bluuebunny/crossref_metadata_2025_split huggingface dataset:
Seed priming with nitric oxide and/or spermine mitigate the chromium toxicity in rice (
Authors: Basit Farwa , Ulhassan Zaid , Mou Qingshan , Nazir Muhammad Mudassar , Hu Jin , Hu Weimin , Song Wenjian , Sheteiwy Mohamed Salah , Zhou Weijun , Bhat Javaid Akhter , Jeddi Kaouthar , Hessini Kamel , Guan Yajing 
Published: January 2022

Chromium (Cr) is a serious environmental contaminant that drastically limited the crop yields. Nitric oxide (NO) and spermine (Spm) portrayal significance in improving the plant tolerance against abiotic stresses. Therefore, we investigate the protective efficacy of seed priming with NO (100 μM) and/or Spm (0.01 mM) in minimising the Cr-induced toxic effects in rice (Oryza sativa L.) plants. Our outcomes revealed that Cr alone treatments (100 μM) notably reduced the seed germination rate, plant growth, photosynthetic apparatus, nutrients uptake and antioxidant defence system, but extra generation of reactive oxygen species (ROS). Interestingly, the combine applications of NO and Spm significantly reversed the Cr-induced toxic effects by reducing the Cr-accumulation, maintaining the nutrient balance, improving the germination indices, levels of photosynthetic pigments (chl a by 24.6%, chl b by 36.3%, chl (a + b) by 57.2% and carotenoids by 79.4%), PSII, photosynthesis gas exchange parameters and total soluble sugar (74.9%) by improving antioxidative enzyme activities. As a result, NO + Spm lowered the accumulation of oxidative markers (H2O2 by 93.9/70.4%, O2˙− by 86.3/69.9% and MDA by 97.2/73.7% in leaves/roots), electrolyte leakage (71.4% in leaves) and improved the plant growth traits. Based on these findings, it can be concluded that NO triggers Spm to minimise the Cr-accumulation and its adverse effects on rice plants. Additionally, combined treatments (NO + Spm) were more effective in minimising the Cr-induced toxic effects in comparison to NO and Spm alone treatments. Thus, co-exposure of NO and Spm may be utilised to boost rice tolerance under Cr stress conditions.
Probabilistic Pareto plan generation for semiautomated multicriteria radiation therapy treatment planning
Authors: Zhang Tianfang , Bokrantz Rasmus , Olsson Jimmy 
Published: January 2022

Abstract

Objective. We propose a semiautomatic pipeline for radiation therapy treatment planning, combining ideas from machine learning–automated planning and multicriteria optimization (MCO). Approach. Using knowledge extracted from historically delivered plans, prediction models for spatial dose and dose statistics are trained and furthermore systematically modified to simulate changes in tradeoff priorities, creating a set of differently biased predictions. Based on the predictions, an MCO problem is subsequently constructed using previously developed dose mimicking functions, designed in such a way that its Pareto surface spans the range of clinically acceptable yet realistically achievable plans as exactly as possible. The result is an algorithm outputting a set of Pareto optimal plans, either fluence-based or machine parameter–based, which the user can navigate between in real time to make adjustments before a final deliverable plan is created. Main results. Numerical experiments performed on a dataset of prostate cancer patients show that one may often navigate to a better plan than one produced by a single-plan-output algorithm. Significance. We demonstrate the potential of merging MCO and a data-driven workflow to automate labor-intensive parts of the treatment planning process while maintaining a certain extent of manual control for the user.
Experimental validation of a linac head Geant4 model under a grid computing environment
Authors: Didi Samir , Bahhous Karim , Zerfaoui Mustapha , Aboulbanine Zakaria , Ouhadda Hassan , Halimi Abdellah 
Published: January 2022

Abstract

Background and purpose

. This work aims to present the strategy to simulate a clinical linear accelerator based on the geometry provided by the manufacturer and summarize the corresponding experimental validation. Simulations were performed with the Geant4 Monte Carlo code under a grid computing environment. The objective of this contribution is reproducing therapeutic dose distributions in a water phantom with an accuracy less than 2%.
Materials and methods.
A Geant4 Monte Carlo model of an Elekta Synergy linear accelerator has been established, the simulations were launched in a large grid computing platform. Dose distributions are calculated for a 6 MV photon beam with treatment fields ranging from 5 × 5 cm2 to 20 × 20 cm2 at a source—surface distance of 100 cm.
Results.
A high degree of agreement is achieved between the simulation results and the measured data, with dose differences of about 1.03% and 1.96% for the percentage depth dose curves and lateral dose profiles, respectively. This agreement is evaluated by the gamma index comparisons. Over 98% of the points for all simulations meet the restrictive acceptability criteria of 2%/2 mm.
Conclusion.
We have demonstrated the possibility to establish an accurate linac head Monte Carlo model for dose distribution simulations and quality assurance. Percentage depth dose curves and beam quality indices are in perfect agreement with the measured data with an accuracy of better than 2%.
OP34 Efficacy and safety of advanced induction and maintenance therapies in patients with moderately to severely active Ulcerative Colitis: An indirect treatment comparison using Bayesian network meta-analysis
Authors: Panaccione R , Collins E B , Melmed G Y , Vermeire S , Danese S , Higgins P D R , Zhou W , Ilo D , Sharma D , Sanchez Gonzalez Y , Wang S T 
Published: January 2022

Abstract

Background
The therapeutic armamentarium to treat adult patients with moderately to severely active ulcerative colitis (UC) continues to evolve. With this rapid innovation, the comparative efficacy and safety of more recent advanced therapies remain unknown.

Methods
Bayesian network meta-analysis was used to indirectly compare the efficacy and safety of advanced therapies for induction (6–10 weeks) and maintenance (44–54 weeks post-induction response) in adults with moderately-to-severely active UC. Efficacy was assessed separately in bio-naïve and bio-exposed populations by clinical remission (Full Mayo score [FM] of ≤2 with no subscore &gt;1), clinical response (decrease from baseline in FM ≥3 points and ≥30% with decrease in rectal bleeding score [RBS] of ≥1 or absolute RBS ≤1) and endoscopic improvement (endoscopic score ≤1); ad hoc analyses were conducted on upadacitinib (UPA) RCT data to produce FM outcomes. Safety was assessed by discontinuation due to adverse events (AEs), serious AEs, and serious infections. Induction therapies included UPA 45 mg, adalimumab 160/80 mg, filgotinib 100 and 200 mg, golimumab 200/100 mg, infliximab 10 and 5 mg/kg, ozanimod 0.92 mg, tofacitinib 10 mg, ustekinumab (UST) 6 mg/kg, and vedolizumab (VED) 300 mg. The maintenance analysis included low and high maintenance doses of these therapies. Phase 3 randomized controlled trials (RCTs) were identified via systematic literature review. Random effects models were used to account for expected heterogeneity in endpoints and study design. Guidelines from the National Institute for Health and Care Excellence were followed.

Results
Out of 31 RCTs identified, 23 were included (18 for induction and 14 for maintenance). Odds ratios vs. placebo (PBO), numbers needed to treat/harm, and surface under the cumulative ranking curve estimates are presented for efficacy in bio-naïve (Table 1) and bio-exposed (Table 2) populations and for safety in overall populations (Table 4). Intent-to-treat rates of maintenance efficacy outcomes adjusted by the likelihood of induction response show UPA to be consistently the most efficacious therapy (Table 3). There were no significant differences in serious AEs or serious infections for any advanced therapy vs PBO. For discontinuation due to AEs, only UPA had significantly lower odds vs PBO after induction, while UST and VED had significantly lower odds vs PBO after maintenance (Table 4).

Conclusion
In patients with moderately-to-severely active UC, UPA 45 mg induction and 30 mg maintenance appear more efficacious than other advanced therapies/PBO at inducing and maintaining clinical response, clinical remission, and endoscopic response, with no greater safety assessments vs PBO, over 1-year.
OP37 Bacterial suppression of intestinal fungi via activation of human gut Vδ2+ T-cells
Authors: Mathew L , Savage M , Pardieu C , O’Brien M , Sze S K , Eberl M , Stagg A , Gasparetto M , Kok K , Lindsay J , McCarthy N 
Published: January 2022

Abstract

Background
The human gut is colonized by diverse microbes including fungi such as Candida albicans, which has been implicated in the pathogenesis of Crohn’s disease (CD). Intestinal C. albicans typically exists as commensal yeast, but can also form tissue-invasive filaments that secrete Candidalysin toxin to disrupt epithelial barriers. Commensal gut bacteria produce molecules that induce host immunity, including phosphoantigen HMB-PP which stimulates Vδ2+ T-cell homing to intestine and mucosal expression of IL-22 to promote barrier integrity. We aimed to identify mechanisms of gut barrier defence against fungal invasion in health and CD.

Methods
Colonic biopsies / resected tissue were stimulated or not with HMB-PP in the presence or absence of anti-IL-22 blocking antibody and analysed by flow-cytometry / microscopy to determine extent of fungal outgrowth. Fungal isolates were identified using standard morphological and biochemical criteria before assessment of filamentation, cell wall composition, and NETosis induction.

Results
Mucosal Vδ2+ T-cell activation with bacterial phosphoantigen HMB-PP, in the presence of epithelial damage-associated cytokine IL-15, potently suppressed growth of endogenous fungi in human colonic organ cultures. Vδ2-mediated fungal suppression required IL-22 and was sufficient to restrict the growth of multiple fungal species, including a range of emerging pathogenic moulds as well as archetypal pathobiont C. albicans. In Vδ2-deficient CD patients, mucosal biopsy stimulation with HMB-PP failed to control fungal growth. CD-derived C. albicans strains also displayed rapid filamentation ex vivo and higher levels of NOD2 ligand chitin than were observed in isolates from healthy controls. Comparing hypoxic with oxygenated cultures that mimic inflamed intestine, pSILAC proteomic analysis of a representative CD-derived C. albicans strain confirmed features of invasive growth (e.g. DAO1, IHD1), whereas a healthy control isolate exhibited metabolic hallmarks of symbiosis (Jen1p, SCH9). These divergent characteristics directly impacted on host anti-fungal immune responses, since the CD-derived strain rapidly induced neutrophil extracellular traps in vitro, whereas the healthy control isolate did not.

Conclusion
These data suggest that commensal bacteria can activate host Vδ2 T-cells to suppress fungal invasion of the gut epithelium via an IL22-dependent mechanism that is deficient in CD patients.
DOP01 A multi-centre study to explore the prevalence of Inflammatory Bowel Disease indicators in patients with moderate- to- severe psoriasis: Baseline results from the EPIC study
Authors: Hayee B , Ghosh S , Carter B , Bartlett S , Powles E , Millward R , Watcham S , Blanthorn-Hazell S , Crooks J , Hansell C , Millar J , Williams C , Migas S , Hajne J , Warren R 
Published: January 2022

Abstract

Background
Evidence suggests there is an increased incidence of inflammatory bowel disease (IBD) in the psoriasis (PsO) population. However prior studies may have underestimated the degree of this association, by not considering (pre-)clinical markers or symptoms of IBD (e.g. elevated faecal calprotectin [FCal] and/or IBD red flags). Furthermore, patients with PsO are not typically screened for IBD. Here we describe the prevalence of IBD indicators in patients with moderate-to-severe PsO.

Methods
This was a multi-centre UK study of adults (≥18 years) with moderate-to-severe PsO. Patients were recruited from 12 primary care practices in Greater Manchester between November 2019 – April 2021 (in total, 983 eligible patients from an original cohort of 3485 were invited to participate). Retrospective review of primary care medical records was used to confirm a prior IBD diagnosis at baseline. For patients without a confirmed diagnosis, FCal monitoring and a bespoke questionnaire derived from validated measures of gastrointestinal (GI) symptoms and IBD red flags (CalproQuest IBD and Red Flag Index) were used to screen for IBD risk. Baseline interim data are presented as observed proportions, descriptive statistics, and counts along with 95% confidence intervals (CI).

Results
252 patients were included: mean age was 57 (±15 SD) years and 54% were female (Table 1).

Use of non-steroidal anti-inflammatory drug therapy was reported by 15.5% of patients. In total, 64.7% (CI: 53.4−70.6%) of patients had ≥1 indicator of IBD risk at baseline (i.e., ≥1 of: IBD diagnosis, FCal ≥50 ɥg/g or ≥1 IBD red flag) and 3.6% (CI: 1.7−6.7%) of patients had a confirmed diagnosis of IBD. At baseline, 38.1% (CI: 33.5–46.1%) of patients had elevated (≥50μg/g) FCal (Table 2), and 34.9% (CI: 30.2−42.6%) of patients reported ≥1 IBD red flag. Both elevated FCal and GI symptoms were observed in 26.2% (CI: 21.8−33.5%) of patients.

Figure 1 depicts the overlap between different IBD markers in this cohort.

Conclusion

The risk of IBD in patients with PsO may be higher than previously reported. While 3.6% of patients in this cohort of patients with moderate-to-severe PsO had a confirmed IBD diagnosis, approximately two-thirds of patients exhibited at least one indicator of IBD risk (FCal ≥50μg/g and/or IBD red flag[s]). This study therefore highlights a population for whom further investigation to confirm IBD may be warranted. Prospective follow-up over the next two years will report on the outcomes of investigations, the final diagnoses and treatments in the identified ‘at risk’ cohort.
DOP26 COVID-19 vaccine effectiveness in Inflammatory Bowel Disease patients on tumor-necrosis factor inhibitors: Real world data from a mass-vaccination campaign
Authors: Lev Zion R , Focht G , Lujan R , Mendelovici A , Friss C , Greenfeld S , Kariv R , Ben-Tov A , Matz E , Nevo D , Barak-Corren Y , Dotan I , Turner D 
Published: January 2022

Abstract

Background
Some studies have shown decreased serological response to vaccination in patients on anti-tumor necrosis factor (TNF) medications. While the large majority of these patients do seroconvert after vaccination, titers have generally been lower and one study showed reduced neutralizing and inhibitory functions. One real-world population-based study compared found no increased infection rate in anti-TNF treated patients, but infection rates were low. The low event rate mandates exploration in longer-term population-based data. We used the epi-Israeli IBD Research Nucleus (IIRN) database to explore the effectiveness of COVID-19 vaccination in IBD patients in Israel.

Methods
We included all IBD patients insured in two of the four Israeli HMOs, covering 35% of the population, by validated algorithms, and selected those who received two doses of Pfizer BNT162b2 vaccine. These were matched by date of vaccination ±3 days and demographic variables to non-IBD controls. The primary outcome was incidence of positive COVID-19 PCR following vaccination between December, 2020 to June, 2021.

Results
12,640 IBD patients received two vaccine doses; the matched cohort included 4,946 matched pairs (total 9,892 subjects). Mean age was 50.5±16.1 years and median follow-up was 22 weeks (range 4.1–24.4). Fifteen (0.3%) vaccinated IBD patients tested positive compared with 15 (0.3%) vaccinated non-IBD controls (OR=1 [95%CI 0.49–2.05], p=1.0). Patients on anti-TNF and/or corticosteroids did not have a higher incidence of positivity – neither compared to the entire group nor to IBD patients treated with vedolizumab/ustekinumab, even after precise matching for demographics, underlying diseases and IBD severity.

Conclusion
In a large population-based cohort of IBD patients in Israel, vaccine effectiveness was equivalent to non-IBD controls and was not influenced by treatment with anti-TNF or corticosteroids. Notwithstanding previous findings of impaired serological response in anti-TNF treated IBD patients, this real-world large-scale study shows that vaccine protection is robust in IBD patients, including those on immunosuppressive medications.
DOP52 Development of a host-microbe interaction workflow to reveal the cell- and condition-specific effects of a commensal bacteria upon IBD
Authors: Potari-gul L , Modos D , Fonseca S , Madgwick M , Thomas J P , Sudhakar P , Booth C , Stentz R , Carding S R , Korcsmaros T 
Published: January 2022

Abstract

Background
Humans are colonized by complex microbial communities which contribute to physiological processes in the host. The communication between microbes and host is crucial to maintain the homeostasis and gut health. Disruption in the microbiome composition leads to increased inflammation and appearance of diseases, such as inflammatory bowel disease (IBD). Interspecies interaction prediction combined with gene expression patterns on individual cell level by single-cell omics data reveals a new insight into the molecular background of cell-type specific host-microbe interactions.

Methods
Previously we developed the MicrobioLink pipeline (Andrighetti et al, Cells, 2020), an in silico microbe-host protein-protein interaction prediction algorithm. Here, we implemented a computational workflow based on MicrobioLink to predict and compare the cell-specific effects of a commensal bacteria in healthy and diseased conditions using a publicly available single-cell RNAseq dataset (Smilie et al, Cell, 2019) from colon biopsies describing 51 cell types - including fibroblasts, epithelial and immune cells - in healthy, non-inflamed and inflamed ulcerative colitis (UC). With functional analysis, microbe-affected processes have been discovered, while reliable network biology resources, such as OmniPath and Reactome, were used to identify the direct mechanism of action of the bacterial molecules.

Results
Demonstrating the applicability of the new computational workflow, we analysed the effect of a common gut commensal bacteria - Bacteroides thetaiotaomicron (Bt) - on human immune cells focusing on the Toll-like receptor (TLR) signalling. We found that extracellular vesicles (EVs) secreted by Bt may be able to modulate the TLR pathway intracellularly. The analysis highlighted that Bt targets differ among cells and between the same cells in healthy versus UC conditions. The in silico findings were validated in EV-monocyte co-cultures demonstrating the requirement for TLR4 and Toll-interleukin-1 receptor domain-containing adaptor protein (TIRAP) in EV-elicited NF-kB activation.

Conclusion
The current pipeline offers potentially interesting connection points and detailed mechanistic insight containing mechanistic information about microbe-host interactions. This information can be tested and harnessed to understand better how microbial proteins may be of therapeutic value in inflammatory diseases, such as IBD.
P013 A single cell approach reveals immune cell dynamics in Inflammatory Bowel Disease (IBD) and highlights association of CD8 intraepithelial lymphocytes (IELs) with response to vedolizumab treatment
Authors: Paraskevopoulou M , Mayer L , Krueger A , Pattekar A , Ramos A , Fulton M , Wai Lau C , Chau L , Ren Y , Tondon R , Al Garawi A , Bittinger K , Fogt F , Yajnik V , Lee H , Lewis J , Wu G , Bewtra M , Tomov V , Juarez J 
Published: January 2022

Abstract

Background
Dysregulated immunity in the gut is central to the pathogenesis of inflammatory bowel disease (IBD) and its contribution to patient responses following biologic treatment is poorly understood. Single cell protein- and sequencing-based analyses have provided unprecedented understanding of cell heterogeneity and function in IBD. In this study, recent cytometry by time of flight (CyTOF) and single cell transcriptomics technology advancements have been leveraged to characterize the intestinal mucosa of IBD patients treated with vedolizumab.

Methods
Single cell RNA sequencing from IBD mucosa biopsies were analysed to derive cell molecular signatures and deconvolute bulk transcriptomic datasets of UC patients treated with biologics. Cellular abundance differences in response to therapy were in-silico validated in both vedolizumab and anti-TNF treated patients. CyTOF analysis of intestinal biopsies from 24 UC patients and 29 healthy controls (HC) was applied to complement transcriptomic findings and further understand T cell dysregulation in disease activity and treatment response. CyTOF panels were focused on T cell polarization, memory differentiation, effector function and homing. Mucosal microbiota analysis by 16S rRNA gene sequencing was employed and correlated with patient/host cellular dynamics.

Results
Deconvolution analysis of UC bulk transcriptomic data with single cell molecular signatures from mucosa biopsied samples (Smillie et al.) revealed decreased abundance of CD8 IELs along with increased activated T cells, inflammatory/activated stromal cells in non-responders to both vedolizumab and anti-TNF therapy compared with responders and HC. CyTOF analysis of intestinal biopsies from patients responding or not responding to biologic treatment confirms cellular alterations at the protein level. Specifically, in patients that respond to vedolizumab, we observed greater levels of immune cells with CD8 IEL phenotype (CD8+ CD69+ CD103+) similar to HC. In contrast, in non-responder patients we observed lower levels of these cells but higher abundances of CD8+ Tc17 and CD4+ Th17 cells. In non-responders, Tregs were also elevated compared with responders and HC. Assessment of mucosal biopsies with 16S rRNA gene analysis also revealed microbial metabolic pathways supportive of CD8 IEL development associated with elevated CD8 IELs in vedolizumab treatment responders.

Conclusion
This multi-modal and deep molecular phenotyping approach revealed CD8 IELs to be associated with healthy intestinal tissue and treatment response to vedolizumab. These findings suggest that CD8 IELs may be beneficial for supporting and restoring tissue homeostasis.