bluuebunny/crossref_metadata_2025 huggingface dataset:
A coupling voltage based adaptive reclosing scheme for flexible DC grid
Authors: Wei Xiuyan , Zou Guibin , Zhang Shuo , Zhang Chengquan
Published: January 2022

The total electric field around the DC line is composed of both the ion flow field produced by coronae and the electrostatic field produced by the conductor charge. Under the effect of the total electric field, the disconnected pole will generate a coupling voltage. Therefore, based on the coupling voltage, this paper proposes an adaptive reclosing scheme for flexible DC grid to prevent power supply interruption caused by temporary fault. First, the disconnected pole coupling voltage (DPCV) under the total electric field is analysed when single pole to ground fault (SPGF) and pole to pole fault (PPF) occur respectively. Then, according to the DPCV difference between permanent fault and temporary fault, a fault property identification (FPI) criterion is constructed. The scheme is very simple and not affected by the transition resistance, fault position and wiring mode which has high reliability. Compared with the non‐selective reclosing strategy, the adaptive reclosing scheme can avoid the secondary impact on the system from the permanent fault. Extensive simulations and experiments verify the effectiveness of the proposed adaptive reclosing strategy.
Data‐driven look‐ahead voltage stability assessment of power system with correlated variables
Authors: Nejadfard‐jahromi Saeed , Mohammadi Mohammad
Published: January 2022

Probabilistic voltage stability assessment (VSA) of distribution systems has recently gained significant research attention due to the proliferation of renewable energy sources (RESs). This study presents a nonparametric data‐driven VSA in a look‐ahead framework by considering correlated variables. First, an accurate but relatively fast correlation model is developed by considering stochastic interdependency with unknown dependency structure. Then, the probabilistic density function (PDF) of the voltage stability index is estimated for near‐future minutes. The proposed method employs Bernstein vine copula (BVC) for estimating the unknown underlying dependence structure among different variables. This non‐parametric method imposes no assumption on the dependence structure and can handle the problems where no information is available for judging about dependence structure and its belongingness to a specific type of copula function. Additionally, global sensitivity analysis (GSA), with an embedded surrogate model based on the extreme learning machine (ELM), is utilized to rank the loads and RESs according to their contribution to voltage stability margin. Furthermore, a parallel implementation of vine copula construction and dimension reduction is developed based on the GSA to speed up the proposed VSA. The efficiency of the proposed method is examined by simulating the results of modified IEEE 33‐node and 123‐node systems.
Improving the performance of automotive vision‐based applications under rainy conditions
Authors: Hamzeh Yazan , Mohammadi Alireza , Rawashdeh Samir A.
Published: January 2022

Input images are the main source of information for vision‐based algorithms. The presence of raindrops in input images degrades their quality and, consequently, reduces the quality of the target vision‐based algorithm that consumes them. Many image restoration algorithms were proposed in the literature to remove rain presence in images to improve the input image quality. These algorithms, however, cannot remove all the raindrop presence and sometimes introduce undesirable side‐effects, such as the blurring rain‐occluded sections of the image and incorrectly de‐raining areas in the image that are clear. It is hypothesized that a comparable performance improvement can be achieved by decreasing the sensitivity of vision‐based algorithms to noisy input images, rather than denoising these images, through the process of de‐raining. To test this hypothesis, the performance of state‐of‐the‐art object detection and semantic segmentation models was evaluated, with de‐rained image datasets used as input, and compared it to that performance of the same models, retrained with rained image sets. Results showed that the performance of the retrained models was better than that of the baseline detector with de‐rained images used as input.
Aeroelastic scaling of flying demonstrators: mode tracking technique
Authors: Mas Colomer Joan , Bartoli Nathalie , Lefebvre Thierry , Morlier Joseph
Published: January 2022

Aeroelastic scaling theory shows that the design problem of aeroelastically equivalent scaled aircraft can be treated as a structural-only design problem if the aerodynamic shape and airflow properties of the full scale aircraft are preserved. In that case, the theory shows that it is sufficient to match the scaled natural mode shapes, frequencies and mass of the reference aircraft. In this paper, we present a new method for the dynamic scaling of flexible structures where the objective function is based on the modal assurance criterion (MAC). This criterion is used for a mode tracking strategy during the optimization process. Finally, we apply this method to a scaled version (1:5) of the uCRM wing, achieving an agreement greater than 99% on the average MAC value of the first 5 modes.
Le modèle managérial de la recherche
Authors: Brette Romain
Published: January 2022

Faire de la science est un engagement moral : s’efforcer de dire le vrai sur le monde. Le modèle managérial de la recherche, fondement idéologique des réformes du système de recherche engagées en France depuis les années 2000, s’y oppose frontalement. Il consiste à identifier le chercheur à un homo economicus cherchant en premier lieu à maximiser son intérêt personnel, qu’une bureaucratie tente d’aligner sur des objectifs de performance chiffrés. Ce modèle est incohérent et destructeur. La science est permise par la curiosité, l’émulation et l’éthique intellectuelle. Ce sont donc ces traits humains qu’une organisation rationnelle de la recherche doit tenter de favoriser et d’exploiter.
Robust grasshopper-inspired millirobot operates at low voltages
Authors: Piccone Ashley
Published: January 2022

The millirobot can carry nearly 100 times its weight at voltages two order of magnitude smaller than previous devices.
Non-Kolmogorov turbulence in carotid artery stenosis and the impact of carotid stenting on near-wall turbulence
Authors: Saqr Khalid M. , Kano Kiyomitsu , Rashad Sherif , Niizuma Kuniyasu , Kaku Yasuhiko , Iwama Toru , Tominaga Teiji
Published: January 2022

Endovascular stents have become a standard management procedure for carotid artery stenosis. Recent discoveries related to the complex turbulence dynamics in blood flow necessitate revisiting the pathology of carotid stenosis itself and the impact of stenting on blood hemodynamics. In the present work, and for the first time, the therapeutic hemodynamic changes after carotid artery stenting are explored via high-resolution large eddy simulation of non-Newtonian multiharmonic pulsatile flow in realistic patient-specific geometries. The focus of the present study is the transition to turbulence before and after stent deployment. Transition to turbulence was characterized in space, time, and frequency domains. The multiharmonic flow had generalized a time-dependent Reynolds number of 115 ± 26 at the inlet plane of the computational domain. The inlet boundary condition was defined as a multiharmonic waveform represented by six harmonics that are responsible for transferring at least 94% of the mass flow rate in the common carotid artery. Multiharmonic non-Newtonian pulsatile flow exhibited non-Kolmogorov turbulence characteristics. The stent was found to cause a significant reduction in the velocity oscillations downstream the stenosis throat and restore the inverse kinetic energy cascade. It also stabilized hemorheological fluctuations downstream the stenosis throat. Finally, the stent had a significant effect on the kinetic energy cascade at a distance of 10 µm from the artery wall at the carotid bifurcation and stenosis throat. These findings are important to guide the design and optimization of carotid stents and have significant value in understanding the mechanisms of vascular remodeling and carotid stenosis pathophysiology and symptomatology.
Engineering pan–HIV-1 neutralization potency through multispecific antibody avidity
Authors: Rujas Edurne , Cui Hong , Burnie Jonathan , Aschner Clare Burn , Zhao Tiantian , Insausti Sara , Muthuraman Krithika , Semesi Anthony , Ophel Jasper , Nieva Jose L. , Seaman Michael S. , Guzzo Christina , Treanor Bebhinn , Julien Jean-Philippe
Published: January 2022

Significance

The high genetic diversity of HIV-1 continues to be a major barrier to the development of therapeutics for prevention and treatment. Here, we describe the design of an antibody platform that allows assembly of a highly avid, multispecific molecule that targets, simultaneously, the most conserved epitopes on the HIV-1 envelope glycoprotein. The combined multivalency and multispecificity translates into extraordinary neutralization potency and pan-neutralization of HIV-1 strains, surpassing that of the most potent anti-HIV broadly neutralizing antibody cocktails.
The DsrD functional marker protein is an allosteric activator of the DsrAB dissimilatory sulfite reductase
Authors: Ferreira Delfim , Barbosa Ana C. C. , Oliveira Gonçalo P. , Catarino Teresa , Venceslau Sofia S. , Pereira Inês A. C.
Published: January 2022

Significance

Metagenomic data have recently transformed our view of the role played by sulfur metabolism in anoxic environments by showing that this trait is much more widespread than previously believed. A key enzyme in sulfur metabolism is the dissimilatory sulfite reductase DsrAB that is ubiquitous in organisms with a reductive, oxidative, or disproportionating activity. However, the function of some
dsr
genes, such as
dsrD
, has so far been unknown despite its use as a functional marker to genomically assign the type of sulfur energy metabolism, sometimes with unclear results. Here, we disclose the function of DsrD as an activator of DsrAB that significantly increases its activity, providing important insights into the mechanism of this enzyme in different types of sulfur metabolism.
Assessment and English as a medium of instruction
Authors: Hultgren Anna Kristina , Owen Nathaniel , Shrestha Prithvi , Kuteeva Maria , Mežek Špela
Published: January 2022

As English as a Medium of Instruction (EMI) continues to expand across the globe, there is a glaring absence of
research on assessment. This article reviews the scarce literature to date and maps out a research agenda for the future. Drawing
on Shohamy’s (2001, 2007) Critical Language Testing and McNamara et al.’s (2019) notions of “fair” and “just” language assessment, our reading of the literature
to date is that it has revealed considerable complexities around implementing assessment in EMI contexts, with key questions
centring not only on what and who to assess but also on how and why assessment should take place. In outlining a research agenda
for the future, we suggest that one way of bypassing such challenges may be to carve out a greater role for assessment for
learning in higher education. This could capitalize on – and raise stakeholders’ awareness of – bodies of
knowledge that are well established within applied linguistics about the integral role of language in learning.
Whilst we acknowledge challenges in securing institutional buy-in for putting this agenda into practice, we suggest that doing so
could turn assessment challenges into opportunities and significantly enhance learning not only in EMI contexts but beyond.
How children learn to use a writing system
Authors: Nag Sonali
Published: January 2022

Decoding a writing system is an impressive task requiring recognition of connections between printed symbols and the language they represent. Recognising the linguistic anchors for individual symbols is however not enough. Inferences are needed about unseen and often unstated encoding principles. This paper reviews task demands implicit in children’s books and find the models of orthographic learning in an Indic writing system must go beyond a focus on intra-symbol cues, the size of the symbol set, and the nature of sound-symbol mapping. The child-directed print corpus also shows a substantial demand for recognition of multimorphemic words. Since children encounter an ever-expanding variety of such words in the books they read, it is essential to mount systematic studies on morphological development. At a methodological level, this exploratory study shows the limitations of building models of literacy development when real world encounters with a writing system are not adequately taken into account.
Coaxial multi-ring optical vortex generation based on compound spiral phase plates
Authors: Liu Xiaoxuan , Zhou Jinyun , Xue Jiancai , Meng Ziming
Published: January 2022

We propose a new kind of compound optical vortex (COV) generator in this paper. The device consists of an inner spiral phase plate (SPP) and an outer annular spiral phase plate. There is an opaque band between two SPPs. Under the flat-top beam irradiation, concentric multi-ring COV rings with different topological charges in different radial radii can be generated. The theoretical analysis lays a theoretical foundation for the design of the COV generator, and the simulation results prove the effectiveness of the design. The unique characteristics of COV are discussed and some of its potential application scenarios are presented. This work provides a design method for generating COV using compound SPPs, and the advanced COV structure can help to expand the scope of utilization of vortex beam in optical tweezers, optical communication and other fields.
Towards decoding selective attention through cochlear implant electrodes as sensors in subjects with contralateral acoustic hearing
Authors: Aldag Nina , Büchner Andreas , Lenarz Thomas , Nogueira Waldo
Published: January 2022

Objectives. Focusing attention on one speaker in a situation with multiple background speakers or noise is referred to as auditory selective attention. Decoding selective attention is an interesting line of research with respect to future brain-guided hearing aids or cochlear implants (CIs) that are designed to adaptively adjust sound processing through cortical feedback loops. This study investigates the feasibility of using the electrodes and backward telemetry of a CI to record electroencephalography (EEG). Approach. The study population included six normal-hearing (NH) listeners and five CI users with contralateral acoustic hearing. Cortical auditory evoked potentials (CAEP) and selective attention were recorded using a state-of-the-art high-density scalp EEG and, in the case of CI users, also using two CI electrodes as sensors in combination with the backward telemetry system of these devices, denoted as implant-based EEG (iEEG). Main results. In the selective attention paradigm with multi-channel scalp EEG the mean decoding accuracy across subjects was 94.8% and 94.6% for NH listeners and CI users, respectively. With single-channel scalp EEG the accuracy dropped but was above chance level in 8–9 out of 11 subjects, depending on the electrode montage. With the single-channel iEEG, the selective attention decoding accuracy could only be analyzed in two out of five CI users due to a loss of data in the other three subjects. In these two CI users, the selective attention decoding accuracy was above chance level. Significance. This study shows that single-channel EEG is suitable for auditory selective attention decoding, even though it reduces the decoding quality compared to a multi-channel approach. CI-based iEEG can be used for the purpose of recording CAEPs and decoding selective attention. However, the study also points out the need for further technical development for the CI backward telemetry regarding long-term recordings and the optimal sensor positions.
Exhaled breath condensate (EBC) for SARS-CoV-2 diagnosis still an open debate
Authors: Loconsole Daniela , Paola Pierucci , Daniele Casulli , Federica Barratta , Maria Chironna , Giovanna Elisiana Carpagnano
Published: January 2022

The real-time PCR (RT-PCR) on nasopharyngeal swabs (NPS) is the gold standard for the diagnosis of SARS-CoV-2. The exhaled breath condensate (EBC) is used to perform collection of biological fluid condensed in a refrigerated device from deep airways’ exhaled air. We aimed to verify the presence of SARS-CoV-2 virus in the EBC from patients with confirmed SARS-CoV-2 infection by RT-PCR, and to determine if the EBC may represent a valid alternative to the NPS. Seventeen consecutive patients admitted to the Emergency Department of the Policlinico were enrolled in the present study with RT-PCR, clinical and radiological evidence of SARS-CoV-2. Within 24 h from the NPS collection the EBC collection was performed on SARS-CoV-2 positive patients. Informed written consent was gathered and the Ethic Committee approved the study. The mean age of patients was 60 years (24–92) and 64.7% (11/17) were male. Patient n.9 and n.17 died. All NPS resulted positive for SARS-CoV-2 at RT-PCR. RT-PCR on EBC resulted negative for all but one patients (patient n.12). In this study we did not find any correlation between positive NPS and the EBC in all but one patients enrolled. Based on these data which greatly differ from previous reports on the topic, this study opens several questions related to small differences in the complex process of EBC collection and how EBC could be really standardized for the diagnosis of SARS-CoV-2 infection. Further studies will be warranted to deepen this topic.
Ship stabilization technology a feature used for energy efficiency
Authors: Ivanovich Epikhin Aleksey , Vasilescu Mihail-Vlad , Scurtu Ionut Cristian
Published: January 2022

From this article the reader can find information regarding ship stabilization technology. Types of stabilization system, comparison between different types of gyrostabilizers, the technical features that differentiate modern marine gyrostabilizer products, advantages and disadvantages of active stabilizers. Shipping is one of the world’s most polluting industries. More than 90000 ships which are crossing the oceans each year, using classical propulsion, are burning nearly two billion barrels of fossil fuels. As a result, is the belch out of large quantities of polluting emissions into the air, principally in the form of sulphur dioxide, nitrogen oxides and particulate matter, which have been steadily rising and endangering human health especially on the principle shipping routes. They create between 2 and 3 per cent of the world’s total greenhouse gas emissions such as carbon dioxide, contributing to global warming. In order to decrease the amount of burning fuel for the navy industry, it appeared the ship stabilization technology, which helps the ship to reduce the rolling created by wind and waves, so it will reduce the quantity of burn fuel and last but not least will reduce the polluting emissions, in the same time for the owners increasing the economic efficiency of the ship.
Thin and stretchable extracellular matrix (ECM) membrane reinforced by nanofiber scaffolds for developing in vitro barrier models
Authors: Youn Jaeseung , Hong Hyeonjun , Shin Woojung , Kim Dohui , Kim Hyun Jung , Kim Dong Sung
Published: January 2022

An extracellular matrix (ECM) membrane made up of ECM hydrogels has great potentials to develop a physiologically relevant organ-on-a-chip because of its biochemical and biophysical similarity to in vivo basement membranes (BMs). However, the limited mechanical stability of the ECM hydrogels makes it difficult to utilize the ECM membrane in long-term and dynamic cell/tissue cultures. This study proposes a thin but robust and transparent ECM membrane reinforced with silk fibroin (SF)/polycaprolactone (PCL) nanofibers, which is achieved by in situ self-assembly throughout a freestanding SF/PCL nanofiber scaffold. The SF/PCL nanofiber-reinforced ECM (NaRE) membrane shows biophysical characteristics reminiscent of native BMs, including small thickness (<5 μm), high permeability (<9 × 10−5 cm s−1), and nanofibrillar architecture (∼10–100 nm). With the BM-like characteristics, the nanofiber reinforcement ensured that the NaRE membrane stably supported the construction of various types of in vitro barrier models, from epithelial or endothelial barrier models to complex co-culture models, even over two weeks of cell culture periods. Furthermore, the stretchability of the NaRE membrane allowed emulating the native organ-like cyclic stretching motions (10%–15%) and was demonstrated to manipulate the cell and tissue-level functions of the in vitro barrier model.
Research on phase-locked loop technique based on three-dimensional coordinate transformation
Authors: Tan Guangjun , Chen Zhi , Zhao Wei , Sun Xiaofeng
Published: January 2022

The traditional phase-locked loop (PLL) technique widely used in three-phase four-wire system can only obtain one phase angle, and cannot obtain other parameters of unbalanced voltages, such as the amplitude and phase angle of each phase voltage. In order to improve the performance of PLL in unbalanced three-phase four-wire system with disturbance and reduce the order of PLL to improve the stability of the system, a PLL technique based on three-dimensional (3D) coordinate transformation was proposed in this paper. Firstly, the phase detector error of three-phase unbalanced voltage was deduced based on the 3D coordinate transformation. The error can be regarded as the expression form in Hilbert space after linearizing of it. Based on the correspondence between the orthonormal basis in Hilbert space and the unit vectors in Euclidean space, the error can be mapped to Euclidean space, and the detection control law for each voltage parameter can be designed respectively based on the principle of perpendicular decoupling. Then, the voltage parameter detection control law in Euclidean space is mapped back to Hilbert space, so the PLL technique scheme can be obtained which is beneficial to the implementation in the actual system. The control law of each unbalance indices, such as the amplitude and initial phase of each phase voltage, can be decoupled into a first-order or second-order system, so the system structure is simple, and the control parameter design is convenient. The detection of unbalance indices of the three-phase unbalanced voltages with zero-sequence component can be realized with fast and stable characteristics. The simulation and experiments of the proposed PLL technique are carried out finally under several transient conditions of grid voltages, stable within a quarter cycle at the fastest and always stable in 50 ms, so as to validate the rapidness and stability of the proposed PLL technique.
OP04 Vedolizumab intravenous is effective across multiple treatment targets in chronic pouchitis: Results of the randomised, double-blind, placebo-controlled EARNEST trial
Authors: Travis S , Silverberg M S , Danese S , Gionchetti P , Löwenberg M , Jairath V , Feagan B G , Bressler B , Lindner D , Escher A , Jones S , Shen B
Published: January 2022

Background

Pouchitis is a common complication of ileal pouch-anal anastomosis (IPAA) after proctocolectomy in ulcerative colitis (UC). There are currently no approved therapies for chronic pouchitis. Here, we report a multicentre trial of intravenous (IV) vedolizumab (VDZ) for chronic pouchitis after IPAA in patients with UC.

Methods

EARNEST was a randomised, double-blind, placebo (PBO)-controlled, phase 4 study of VDZ in patients aged 18–80 years with chronic pouchitis after proctocolectomy with IPAA for UC (NCT02790138). Male and female patients with a history of IPAA for UC and chronic pouchitis were eligible. Patients were randomised (1:1) to receive VDZ IV (300 mg) or PBO on Day 1 and at Weeks (W) 2, 6, 14, 22 and 30, as well as ciprofloxacin for the first 4 weeks. The primary endpoint was modified Pouchitis Disease Activity Index (mPDAI) remission at W14; efficacy was also assessed through other mPDAI/PDAI secondary endpoints and endoscopic exploratory endpoints (assessed by a central reviewer) at W14 and W34. Safety (adverse events [AEs]) was monitored throughout the study.

Results

In total, 102 patients were treated (51 per group). Patients had a mean age of 40.8 years (VDZ) and 42.9 years (PBO). mPDAI remission rates (comprising clinical symptoms and endoscopy domains) were 31.4% (n=16/51) for VDZ vs 9.8% (n=5/51) for PBO at W14 (p=0.013; Figure 1). Significant differences in favour of VDZ over PBO were also seen in mPDAI remission at W34, mPDAI response at W14 and W34, and PDAI remission (comprising clinical symptoms, endoscopy and histology domains) at W14 and W34 (Figure 1). The rate of sustained remission (defined as remission at both W14 and W34) was higher for VDZ vs PBO on both the mPDAI (VDZ 27.5% [n=14/51] vs PBO 5.9% [n=3/51]; difference 21.6 percentage points [95% confidence interval (CI), 6.5–37.0]) and the PDAI (VDZ 31.4% [n=16/51] vs PBO 7.8% [4/51]; difference 23.5 percentage points [95% CI, 8.0–38.8]). Endoscopic ulceration analysis showed greater reductions in number of ulcers from baseline for VDZ over PBO at W14 and W34 (Figure 2). A higher proportion of patients in the VDZ vs PBO group had an improved SES-CD score and achieved SES-CD remission of pouchitis (Figure 2). AE rates were similar between groups and no new safety signals were identified (Table).

Conclusion

This is the first and largest randomised, double-blind PBO-controlled trial of biologic therapy to show significant benefits across multiple treatment outcomes in patients with chronic pouchitis after IPAA for UC. VDZ showed consistent treatment benefits over PBO across clinical, endoscopic and histologic endpoints, together with safety consistent with its established profile.
OP23 The efficacy and safety of guselkumab induction therapy in patients with moderately to severely active Ulcerative Colitis: Phase 2b QUASAR Study results through week 12
Authors: Dignass A , Rubin D , Bressler B , Huang K H , Shipitofsky N , Germinaro M , Zhang H , Johanns J , Feagan B , Sandborn W , Sands B , Hisamatsu T , Lichtenstein G , Panes J , Allegretti J
Published: January 2022

Background

The QUASAR Induction Study 1 (NCT04033445) is a phase 2b randomized, double-blind, placebo-controlled, dose-ranging study to evaluate the efficacy and safety of guselkumab (GUS), an interleukin-23 p19 subunit antagonist, as induction therapy in patients with moderately to severely active ulcerative colitis (UC) who had an inadequate response or intolerance to conventional (ie, thiopurines or corticosteroids) or advanced therapy (ie, tumor necrosis factor alpha antagonists, vedolizumab, or tofacitinib).

Methods

Patients included in these analyses had moderately to severely active UC (defined as a modified Mayo score of 5 to 9, inclusive) with a Mayo rectal bleeding subscore ≥ 1 and a Mayo endoscopy subscore ≥ 2 obtained during central review of video endoscopy at baseline. Patients were randomized 1:1:1 to receive IV GUS 200 mg, 400 mg, or placebo at Weeks 0, 4, and 8. The primary endpoint was clinical response at Week 12, and major secondary endpoints included clinical remission, symptomatic remission, endoscopic improvement, histo-endoscopic mucosal improvement, and endoscopic normalization at Week 12. Type 1 error was controlled at the 0.05 significance level for the primary endpoint; no other endpoints were controlled for multiplicity. Safety was assessed through Week 12.

Results

Three hundred thirteen patients were randomized in the primary analysis population (mean age, 41.6 yrs; male 59.1%, mean UC duration, 7.55 yrs; mean Mayo score, 9.2; endoscopy subscore of 3 indicating severe disease, 70%; baseline oral corticosteroid use, 39.6%). Approximately 50% had a prior inadequate response or intolerance to advanced therapy for UC. The baseline demographics and disease characteristics were generally similar among treatment groups (Table 1). At Week 12, a significantly greater proportion of patients treated with GUS 200 mg and 400 mg achieved clinical response compared with placebo (61.4% and 60.7% vs 27.6%, respectively, both p<0.001). A greater proportion of GUS-treated patients compared with placebo-treated patients achieved the major secondary endpoints at Week 12 (Figure 1). The proportions of patients reporting adverse events, serious adverse events, and adverse events leading to discontinuation in the GUS groups were not greater compared with placebo (Table 2). No serious infections were reported for GUS. No cases of malignancy or death were reported.

Conclusion

In patients with moderately to severely active UC, GUS induction treatment demonstrated superior efficacy compared with placebo treatment. Overall, safety results through Week 12 were consistent with the known safety profile of GUS in approved indications. The efficacy and safety of GUS 200 mg and 400 mg were comparable.
DOP30 Long-term outcomes of Crohn’s perianal fistulas treatment: anti-TNF with surgical closure versus anti-TNF alone (PISA-II) - A patient preference RCT
Authors: Meima - van Praag MD E , Stoker J , D’Haens G , Gecse K , Dijkgraaf M , Bemelman W , Buskens C
Published: January 2022

Background

The PISA-II trial showed that anti-TNF induction combined with surgical closure induces MRI healing more frequently than anti-TNF alone at 18 months follow-up (FU) and that this was associated with no recurrences at the time. The aim of this study was to compare long-term outcomes of both treatment arms.

Methods

In this FU study, data were collected from patients who participated in the PISA-II trial, a multicentre, international patient preference randomised controlled trial that compared anti-TNF induction combined with surgical closure to anti-TNF therapy alone as treatment for Crohn’s perianal fistulas. FU data were collected from the time of enrolment in the PISA-II trial until November 2021. Primary outcome was radiological healing at MRI and secondary outcomes included long-term clinical closure, recurrences, anti-TNF trough levels (suboptimal level was defined as infliximab <5.0ug/ml, adalimumab <5.9ug/ml), incontinence (improved, decreased or never had), and a decisional regret scale.

Results

Long-term FU data were collected from 88 out of 94 patients included in the PISA-II trial, 35/38 in the surgical closure arm and 53/56 in the anti-TNF treatment arm. Median FU was 5 years (IQR 4–7). During long-term FU radiological healing occurred in significantly more patients in the surgical closure arm (40% vs 17%; P=0.018). Long-term clinical closure occurred in 71% in the surgical closure arm and in 60% in the anti-TNF treatment arm (P=0.533). Recurrences occurred in 20% in the surgical closure arm and in 36% in the anti-TNF treatment arm (P=0.111). One patient with radiological healing developed a recurrence (4.3%) vs 12/57 (21.1%) patients with clinical closure. Trough levels were available in 32/53 patients treated with anti-TNF. Around the time of recurrence a suboptimal anti-TNF serum trough level occurred in 6/10. In the surgical closure arm, 6 patients had more and 6 patients had less incontinence problems after treatment, comparable to the 5 patient in the anti-TNF treatment arm with more and 8 with less incontinence problems. All patients in the surgical closure arm who completed the questionnaire (strongly) agreed that undergoing surgery was the right decision and 79% of the patients in the anti-TNF arm (strongly) agreed, 14% neither agreed nor disagreed and 7% disagreed that anti-TNF treatment was the right decision.

Conclusion

This study further supports the previous finding that anti-TNF induction combined with surgical closure should be considered in patients with Crohn’s perianal fistulas as long-term outcomes are favourable. Interestingly, surgical closure does not seem to be correlated to decreased continence, and all patients agreed that surgery was the right decision.
DOP49 Context-dependent roles of High-mobility group box 1 (HMGB1) during intestinal inflammation and carcinogenesis
Authors: Zierz E , Foelsch K , Pelczar P , Qi M , Alawi M , Clauditz T , Gagliani N , Huber S , Huebener P ,   Huebener
Published: January 2022

Background

HMGB1 is a ubiquitously expressed nucleoprotein with proinflammatory functions following cellular release. The protein is passively released during tissue necrosis, acting as a damage-associated molecular pattern, but can also be actively secreted by immune cells. Stool and serum HMGB1 levels have been suggested as markers of both inflammatory bowel disease (IBD) activity and colorectal cancer (CRC) invasiveness, and antibody-mediated HMGB1 neutralization was beneficial in animal models of IBD. We explored context-dependent functions of HMGB1 in the injured intestine using novel experimental mice with cell-specific genetic HMGB1 deficiency.

Methods

To circumvent the postnatal lethality of global HMGB1 deficiency in animals, we used the Cre-lox system to generate enterocyte-specific (Hmgb1ΔIEC , Villin-Cre) and myeloid cell-specific (Hmgb1ΔLysM , LysM-Cre) HMGB1-knockout mice. Animals were subjected to well-established models of acute (DSS, Citrobacter rodentium) and chronic (AOM+DSS, CD45RBhigh T cell transfer colitis, Apc+/min) intestinal injury, followed by clinical, endoscopic, histological and molecular analysis. HMGB1 expression was assessed in human IBD and CRC specimens.

Results

IBD and CRC biopsies exhibited high levels of HMGB1 expression in epithelia, immune cells, tumor cells and the peritumoral stroma. HMGB1 deficiency from enterocytes and myeloid cells did not alter Citrobacter- or T cell transfer-induced enterocolitis, when epithelial injury was comparably low. In contrast, Hmgb1ΔIEC mice exhibited aggravated DSS-induced colitis, as evidenced by severe weight loss as well as exacerbated neutrophil- and monocyte-driven mucosal inflammation compared to Hmgb1f/f . Whole tissue RNA sequencing indicated defective cellular proliferation in injured Hmgb1ΔIEC intestines. In the AOM+DSS-model, Hmgb1ΔIEC had a comparable tumor burden to Hmgb1f/f , whereas Hmgb1ΔLysM had significantly fewer and smaller tumors, potentially linked to metabolic alterations in the tumor micromilieu. In the Apc+/min model, enterocyte HMGB1 deficiency effectuated more and larger tumors, whereas leukocyte HMGB1 did not affect tumor load.

Conclusion

Contrasting antibody-mediated HMGB1 neutralization in animal models of IBD, our findings from genetic HMGB1 deletion studies reveal a critical role of enterocyte HMGB1 in the maintenance of the intestinal barrier during severe colitis. Impaired epithelial regeneration or inefficient local immune cell expansion in Hmgb1ΔIEC may account for the aggravated phenotype. HMGB1 from enterocytes and immune cells context-dependently affect maladaptive intestinal would healing, potentially mediated by cell-intrinsic and -extrinsic mechanisms that warrant further investigation.
DOP57 Development and validation of a convolutional neural network for the automatic detection of enteric ulcers and erosions in capsule endoscopy: A multicentric study
Authors: Afonso J , Mascarenhas M , Ribeiro T , Cardoso P , Gonçalves R , Ferreira J , Andrade A P , Mascarenhas Saraiva M , Cardoso H , Macedo G
Published: January 2022

Background

Capsule endoscopy (CE) is the gold-standard for the evaluation of the enteric mucosa in patients with suspected or known inflammatory bowel disease, particularly Crohn’s disease. Ulcers and erosions of the small bowel are common findings and their identification in CE is paramount for an accurate disease stratification.

Several artificial intelligence (AI) algorithms have been developed to aid endoscopists to detect lesions in different endoscopic modalities. With this project we intend to develop and test an AI algorithm for the automatic identification of ulcers and erosions in the small bowel mucosa.

Methods

A total of 2565 CE exams from two different centers (1483 from São João University Hospital and 1082 from ManopH Gastroenterology Clinic) were used to develop the Convolutional Neural Network (CNN). 55320 frames of the enteric mucosa were obtained, 18396 containing enteric ulcers and erosions, and 36924 containing normal mucosa. 90% of the frames were used to develop the training dataset and 10% were used to test the network. The patients included on the training dataset were excluded from the testing dataset. This patient split brings the technology performance closer to that of a real-life setting. The output provided by the CNN was compared to the classification provided by a consensus of experts.

Results

Our model was able to automatically detect ulcers and erosions in the enteric mucosa with an accuracy of 93.2%, sensitivity of 90.4% and a specificity of 93.9%. The mean processing time for the validation dataset was 29 seconds (approximately 306 frames/second).

An example of the output obtained after the network application can be seen in Figure 1.

Conclusion

The authors developed a CNN for the automatic identification of enteric ulcers and erosions in CE videos and tested it in AI naïve patients. This represents an evolution in the technology readiness level into a real-life clinical setting, that will surely improve the diagnostic yield of CE exams, which will ultimately translate into better patient care.
DOP79 Biomarkers for IBD using OLINK Proteomics inflammation panel: Preliminary results from the COLLIBRI consortium
Authors: Sudhakar P , Salomon B , Verstockt B , Ungaro R , Aden K , D’Haens G , Komori K , Guay H , Silverberg M , Vermeire S , Halfvarson J
Published: January 2022

Background

Circulating serum proteins have provided insights into disease pathogenesis and are being used to identify prognostic, diagnostic and therapeutic biomarkers for chronic inflammatory diseases. With this pilot project, the Collaborative IBD Biomarker Research Initiative (COLLIBRI) consortium aimed to unravel disease heterogeneity in inflammatory bowel disease (IBD).

Methods

Serum samples were cross-sectionally obtained from 3,390 individuals (Crohn’s disease (CD), n=1815; ulcerative colitis (UC), n=1170; healthy, n=405) recruited at nine centres from Sweden and Belgium. Relative levels of 92 proteins were analysed using the Proseek Multiplex Inflammation I Probe kit 96x96 (Olink Proteomics, Uppsala, Sweden) and reported as arbitrary units, i.e., normalised protein expression on a log2 scale. Using a multivariate integrative approach, we identified protein signatures distinguishing CD and UC samples and attempted to identify clusters or subgroups within patients. Recruiting centre, cohort and batch information were considered for the integrative analysis. Optimisation was performed for identifying the number of components and features per component using 5-fold cross-validation and Leave-One-Group-Out-Cross-Validation, respectively. Information on transcriptional regulators was retrieved from the ReMap project using the orthogonal regulatory resource ChEA3.

Results

A panel of 8 proteins was identified which could segregate CD and UC patients (Figure 1). FGF19 exhibited a consistent trend of expression (downregulated in CD) across all batches of datasets. An integrated AUC of 72.5% was achieved across the different batches of samples used in the study with the highest AUC (79.2%, P-value 8.5e-07) being recorded for a single batch of samples (CD = 42, UC = 56). On a centre-specific dataset, the cross-centre integrated signature achieved an AUC of 75.1%. We identified three transcription factors (MEF2A, BATF, NFKB2), of which the two latter ones are known to modulate intestinal inflammation and which could potentially regulate the expression of at least half of the genes encoding the proteins in the predictive 8-protein panel.

Conclusion

We identified an integrated proteomic biomarker panel capable of separating CD and UC patients. Through further integration of confounder variables along with using other supervised and unsupervised approaches, subsequent analyses may further refine the molecular heterogeneity among CD and UC patients. Our results demonstrate the need for large datasets to identify relevant clusters of patients with IBD, since the diagnosis exhibits a high degree of clinical heterogeneity.

*Equally contributed
P040 Reduced serological response to COVID-19 vaccines in patients with IBD is further diminished by TNF inhibitor therapy; Early results of the VARIATION study (VAriability in Response in IBD Against SARS-COV-2 ImmunisatiON)
Authors: Doherty J , Stack R , O’ Morain N , Girod P , Tosetto M , Inzitari R , Sheridan J , Cullen G , Buckley M , Mulcahy H , Ryan E J , Daghfal D , Doran P , O Morain C , Doherty G
Published: January 2022

Background

Patients with inflammatory bowel disease (IBD) have attenuated responses to current vaccinations. There is a limited body of evidence suggesting patients with IBD receiving TNF antagonists have an attenuated response to vaccination against COVID-19. We sought to determine the impact of IBD and various medications for the treatment of IBD on antibody responses to vaccination against COVID-19.

Methods

Patients with IBD (n=270) and healthy controls (HC, n=116) were recruited prospectively and quantitative antibody responses were assessed following 1st and 2nd doses of COVID-19 vaccination. The impact of IBD and medications for treatment of IBD on vaccine response rates was investigated.

Results

All HC seroconverted post complete vaccination [100%]. A small proportion of patients with IBD failed to seroconvert [2%]. Median IgG spike protein (SP) antibody levels post-complete vaccination in our IBD cohort was significantly lower than HC [2,613 AU/mL versus 6,871 AU/mL, p=<0.001]. A diagnosis of IBD and viral-vector vaccine use were independently associated with lower IgG SP antibody levels. Patients with IBD receiving anti-TNF therapy had significantly lower IgG SP antibody levels [2444.6 AU/mL] than IBD patients not receiving these agents [3867.6 AU/mL]. Patients with IBD not receiving TNF inhibitors still showed attenuated responses compared to HC receiving a similar vaccine [p = < 0.001].[Figure 1]. IgG SP antibody levels in our IBD cohort reduced rapidly during follow up.

Conclusion

Patients with IBD who do not seroconvert post-vaccination against COVID-19 are a vulnerable cohort. Patient with IBD have attenuated serological responses to SARS-CoV-2 vaccination. Use of anti-TNF therapy further impacts IgG SP antibody levels. Impaired response to vaccination in our study highlights the importance of booster vaccination programmes for patients with IBD.
P075 Neutrophils prevent rectal bleeding in Ulcerative Colitis by peptidyl-arginine deiminase-4-dependent immunothrombosis
Authors: Leppkes M , Lindemann A , Gößwein S , Paulus S , Roth D , Hartung A , Liebing E , Zundler S , Acera M G , Patankar J V , Mascia F , Scheibe K , Hoffmann M , Uderhardt S , Schauer C , Foersch S , Neufert C , Vieth M , Schett G , Atreya R , Kühl A A , Bleich A , Becker C , Herrmann M , Neurath M F
Published: January 2022

Background

Bleeding ulcers and erosions are hallmarks of active ulcerative colitis (UC). However, the mechanisms controlling bleeding and mucosal haemostasis remain elusive.

Methods

We used high resolution endoscopy and colon tissue samples of active UC (n = 36) as well as experimental models of physical and chemical mucosal damage in mice deficient for peptidyl-arginine deiminase-4 (PAD4), gnotobiotic mice and controls. We employed endoscopy, histochemistry, live-cell microscopy and flow cytometry to study eroded mucosal surfaces during mucosal haemostasis.

Results

Erosions and ulcerations in UC were covered by fresh blood, haematin or fibrin visible by endoscopy. Fibrin layers rather than fresh blood or haematin on erosions were inversely correlated with rectal bleeding in UC. Fibrin layers contained ample amounts of neutrophils co-aggregated with neutrophil extracellular traps (NETs) with detectable activity of peptidyl-arginine deiminases (PAD). Transcriptome analyses showed significantly elevated PAD4 expression in active UC. In experimentally inflicted wounds, we found that neutrophils underwent NET formation in a PAD4-dependent manner hours after formation of primary blood clots, and remodelled clots to immunothrombi containing citrullinated histones, even in the absence of microbiota. PAD4-deficient mice experienced an exacerbated course of DSS-induced colitis with markedly increased rectal bleeding (96 % vs 10 %) as compared to controls. PAD4-deficient mice failed to remodel blood clots on mucosal wounds eliciting impaired healing. Thus, NET-associated immunothrombi are protective in acute colitis, while insufficient immunothrombosis is associated with rectal bleeding.

Conclusion

Our findings uncover that neutrophils induce secondary immunothrombosis by PAD4-dependent mechanisms. Insufficient immunothrombosis may favor rectal bleeding in UC.
P274 Bioelectrical impedance analysis identifies low skeletal muscle index in patients with Inflammatory Bowel Disease
Authors: Nguyen A , Holt D , Burns M , Herath M , Gibson P R , Ebeling P , Milat F , Moore G
Published: January 2022

Background

Low skeletal muscle index (SMI) has been associated with increased need for surgery and post-surgical complications in patients with Inflammatory Bowel Disease (IBD). On dual energy X-ray absorptiometry (DXA), SMI is routinely calculated by dividing limb skeletal muscle mass (kg) by the square of the height (m2). Bioelectrical impedance analysis (BIA) provides a quick, inexpensive and radiation-free method to measure body composition. The aim of this study was to compare BIA with DXA to identify patients with low skeletal muscle mass and to show change over 14 weeks.

Methods

This single-centre prospective study recruited adult patients with IBD and adult controls, matched for gender. Active disease was defined as a faecal calprotectin of ≥150 μg/g. Active IBD patients undergoing biologic induction had repeat body composition measurements at least 14 weeks apart. All patients underwent single-frequency segmental BIA (Tanita BC-418) and DXA (GE Lunar Prodigy). A BIA-predicted SMI was calculated by dividing limb fat-free mass (kg) by the square of the height (m2).

Results

Of 48 patients with IBD, 54% had Crohn’s disease, 56% were male and median age was 29 (IQR 23–40) years. 28 had active disease, 16 inactive disease and 4 had no faecal calprotectin available. Patients with IBD and controls (n=30) had similar total body water, measured by BIA, and differed in albumin levels (39 vs 40.1 g/L, p=0.011). In IBD patients and controls, BIA total fat-free mass correlated strongly with DXA-derived fat-free mass (0.96 and 0.93, both p<0.0001). The BIA-predicted SMI also correlated well with DXA-derived SMI (0.89 and 0.91, both p<0.0001).

The correlation was stronger for Ulcerative Colitis (0.96) compared to Crohn’s disease (0.84). In patients with IBD, the mean difference between BIA-predicted SMI and DXA-derived SMI was 1.1 ± 0.6 kg/m2 with 95% limits of agreement, -0.1 to 2.3 kg/m2. Controls followed a similar trend with a mean difference of 0.5 ± 0.6 kg/m2 and 95% limits of agreement, -0.5 to 1.6 kg/m2.

The BIA-predicted SMI demonstrated a strong ability to identify low DXA-derived SMI for women with IBD (AUC: 0.98) and less so for men (AUC: 0.79). In 14 patients undergoing biologic treatment, change in DXA-derived SMI correlated with BIA-derived SMI (0.76, p=0.003).

Conclusion

An accurate estimate of SMI can be obtained with BIA as point-of-care in clinical practice. Further prospective studies with larger sample sizes are needed to determine the accuracy of BIA in monitoring changes of SMI during IBD treatment.