: results from a pooled collaborative international study
Authors: Mol B , van Nieuwamerongen M , Färkkilä M , Folseraas T , Boberg K , Vesterhus M , Bergquist A , Bogaards H , Ponsioen C
Published: January 2024

Background

It is hypothesized that the gut-liver axis plays a pivotal role in the aetiology of primary sclerosing cholangitis (PSC). Colectomy before liver transplantation is associated with decreased rates of recurrent PSC.1 We previously observed that proctocolectomy with permanent ileostomy is associated with better transplant-free survival in a population-based Dutch cohort.2 The aim of the present study is to confirm the effect of colectomy on PSC disease course in an international context.

Methods

We conducted a retrospective analysis on the International PSC Registry (IPSCR), comprising patients from Finland, Norway, Sweden, and the Netherlands. Endpoints were defined as liver transplantation (LT) and PSC-related death (excluding colorectal carcinoma) and were censored in the first year after colectomy to allow for a delayed protective effect. Cox proportional hazards regression was performed, with correction for the following known risk factors; sex, age at diagnosis, large or small duct PSC, features of auto-immune hepatitis, and inflammatory bowel disease (IBD) status (i.e. ulcerative colitis, Crohn’s disease or IBD unspecified). IBD status and colectomy status were included as time-dependent exposure variables, the latter stratified for extent and indication for colectomy.

Results

A total of 2595 patients were included, of which 1341 from the Netherlands, 560 from Finland, 528 from Norway, and 166 from Sweden. Of all patients 1900(73%) were diagnosed with IBD and 346(15%) had undergone a colectomy; 34(9%) hemi-, 91(26%) subtotal, and 172(50%) proctocolectomy with pouch and 65(19%) with ileostomy. During a total follow-up of 28,282 patient years, 848(33%) patients reached the endpoint LT or PSC-related death.

Hazard ratio (HR) of reaching LT or PSC-related death was significantly decreased in patients with proctocolectomy (0.70(0.52-0.93)) compared to patients without colectomy with variation per country (Netherlands 0.82(0.56-1.19), Finland 0.52(0.24-1.13), Norway 0.59(0.31-1.03), Sweden 0.28(0.06-1.24)). This effect was less pronounced in case of a hemi- or subtotal colectomy (HR 0.84(059-1.20)). The effect was most pronounced in the proctocolectomy with permanent ileostomy group (HR 0.55(0.30-0.99)). Of the known risk factors only a concurrent IBD diagnosis had no significant effect on transplant-free survival.

Conclusion

Our extended data confirm that colectomy is associated with a decreased risk of liver transplantation and PSC-related death. An incremental effect was seen with the extent of the colectomy, with the most pronounced effect in the proctocolectomy group with permanent ileostomy. Our data support the putative role of the gut-liver axis in the disease course of PSC.
DOP57 Cystic fibrosis risk variants confer a protective effect against Inflammatory Bowel Disease in large-scale exome sequencing analysis
Authors: Yu M
Published: January 2024

Background

Genetic mutations that produce defective Cystic fibrosis transmembrane regulator (CFTR) proteins are known to cause cystic fibrosis (CF), a lethal autosomal recessive Mendelian disorder. Existing studies have debated the roles of CFTR mutations in Inflammatory Bowel Disease (IBD), with inconclusive evidence supporting both risk and protective effects.

Methods

We generated the largest IBD exome sequencing callset with 38,744 cases and 69,570 controls of European ancestries from the International Inflammatory Bowel Disease Genetics Consortium. After rigorous quality control analyses, we performed association testing using a logistic mixed-model implemented in REGENIE v.2.2.4. A set of LD-pruned high-confidence variants (MAF > 1% and call rate > 99%) was used for polygenic effect parameter estimation, which was included as covariates. To control for residual population structure and sequencing heterogeneity, we included as covariates a binary variable representing the sample sequencing platform and the top five principal components calculated from LD-prune well-genotyped common SNPs. Sex as a biological variable was also included as a covariate. Firth correction was applied to association tests with P < 0.05 to control for case-control imbalance.

Results

Here, we report two lines of evidence establishing a protective role of CF-causing variants against IBD. First, we found delF508, the known CF-causing variant that accounts for 70% of all CFTR mutations observed in CF patients, is significantly associated with IBD (P=1.7E-10) with a protective effect (BETA=-0.30, SE=0.048). The conclusion remained unchanged if we excluded individuals carrying two copies of delF508. Second, we conducted an unweighted gene burden test of CFTR restricted to all variants (excluding delF508) annotated as CF-causing in the Clinical and Functional Translation of CFTR (CFTR2) database. This burden test indicates a significant association between CF-causing variants and IBD (P=1.1E-6) with a slightly smaller protective effect (BETA=-0.23, SE=0.047). As a negative control, another burden test was performed on CFTR using all rare (MAF<0.001) nonsynonymous non-CF-causing variants. This test showed no significant association (P=0.42).

Conclusion

Leveraging a large-scale IBD exome sequencing dataset, we report two lines of evidence that convincingly suggest CF-causing variants confer a protective effect against IBD. Follow-up experimental studies are warranted to investigate the cellular pathways that CF-causing mutations disrupt to exert such an anti-inflammatory effect, which may provide insights for novel therapeutic interventions for IBD.
DOP59 Integration of in silico analysis and in vitro functional analysis reveals Tissue Factor Pathway Inhibitor 2 (TFPI2) as a master transcriptional regulator and potential target to impede Infliximab resistance in adult UC patients
Authors: Genua F , Lawal O , Kel A , Tosetto M , Stack R , Sheahan K , Yochum G , Doherty G , Das S
Published: January 2024

Background

Standard biological therapy for moderate-severe cases of UC consists in the use of Infliximab (IFX), an anti-tumour necrosis factor α (anti-TNF-α) targeting agent. However, approximately 40% of the patients do not respond to IFX. While transcriptional alterations have been widely associated with non-response to IFX, the precise factors that regulates this altered gene expression remains poorly understood. The aim of this study was perform a robust in silico analysis to identify master transcriptional regulators (MTRs) which regulate gene expression changes in IFX non-responsive UC patients, followed by perturbation in vitro to establish their functional role in UC pathogenesis.

Methods

Differentially expressed genes (DEGs) identified from four independent public datasets were applied to the GeneXplain platform to identify transcription factors (TFs) enriched for the DEG’s. This was followed by an upstream analysis to identify MTR’s which regulate expression of these genes through the TFs. We next explored the role of these MTRs in driving UC-associated phenotype, using siRNA-mediated knock-down in a novel IBD-like in vitro system comprising of normal rectal epithelial cells treated with TNFa.

Results

Over 200 TFs were identified in both upregulated and downregulated genes in IFX non-responders across all data sets. RELA, NANOG, FOSJUN were the top 3 TF’ enriched for upregulated genes in three out of the four datasets. Using the TF data, the upstream analysis identified CXCL8, SELE, PTGS2, FCGR3, TFPI2 as the top five MTRs. Next, we showed that of the 5 MTRs, only TFPI2 (tissue factor pathway inhibitor 2) were significantly upregulated in an IBD-like in vitro model (normal rectal epithelial cell line: CRL1831 +TNFa). siRNA-mediated knock-down of TFPI2 in this model resulted in a significant decrease in genes including TNFAIP6, TNFAIP3, FCGR3B, BIRC3 and CXCL5, all of which were predicted in silico to be upregulated by TFPI2 during the upstream analysis. Intriguingly, we showed that downregulation of TFPI2 resulted in significant amelioration of pro-inflammatory cytokines including IL1β, IFNγ, IL10, IL13, IL6 and IL8.

Conclusion

Our study for the first time identifies key MTRs such TFPI2 which acts as a master regulator of genes whose upregulation drives poor response to IFX. Therefore, these results warrant further in vitro/ex vivo investigation to rationalise their role of TFPI2 as a potential therapeutic target, whose perturbation in UC patient would likely result in improved response to IFX.
DOP68 Natural history of isolated Crohn's Disease perianal fistula
Authors: Sangmo L , Quraishi B , Rajauria P , Colombel J F , Ungaro R , Wong S Y
Published: January 2024

Background

Approximately 20% of patients with Crohn’s disease (CD) have perianal fistulizing CD, which are most often complex PAF. Studies have shown that 4-5% of patients with CD present with PAF without luminal disease, termed isolated perianal CD (iPCD). Little is known about their natural history.

Methods

We performed a retrospective cohort study of patients seen within the Mount Sinai Health System (New York) with an ICD-10 diagnosis code for PAF between 7/22/2008 and 7/22/2022. Medical record review was conducted to identify patients with PAF, considered as possible iPCD, who did not have evidence of luminal disease and had > 6 months of follow-up (Table 1). Demographics, comorbidities, imaging, endoscopy, surgeries, hospitalizations and medication data were collected. These patients were reviewed to determine progression to luminal disease, which was defined as any evidence of luminal ulcers, erosions, or strictures on endoscopy, histology, video capsule exam, or MRE. Descriptive and univariate analyses were performed. Complex PAF was defined by American Gastroenterological Association criteria. Complicated disease course was defined as a composite of any major CD-related surgery, PAF/IBD-related hospitalization or biologic use.

Results

Among 887 patients who presented with PAF, 62.2% (n=552) patients underwent luminal evaluation, of whom 80 patients (14.5%) were found to have no luminal disease and considered as having iPCD (Table 1). 57 of these 80 patients had >6 months follow-up. Luminal disease developed in 13 patients (23%) with a mean time to diagnosis of 4.2 +/- 3.8 years after PAF presentation. Patients who developed luminal CD were more likely to be <30 years old at PAF diagnosis (p=0.0225), had >2 fistulas on imaging (p=0.002), and have concomitant autoimmune conditions (p=0.046) (Table 2). During the follow-up period, the patients who developed luminal CD

were more likely to receive biological therapy (77% vs 16%, p<0.0001) or undergo CD/PAF-related hospitalization (62% vs 30%, p =0.0356) (Table 2). Overall, patients who developed luminal CD had a more complicated disease course (31% vs 2.3%, p=0.007) than those who did not.

Conclusion

Approximately 1 in 4 patients who presented with possible iPCD developed luminal CD at follow-up. Patients who developed luminal CD were more likely to be younger at diagnosis, had more fistula tracts, and had concomitant autoimmune conditions.
DOP85 An anti-fibrotic role for eosinophils in a DSS colitis RAG-/- and an in vitro co-culture model
Authors: Jacobs I , Deleu S , Cremer J , Dilissen E , De Hertogh G , Martens T , Vanden Berghe P , Vermeire S , Breynaert C , Vanuytsel T , Verstockt B
Published: January 2024

Background

In several disease areas, such as in the liver and lungs, a pro-fibrotic role for eosinophils has been suggested. However, information about the role of eosinophils in the development of intestinal fibrosis is scarce. We therefore aimed to assess the functional and mechanistic role of eosinophils in intestinal fibrosis and fibroblast activation.

Methods

Chronic DSS colitis (3 DSS cycles of 1 week DSS administration followed by 2 weeks of recovery (1.75% - 2.25% - 2.25%)) was introduced in 6-8-week-old C57BL/6 RAG-/- mice to induce intestinal fibrosis (Figure 1A). Mice were injected intraperitoneally with anti-CCR3 to deplete eosinophils (n=8) or with an isotype control (n=8). Intestinal fibrosis was assessed based on collagen deposition (hydroxyproline assay, Martius Scarlet Blue staining (MSB) and second harmonics generation (SHG)), while COL1A1 expression was assessed via RT-qPCR. Gene expression was performed using RT-qPCR and protein expression via the MSD platform. Secondly, circulating eosinophils were isolated from non-IBD controls (n=3) and co-cultured with fibroblasts, isolated from resection specimens obtained from the terminal ileum of Crohn’s disease patients undergoing right hemicolectomy (n=3). The effect of eosinophils on fibroblast activation was assessed through the expression of α-SMA via flow cytometry and immunocytochemistry. Lastly, fibroblasts were stimulated with 10ng/mL eosinophil cationic protein (ECP), a protein exclusively produced by eosinophils (n=3), in order to study whether this mediator could affect fibroblast activation.

Results

Anti-CCR3 mediated eosinophil depletion in the chronic DSS model resulted in increased fibrosis based on the hydroxyproline assay (p=0.06) (Figure 1B), MSB (p=0.0009) (Figure 1C) and COL1A1 expression (p=0.03) (Figure 1D). Similarly, we identified an increased collagen deposition in the eosinophil-depleted group based on the SHG (Figure 1E). Furthermore, an increase in the pro-fibrotic IL-1β and TGF-β3 on protein (p=0.03 and p=0.06) and gene level (p=0.04 and p=0.005) could be found in the eosinophil depleted mice. Co-culturing eosinophils with fibroblasts resulted in decreased α-SMA expression, indicative of a decrease in active fibroblasts. This could be observed via both flow cytometry (p=0.001) (Figure 1F) and immunocytochemistry (Figure 1G). Similarly, when fibroblasts were stimulated with ECP, a decrease in α-SMA was observed (p=0.04) (Figure 1H).

Conclusion

Depletion of eosinophils in a chronic DSS RAG-/- model resulted in more intestinal fibrosis. Similarly, in an in vitro setting, eosinophils, as well as ECP, decreased α-SMA expression in fibroblasts, suggesting that eosinophils may inactivate fibroblasts.
DOP86 FOod Additives on the Mucosal barrier study (FOAM): Effect of five emulsifiers on inflammation, intestinal permeability, and the microbiome: preliminary results
Authors: Wellens J , Vanderstappen J , Hoekx S , Vissers E , Luppens M , Raes J , Verstockt B , Ferrante M , Verbeke K , Matthys C , Vermeire S , Sabino J
Published: January 2024

Background

Common emulsifiers are associated with intestinal inflammation and are therefore excluded in new dietary therapeutic strategies in inflammatory bowel disease. Human data are scarce and involve a limited number of emulsifiers. We aimed to investigate the effect of five different emulsifiers on systemic and intestinal inflammation, intestinal permeability, and the gut microbiome.

Methods

We recruited 60 healthy volunteers to a 7-week double-blind placebo controlled randomized trial. After 1 week of recording their habitual diet (baseline), participants followed an emulsifier-free diet (EFD) for 6 weeks, starting at baseline. After 2 weeks, participants combined the EFD with 3 daily brownies that contained either 2.75 g carboxymethyl cellulose, 1.350 mg polysorbate-80, 380 mg carrageenan, 3.55 g soy lecithin, or 8.72 g native rice starch, or no additives (placebo) for a period of 4 weeks. Anthropometric measurements and bio samples were taken at baseline, week 2 and week 6. Blood samples were collected for routine tests, LPS-binding ELISAs, and serum proteomics using the Olink Target 96 Inflammation and Cardiometabolic panels. Stool samples were collected for analysis of the microbiota (16S rRNA sequencing), short chain fatty acids (Gas Chromatography – Mass Spectrometry (GC-MS)), and faecal calprotectin (FC) analysis. Urine samples were collected following the 2-hour lactulose mannitol ratio protocol to measure intestinal permeability (using GC-MS).

Results

Of the 60 healthy volunteers, 2 were excluded due to NSAID use. Median (IQR) age was 25.5 years (23.0-33.0), median BMI was 22.7 kg/m2 (21.2-25.6) and 19.0% were male. There was a median weight loss of 0.1 kg (p=7.6*10-4, paired Wilcoxon, unadjusted p-value). At week 6 and week 2, FC decreased significantly compared to baseline (p= 4.69*10-4, and p=2.81*10-4 respectively, paired Wilcoxon, unadjusted p-value, Table 1 and Figure 1A). No significant increase in FC was noted after consumption of any emulsifier during the trial. In the placebo arm, faecal acetic acid concentration was increased at week 2 (p=0.04). Compared to baseline, there was an increase in both acetic acid and propionic acid concentration (p=0.006 and p=0.04 respectively, paired Wilcoxon, unadjusted p-value, Figure 1B) in the same arm at week 6.

Conclusion

In this double-blind placebo controlled randomized trial faecal acetic and propionic acid increased in the placebo arm, but did not after consumption of any of the emulsifiers. FC did not increase after consumption of any emulsifier. Pending analysis will shed light on the effect of an EFD and distinct emulsifiers on the serum proteome, intestinal permeability and gut microbial changes.
P002 Regulation of miR-338-3p and miR-378a-3p in the intestinal mucosa of Crohn’s disease: Potential targets for modulating inflammation
Authors: Moon J M , Kim K U , Lim E , Hwang H W , Kim K , Seo J , Shin S Y , Min H , Choi C H
Published: January 2024

Background

A growing body of evidence suggests that epithelial cell-derived microRNAs are involved in the pathogenesis of inflammatory bowel disease (IBD). This immunological impairment leads to altered colonic epithelial permeability and the release of inflammatory cytokines, such as IL-33. In this prospective cohort study, we studied the expression of epithelial cell-derived microRNAs (miRNA) in Crohn’s disease (CD) patients compared to healthy controls. We also investigated their potential role in regulating inflammation in experimental IBD animal models.

Methods

We prospectively collected terminal ileum tissue samples via ileocolonoscopy from non-IBD healthy control (n=26), CD patients in remission (n=34) and active CD patients (n=42). CD remission was defined as clinical remission with a Crohn’s disease activity index score of less than 150 and the achievement of endoscopic mucosal healing. Both inflamed and non-inflamed lesions were sampled in the active CD patients. miRNA levels were measured by small-RNA sequencing and also validated via qRT-PCR. Diagnostic abilities of specific miRNAs found were evaluated by receiver operating characteristic (ROC) curve analysis. A signature of miRNAs was selected from RNA sequencing and qRT-PCR and single-strand mimics of these miRNAs were delivered in the 2.5% dextran sodium sulfate colitis model to determine the effect. Histologic grading and immunohistochemistry evaluation and flow cytometry analyses were performed.

Results

From the prospective study cohort of CD and non-IBD healthy control (mean follow-up period of 13.06 months), we found a distinct array of miRNAs between groups. Small-RNA sequencing of CD patients in remission and active state (both in inflamed and non-inflamed tissue) revealed distinct microRNA profiles. Through qRT-PCR validation, we found that the expression levels of miR-141-3p, miR-338-3p, miR-378a-3p, and miR-200b-3p were significantly decreased, while miR-125b-5p, miR-29b-3p and miR-155-5p were significantly increased in the inflamed tissue of active CD patients. ROC curve analysis of these miRNAs suggested that they have varying diagnostic activities related to both clinical disease activity and endoscopic inflammation status. In an IBD animal model, the delivery of miR-338-3p and miR-378-3p demonstrated an anti-inflammatory effect, as evidenced both histologically and in immunohistochemistry data, as well as in flow cytometry analyses. Consistent results were observed when these two miRNAs were combined.

Conclusion

We report miR-338-3p and miR-378a-3p as distinct features in mucosa of CD patients and these data support the promising future of use of these miRNAs as potential therapeutic targets for novel IBD therapies.