bluuebunny/crossref_metadata_2025 huggingface dataset:
Noise Level Analysis in the Education Sector which Located close to the Runway of Sultan Babullah Airport
Authors: Pasri A A , Rizaldan M , Sardan R H
Published: May 2021

Aircraft noise pollution is an annoying sound effect produced by airplane in flight. For instance, some aviation activities; landing and takeoff could produce a harmfulnoisethat would become some distractions for a learning process. Specifically, for those particular education buildings located in a line across the runway service of Babullah airport. Thus, it is necessary to identify the level of noise produced by airplane passing and flying around the area of campus and schools during teaching and learning activities. This research, therefore, aims to discover how much the noise level likely to disturb the learning process then compare with applicable regulations based on Noise Quality Standards. Additionally, the method of this study using a survey of a sound level meter and conducting an equivalent noise level analysis (LEQ) in accordance with SNI 7231: 2009 at each point of the research location. The results of the 5 largest noise level research sites occurred at point L1 with a distance of 125 m in the location of Khairun University which is 65.7 dBA transpired on Monday when Batik Air A320 landed at 13:00 p.m CEST, and at point L5 with a distance of 166 m at SDN 57 location, namely 75.6 dBA, it figured out on Monday during the takeoff with Sriwijaya Air B737-800 at 15:10 p.m. As a result, the noise level had exceeded 55 dBA thresholds for schools or campus either.
Assessment of the Jati Besar Highway of the City of South Ternate Uses Pavement Condition Index (PCI)
Authors: Sabaruddin  , Tata Arbain
Published: May 2021

Jati Besar Ternate road has a width of 7,00 m a type of road with 1/2 UD which has function which functions as a secondary gathering path.. To determine the condition of pavement of the Great Jati road used Pavement Condition Index (PCI) assessment method.. The results showed that the overall condition of road pavement in both good and perfect categories. Types of damage that found in the was road consists of alligator cracking 0,83 %; shoving 0,17%; edge cracking 0,06 %; longitudinal cracking 0,27 %; patching 0,39%; potholes 0,18 %; The average PCI value of Segment total was 97.85 with excellent condition. The type of maintenance required on road of Jati Besar was routine maintenance.
Comparison Between Conventional Methods, Neural Network, and Support Vector Regression in Forecasting Foreign Tourists in Indonesia
Authors: Purwati  , Montreano Donny , Dewi Alina Cynthia
Published: May 2021

Tourism is one of the important sectors in the growth of Indonesia’s economy. To be able to achieve the target and increase foreign tourist visits to Indonesia it is necessary to plan appropriate promotion and sustainable development that must be in line with the development of foreign tourists to be in target, effective and efficient. In this study forecasting to the level of foreign tourists visiting Indonesia in order to obtain accurate data. Forecasting is done by comparing 3 forecast methods, viz. traditional method, Support Vector Regression (SVR), and Backpropagation Neural Network (BPNN) method. In this research, there are 36 monthly visit data from 2017 to 2020 that are used to forecast. The result of this research indicates that the best forecasting is done by the Support Vector Regression (SVR) method with a MAPE value is 2.5614 % whereas, Backpropagation Neural Network (BPNN) has a MAPE value 31.3777%.
Design of IoT-Based Home Fire Detection System Equipped with a Data Logger
Authors: Juwariyah T , Prayitno S , Krisnawati L , Sulasminingsih S
Published: May 2021

In Industrial Era 4.0, one of the solutions to secure a house from potential fires is to design a smart home. The smart home design described in this paper is the design of a home monitoring system for potential fires. Home fire early detection monitoring system is designed based on the IoT concept and is equipped with a data logger. Data loggers function as data logging and data recorders from time to time. The hardware system design consists of Arduino Mega2560, ESP8266, fire sensor, gas sensor and datalogger module as data storage. The software design that also functions as a system monitoring display is the Blynk application on Android smartphones. Fire sensor and gas sensor activities were recorded on the data logger module. The system test was carried out around the gas stove in the kitchen room. The system design results were displayed via the Blynk application on a smartphone. Fire detection system is a change in the Virtual Button from the initial color to red. While the monitoring display of the gas detection system is in the form of moving the Virtual Level when a gas leak is detected. Fire sensor activity recording data from the datalogger is displayed in the form of a graph of the relationship of the working voltage of the fire sensor versus time. While the data recording of gas sensor activity from the datalogger is displayed in the form of a graph of the relationship of gas concentration versus time. All system response results and graphic data are displayed in realtime through the Blynk application on a smartphone. In addition, system performance data records are stored on a micro SD card for further analysis. From the results of the design of this system is expected to be a reference of home monitoring technology from potential fire equipped with a data storage system.
The Energy Change Props from Used Goods to Reduce Impact of Environmental Pollution in the Land of Anim ha
Authors: Sari Desy Kumala , Waremra Richard Samuel , Setiawan Muchamad Rizki Eka
Published: May 2021

Efforts in the world of education to reduce the impact of environmental pollution in the land of Anim Ha are to utilize waste as a learning medium. This research aims to develop learning media in the form of teaching aids using used items. Learning media are made in the form of teaching aids for wind power generation. This visual aid can be used to show the change of energy from wind energy to motion energy and motion energy to electrical energy. The results of observations using visual aids were developed, namely the resulting voltage of 0.4 volts with wind speeds of 2.4 m/s and 4.5 m/s. The coach made still has the disadvantage of a small dynamo so that the voltage generated was small.
Commodification of Environmental Discourse in the Process of Producing Space in Bukit Baruga Housing, Makassar
Authors: Idrus Idham Irwansyah , Salman Darmawan , Agustang Andi
Published: May 2021

An Eco-friendly Housing is an alternative choice of housing emerged along with the development of environmental discourse. The environmental discourse is commodified in the process of producing spatial space to increase the value of the product mark, which is the house. Commodification is defined as turning non-commodity goods into a commodity goods or adding value to a commodity goods, thus the value is more valuable than before, and it can be traded for profit.

This study used a descriptive research with a qualitative approach to describe the current phenomenon taking place. The study was conducted in the Bukit Baruga Housing, Makassar, which is a housing developed with the concept of an environmental insight since 1996.

With knowledge related to environmental discourse and power over capital possessed by the development company, it presents a simulation spaces with various signs and symbols of environmental insight. The process of commodification is carried out by the developer company through three stages, which are the stage of planning and development, marketing, and management.
Unconfined Compressive Strength of Rehabilitated Road Base via Polymer-Modified Cold In-Place Recycling (CIPR)
Authors: Tan Poi-Cheong , Chan Chee-Ming
Published: May 2021

Cold In-Place Recycling (CIPR) is a road maintenance technology, which chemically stabilize, recycle and improve existing asphalt concrete together with road base underneath. Cement is the most common chemical for CIPR adopted in Malaysia. However, shrinkage crack remains as unresolved technical drawback of cement stabilization, road practitioners are always seeking alternative materials to replace cement in CIPR. A proprietary product, Polymer Modified Cementitious (PMC) chemical binder was identified as the research object to verify the suitability in CIPR application and to study the strength-gain over time, through laboratory testing. To replicate CIPR process, Crusher run (CR) and Recycled Asphalt Pavement (RAP) were mixed at various ratio to study the effect of CR to RAP ratio on strength gained; with PMC added in dosage between 2-4% per dry weight of the materials to compare strength gain at different dosage. Samples were compacted and cured for 7 days then subjected to Unconfined Compressive Test where the strength UCS (qu7) was recorded. Strength-gain over time from 1 day to 28 days, for a specific CR-RAP ratio at fixed PMC dosage was also studied. It was found that UCS was directly proportionate to PMC dosage and amount of CR component in the mixture. This study concluded that at various combination of CR-RAP ratio, with varying PMC dosage, minimum requirement of UCS (7-day) of 2 MPa for road base application specified by local authority is achievable. The correlation between strength and curing duration obtained serves as guideline to extrapolate long-term strength from short-term strength.
An 18 slot, 8-pole Permanent Magnet Synchronous Generator for Small-Scale Wind Turbine Energy Conversion: Design, Fabrication, and Experiments
Authors: Damanik Natalina , Purba Sahrijal , Calle M. Al Roshady S. , Kurniawan M. Arie
Published: May 2021

Compact permanent magnet synchronous generators (PMSGs) for renewable energy conversion are required for remote areas. In this work, an 18-slot, 8-pole PMSG (18S8P PMSG) was designed and fabricated for small-scale wind turbine energy conversion. Finite element analysis was conducted to assess the magnetic flux density distribution of the 18S8P PMSG prototype. The simulation results showed that most of the magnetic flux values were within 0.4–1.5 T, which was well below the saturation level for 35JN360 material. The magnetic flux intensities of the stator and rotor cores were within the optimal magnetic permeability range of the 35JN360 material. There were seven steps involved in fabricating the 18S8P PMSG prototype: (1) material cutting, (2) burring, (3) stacking, (4) welding, (5) coil winding, (6) configuration wiring, and (7) assembling. The electromagnetic performance results showed that the back electromotive force voltage of the 18S8P PMSG prototype seemed to be proportional to the rotor speed, where KE
was 0.52 V·s/rad. The no load torque maximum of 18S8P PMSG is 1.7 N.m at 5000 rpm. The mechanical performance results showed that the highest power output (2500 W) was obtained for the 18S8P PMSG prototype at a rotor speed of 5000 rpm using the 20-Ω load model. The maximum efficiency of this prototype was 85.4%.
NP–hard problems naturally arising in knot theory
Authors: Koenig Dale , Tsvietkova Anastasiia
Published: May 2021

We prove that certain problems naturally arising in knot theory are NP–hard or NP–complete. These are the problems of obtaining one diagram from another one of a link in a bounded number of Reidemeister moves, determining whether a link has an unlinking or splitting number

k
k

, finding a

k
k

-component unlink as a sublink, and finding a

k
k

-component alternating sublink.
Orthopaedic physiotherapists’ perceptions of mechanisms for observed variation in the implementation of physiotherapy practices in the early postoperative phase after hip fracture: a UK qualitative study
Authors: Volkmer Brittannia , Sadler Euan , Lambe Kate , Martin Finbarr C , Ayis Salma , Beaupre Lauren , Cameron Ian D , Gregson Celia L , Johansen Antony , Kristensen Morten Tange , Magaziner Jay , Sackley Catherine , Smith Toby O , Sobolev Boris , Sheehan Katie J
Published: May 2021

Objective

to explore physiotherapists’ perceptions of mechanisms to explain observed variation in early postoperative practice after hip fracture surgery demonstrated in a national audit.

Methods

a qualitative semi-structured interview study of 21 physiotherapists working on orthopaedic wards at seven hospitals with different durations of physiotherapy during a recent audit. Thematic analysis of interviews drawing on Normalisation Process Theory to aid interpretation of findings.

Results

four themes were identified: achieving protocolised and personalised care; patient and carer engagement; multidisciplinary team engagement across the care continuum and strategies for service improvement. Most expressed variation from protocol was legitimate when driven by what is deemed clinically appropriate for a given patient. This tailored approach was deemed essential to optimise patient and carer engagement. Participants reported inconsistent degrees of engagement from the multidisciplinary team attributing this to competing workload priorities, interpreting ‘postoperative physiotherapy’ as a single professional activity rather than a care delivery approach, plus lack of integration between hospital and community care. All participants recognised changes needed at both structural and process levels to improve their services.

Conclusion

physiotherapists highlighted an inherent conflict between their intention to deliver protocolised care and allowing for an individual patient-tailored approach. This conflict has implications for how audit results should be interpreted, how future clinical guidelines are written and how physiotherapists are trained. Physiotherapists also described additional factors explaining variation in practice, which may be addressed through increased engagement of the multidisciplinary team and resources for additional staffing and advanced clinical roles.
Geographic Variability of Nodular Lymphocyte-Predominant Hodgkin Lymphoma
Authors: Xia Daniel , Sayed Shahin , Moloo Zahir , Gakinya Samuel M , Mutuiri Anderson , Wawire Jonathan , Okiro Patricia , Courville Elizabeth L , Hasserjian Robert P , Sohani Aliyah R
Published: May 2021

Objectives

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) differs from classic Hodgkin lymphoma (CHL) in terms of clinicopathologic features, including Epstein-Barr virus (EBV) association. CHL geographic variability is well known, with higher frequencies of mixed-cellularity subtype and EBV positivity in low/middle-income countries (LMICs), but there are few well-characterized series of NLPHL from LMICs.

Methods

We detail clinicopathologic findings of 21 NLPHL cases received in consultation from Kenya and summarize reports of NLPHL with EBV testing published since 2000.

Results

Median age of consultation cases was 36 years, and male/female ratio was 3.2. All cases involved peripheral lymph nodes and showed at least some B-cell–rich nodular immunoarchitecture, with prominent extranodular lymphocyte-predominant (LP) cells and T-cell–rich variant patterns most commonly seen. LP cells expressed pan–B-cell markers, including strong OCT2; lacked CD30 and CD15 expression in most cases; and were in a background of expanded/disrupted follicular dendritic cell meshworks and increased T-follicular helper cells. LP cells were EBV negative in 18 cases. Historical cases showed a low rate of EBV positivity with no significant difference between LMICs and high-income countries.

Conclusions

Unlike CHL, NLPHL shows few geographic differences in terms of clinicopathologic features and EBV association. These findings have implications for diagnosis, prognostication, and treatment of patients with NLPHL in LMICs.
Alcohol Consumption Is a Modifiable Risk Factor for Breast Cancer: Are Women Aware of This Relationship?
Authors: Agabio Roberta , Madeddu Clelia , Contu Paolo , Cosentino Sofia , Deiana Monica , Massa Elena , Mereu Alessandra , Politi Carola , Sardu Claudia , Sinclair Julia M A
Published: May 2021

Aims

Despite alcohol consumption being a dose-dependent risk factor for breast cancer, a recent study conducted in the UK found <20% of women attending breast screening programmes were aware of this relationship and proposed proper information campaigns need to be conducted. We aimed to investigate the awareness of this relationship among a related sample of Italian women to evaluate whether similar information campaigns should also be conducted in Italy.

Methods

The questionnaire used by the UK study was translated into Italian, slightly modified for the Italian context, validated and submitted to a sample of Italian women.

Results

Overall 507 women were interviewed. Among them, 160 were classified as breast cancer screening attenders (SG), 44 as symptomatic breast clinic attenders (CAG) and 303 as non-screening group (NSG). Alcohol was correctly identified as a risk factor for breast cancer by 16.9, 11.4 and 14.9% of participants of SG, CAG and NSG, respectively without differences between the three groups. Despite the methodological differences, the rates of participants who correctly identified alcohol as a risk factor among women attending breast screening programmes were surprisingly similar between the study conducted in UK (15.7%) and the present study (16.9%).

Conclusion

The results of the present study confirm the limited awareness of the relationship between alcohol consumption and risk of developing breast cancer among women and suggest the urgent need to conduct proper awareness-raising campaigns to counter this in the Italian female population.
Incidental Verbal Semantic Processing Recruits the Fronto-temporal Semantic Control Network
Authors: Jedidi Z , Manard M , Balteau E , Degueldre C , Luxen A , Phillips C , Collette F , Maquet P , Majerus S
Published: May 2021

The frontoparietal semantic network, encompassing the inferior frontal gyrus and the posterior middle temporal cortex, is considered to be involved in semantic control processes. The explicit versus implicit nature of these control processes remains however poorly understood. The present study examined this question by assessing regional brain responses to the semantic attributes of an unattended stream of auditory words while participants’ top–down attentional control processes were absorbed by a demanding visual search task. Response selectivity to semantic aspects of verbal stimuli was assessed via a functional magnetic resonance imaging response adaptation paradigm. We observed that implicit semantic processing of an unattended verbal stream recruited not only unimodal and amodal cortices in posterior supporting semantic knowledge areas, but also inferior frontal and posterior middle temporal areas considered to be part of the semantic control network. These results indicate that frontotemporal semantic networks support incidental semantic (control) processes.
A Cortical Surface-Based Meta-Analysis of Human Reasoning
Authors: Shin Minho , Jeon Hyeon-Ae
Published: May 2021

Recent advances in neuroimaging have augmented numerous findings in the human reasoning process but have yielded varying results. One possibility for this inconsistency is that reasoning is such an intricate cognitive process, involving attention, memory, executive functions, symbolic processing, and fluid intelligence, whereby various brain regions are inevitably implicated in orchestrating the process. Therefore, researchers have used meta-analyses for a better understanding of neural mechanisms of reasoning. However, previous meta-analysis techniques include weaknesses such as an inadequate representation of the cortical surface’s highly folded geometry. Accordingly, we developed a new meta-analysis method called Bayesian meta-analysis of the cortical surface (BMACS). BMACS offers a fast, accurate, and accessible inference of the spatial patterns of cognitive processes from peak brain activations across studies by applying spatial point processes to the cortical surface. Using BMACS, we found that the common pattern of activations from inductive and deductive reasoning was colocalized with the multiple-demand system, indicating that reasoning is a high-level convergence of complex cognitive processes. We hope surface-based meta-analysis will be facilitated by BMACS, bringing more profound knowledge of various cognitive processes.
Habit and emotion: John Dewey’s contribution to the theory of change
Authors: Petit Emmanuel , Ballet Jérôme
Published: May 2021

To construct their theoretical framework, the US institutionalist authors, Thorstein Veblen and John Commons, drew on the conception of habit which had been developed by Charles Sanders Peirce, William James and John Dewey from the pragmatist movement. Peirce, James and Dewey see habit as a generally effective form of action conduct, although Dewey focuses more on an analysis of habit transformation and transaction than on habit itself. At the heart of this process of transformation is emotion. Emotion signals the need for change and at the same time is an active agent in habit reconfiguration. Compared to nudge theory, Dewey’s approach, therefore, emphasises the emotional (and not just cognitive) dimension of habit change.
DOP49 Effectiveness and safety of vedolizumab in a matched cohort of elderly and young Inflammatory Bowel Disease patients - LIVE Study-Group
Authors: Pugliese D , Privitera G , Armuzzi A
Published: May 2021

Background

Vedolizumab is the first biologic tested for the treatment of elderly patients with moderate-to-severely active ulcerative colitis (UC) and Crohn’s disease (CD) in the GEMINI program. However, little real-life data have been reported on its use in the elderly population. In this work, we present data on vedolizumab effectiveness and safety in a large cohort of elderly UC and CD patients matched to younger patients.

Methods

The Long-term Italian Vedolizumab Effectiveness (LIVE) study included CD and UC patients started on vedolizumab from April 2016 to June 2017 at 47 centers of the Italian Group for the study of Inflammatory Bowel Disease (IG-IBD). Elderly (E-) patients (≥ 65-year-old) were included for this analysis and matched 1:2 to younger (Y-) patients; patients were then prospectively followed-up until June 2019. Primary endpoints were vedolizumab persistence and safety.

Results

Of 1111 patients, 198 E-patients (mean age 71 ± 5 years; 108 UC,90 CD) were included in the analysis and matched with 396 Y-patients (45 ±12 years; 205 UC,191 CD). After matching, the 2 cohorts were overall comparable, but patients in the Y-group were significantly more likely to have perianal disease, previous exposure to immunosuppressants, and to anti-TNF-α and less likely to be on concomitant steroids at baseline. For UC, persistence in the E- and Y-groups were 69.9% vs and 81.4% at 12 months, and 51.4% vs 67.6% at 24 months (p<0.05 for both). Significant differences were also observed in terms of steroid-free clinical remission (SFCR) (31.5% vs 42.9%,32.4% vs 42.9% at 12 and 24 months, p<0.05 for both) and biochemical remission (22.2% vs 38%,25.9% vs 40.5% at 12 and 24 months, p<0.05 for both). Endoscopic remission was observed in 17/75 (22.7%) E-patients and 50/141 (35.5%) Y-patients (p=0.05). For CD, persistence was 75.6% vs 75.1% at 12 months, 52.4% vs 59.4% at 24 months, for the E- and Y- group respectively (p=ns for both). Similarly, rates of SFCR were comparable between the 2 cohorts. Notably, a significantly higher rate of biochemical remission was observed in the Y-group at 24 months (21.1% vs 30.9%, p<0.05). Endoscopic remission was observed in 13/48 (27.1%) E-patients and 25/98 (28.1%) Y-patients (p=ns). A total of 51 and 94 adverse events (AEs) were observed in the E-group and Y-group, respectively: the rate of AEs was comparable between the 2 groups (p=ns). Of note, E-patients had a higher likelihood of suspending vedolizumab due to AEs (p<0.05).

Conclusion

The data show that vedolizumab can be considered a safe option in elderly patients; however, its efficacy in elderly UC patients (in terms of persistence, SFCR and biochemical remission) seems to be reduced compared to younger UC patients, while no difference was observed in CD.
N17 The Perceptions and Experiences of People Living with Inflammatory Bowel Disease of Nursing Care A Qualitative Evidence Synthesis
Authors: Conmy C
Published: May 2021

Background

Inflammatory bowel disease is a chronic condition of the bowel which is known to be very challenging for patients especially during times of active disease or flare ups of their symptoms. Those affected have to adapt their lives to the chronic nature of their condition. The aim of this review was to synthesise qualitative evidence on the perceptions and experiences of those living with inflammatory bowel disease on nursing care received in all health care settings and identify barriers and facilitators for optimal nursing care. Qualitative evidence synthesis guided by Thomas & Harden’s (2008) method of thematic synthesis was used.

Methods

A systematic search was carried out in CINAHL, Embase, Medline, Cochrane and Google Scholar using combinations of key words. Searches were imported into Covidence which is an online software product used for systematic reviews. Title and abstract screening and full text screening were carried out to screen for eligible papers. Included studies were critically appraised using Critical Appraisal Support Programme (CASP) and thematic synthesis of the data was conducted. Eleven studies were included in the synthesis.

Results

From the thematic synthesis of the included studies three analytical themes were developed;

1) Meaningful care for patients,

2) Accessible support and information

3) “A constant” for people with IBD.

Conclusion

This review demonstrated the positive and negative experiences of patients with inflammatory bowel disease on the nursing care they received. It raises key issues for patients which can be addressed by nursing when caring for patients. The results will inform nursing on what is important to patients and how their healthcare needs can be met in all settings. This review will also support evidence for nurses to obtain resources and improve patient care.
OP14 Extracellular RNAs as liquid biopsy non-invasive biomarker in IBD
Authors: Verstockt B , Verstockt S , Sabino J , Ferrante M , Vermeire S
Published: May 2021

Background

Extracellular RNAs (exRNAs) are RNA species present outside of the cells in which they were transcribed. They are found in human serum, though the exact role of circulating exRNAs remains to be established, especially in inflammatory bowel diseases (IBD). Besides their potential help in our pathophysiological understanding of disease, they might serve as liquid biopsies or non-invasive biomarkers. We characterised exRNAs in serum from IBD patients, and questioned their potential in separating ulcerative colitis (UC) from Crohn’s disease (CD).

Methods

We carried out SILVER-seq (Small Input Liquid Volume Extracellular RNA-sequencing) on serum droplets (5-7ml) from a cross-sectional cohort of 26 IBD patients (15 UC, 11 CD) with active endoscopic disease (Mayo endoscopic sub score or Simple Endoscopic Score for Crohn’s disease) (Table 1). Normalization and differential expression were done using DESeq2 R package, co-expression network analyses performed using WGCNA (FDR adjusted p ≤0.05). Using randomized generalized linear modelling (RGLM), a diagnostic exRNA marker was designed to separate UC from CD samples (15 UC, 11 CD).

Results

We detected 60,675 exRNAs in serum from IBD patients, capturing 76.1% of all genes expressed in intestinal tissue, and including highly abundant intestinal genes (e.g MUC2) and intestinal barrier genes (e.g claudin 8, occludin and RETNLB). Co-expression network analysis identified 69 clusters of which 1 significantly correlated with the distinction between CD and UC (FDR p=0.003, r=-0.70). One of the hub genes within this module (consisting of 148 genes, upregulated in UC) was GNA12 (p=2.3E-4, r=0.66 for correlation with the module eigengene), encoding for a membrane bound GTPase that plays a key role in tight junction assembly and has previously been identified as UC-specific SNP in GWAS (Figure 1). Serum GNA12 expression was not associated with faecal calprotectin (p=0.55, r=0.12), disease duration (p=0.24, r=0.25), age (p=0.43, r=0.16) or gender (p=1.0), but did correlate with other UC-specific genes including TNFRSF14 (p=0.04, r=0.4), HNF4A (p=0.04, r=-0.4) and CAMK2A (p=0.004, r=0.54). Through machine learning within the UC-specific module (containing 148 genes), we identified an 8-gene exRNA panel, including GNA12, that could accurately discriminate between UC and CD patients (accuracy 96.2%).

Figure 1: Visualisation of the identified exRNA network including GNA12

Conclusion

Liquid biopsies are a novel non-invasive tool in IBD biomarker development. Although larger in-depth studies are required to further validate, explore and characterise the potential of serum exRNAs in the field of IBD, the current pilot project identified a new non-invasive tool to accurately distinguish CD from UC patients.
OP24 Efficacy and safety of upadacitinib induction therapy in patients with Moderately to Severely Active Ulcerative Colitis: Results from the phase 3 U-ACHIEVE study
Authors: Danese S , Vermeire S , Zhou W , Pangan A , Siffledeen J , Hébuterne X , Nakase H , Higgins P , Chen M H , Sanchez-Gonzalez Y , Huang B , Xie W , Liu J , Weinreich M , Pannaccione R
Published: May 2021

Background

An unmet therapeutic need remains in patients with ulcerative colitis (UC). U-ACHIEVE is one of two phase 3 induction trials evaluating the safety and efficacy of the selective Janus kinase–1 inhibitor upadacitinib (UPA) 45 mg once daily (QD) in adults with UC.

Methods

U-ACHIEVE is a multicentre, double-blind, placebo (PBO)–controlled trial (NCT02819635) that randomized patients with moderately to severely active UC 2:1 to UPA 45 mg QD or PBO for 8 weeks. Patients were stratified by response to biologic therapy (inadequate vs non–inadequate responder), baseline corticosteroid use (yes or no), and baseline adapted Mayo score (≤7 or >7). The primary endpoint was proportion of patients achieving clinical remission (per adapted Mayo Score) at week 8.Ranked secondary endpoints included endoscopic improvement, endoscopic remission, and clinical response per adapted Mayo Score at week 8; clinical response per partial adapted Mayo Score at week 2; and histologic-endoscopic mucosal improvement at week 8. Non-responder imputation incorporating multiple imputations for missing data due to COVID-19 are reported. Safety was assessed through week 8.

Results

474 patients were randomized (UPA, n=319; PBO, n=155). Baseline characteristics were well balanced between groups (Table 1). A significantly higher proportion of patients receiving UPA (26.1%) vs PBO (4.8%) achieved clinical remission at week 8 (adjusted treatment difference [95% CI], 21.6% [15.8, 27.4]; P<0.001; Figure 1). For all ranked secondary endpoints, UPA was superior to PBO (P<0.001; Figure 1). A significant difference in clinical response favouring UPA vs PBO was seen as early as week 2 (60.1% vs 27.3%) and was sustained over 8 weeks (79.0% vs 41.6%; Figure 2). There were more serious adverse events (AEs), severe AEs, and AEs leading to study drug discontinuation with PBO (Table 2). The most common AEs were acne, creatine phosphokinase elevation, and nasopharyngitis with UPA and worsening of UC and anaemia with PBO. Incidence of serious infection was similar between UPA and PBO. Neutropenia and lymphopenia were reported more frequently with UPA vs PBO (Table 2).No adjudicated gastrointestinal perforation, major cardiovascular AEs, or thrombotic events and no active tuberculosis, malignancy, or deaths were reported.

Conclusion

In patients with moderately to severely active UC, UPA 45 mg QD induction therapy was superior to PBO in inducing clinical remission/response, and endoscopic remission/response over 8 weeks; responses were significant and rapid. UPA 45 mg QD was well tolerated; safety was comparable with the known safety profile of UPA, and no new safety signals were identified.
OP40 Analysis of clinical features associated with favourable outcomes from ustekinumab treat-to-target strategy in Crohn’s Disease patients in the STARDUST trial
Authors: Danese S , Vermeire S , Dignass A , Panés J , D’Haens G , Magro F , Le Bars M , Nazar M , Lahaye M , Ni L , Bravatà I , Gaya D R , Peyrin-Biroulet L
Published: May 2021

Background

The 48-week (W) interventional STARDUST trial assessed whether a treat-to-target (T2T) strategy using ustekinumab (UST) may optimize Crohn’s disease (CD) outcomes; primary efficacy and safety data have been reported before.1 Here we assessed which patient (pt) subgroups may benefit from T2T vs standard of care (SoC) in achieving endoscopic response after 1 year of UST treatment.

Methods

Adult pts with moderate–severely active CD (CD activity index [CDAI] 220–450) and Simple Endoscopic Score in CD [SES-CD] ≥3) who failed conventional therapy and/or 1 biologic were included. Pts received iv, weight-based UST ~6 mg/kg at W0 (baseline [BL]); then SC UST 90 mg at W8. At W16, CDAI 70 responders were randomized (1:1) to T2T or SoC arms. Pts in the T2T arm were assigned to SC UST q12w or q8w based on 25% improvement in SES-CD score vs BL. From W16–48, UST dose was further intensified up to q4w if the following were not met: CDAI <220 and ≥70-point improvement from BL, and C-reactive protein ≤10 mg/L or faecal calprotectin (FCal) ≤250 µg/g. Pts who failed treatment target despite UST q4w were discontinued. In the SoC arm, UST dose was assigned based on EU SmPC (q12w or q8w). We report the treatment effect for the primary endpoint (endoscopic response [≥50% improvement in SES-CD score vs BL] at W48), evaluated for subgroups of pts, based on demographics at BL. For each subgroup, the odds ratio (OR) and 95% confidence interval (CI) of T2T vs SoC were provided based on the logistic regression model that included treatment arm and stratification factors (prior exposure to biologics [none or 1] and SES-CD score [≤16, > 16] at BL) as independent variables.

Results

Of 500 pts enrolled, 441 were randomized to T2T (n=220) or SoC (n=221); 79.1% and 87.3% completed W48. At W48, pts randomized to T2T were more likely to achieve endoscopic response compared to SoC (p<0.05), if they had at BL: (i) longer disease duration (>median [79.1 months]; OR 2.2; 95%CI 1.17–3.94); (ii) clinically moderate disease (CDAI ≤300; OR 1.7; 95%CI 1.03–2.76); (iii) normal FCal (≤250; OR 3.0; 95%CI 1.22–7.56), (iv) endoscopically active CD (SES-CD ≥4 for ileal or ≥6 for colonic and/or ileocolonic disease; OR 1.8; 95%CI 1.10–2.91); and (v) history or presence of strictures/fistula or occurrence of an intra-abdominal abscess (OR 2.3; 95%CI 1.06–5.01 and OR 3.5; 95%CI 1.07–11.19, respectively; Figure 1).

Conclusion

T2T was more effective than SoC (p<0.05) in achieving endoscopic response after 1 year of UST treatment in certain subgroups including pts with higher endoscopic scores at BL and those with history/presence of bowel damage.

Reference
P008 Store-operated calcium entry controls immune cell function and activation in Inflammatory Bowel Disease
Authors: Letizia M , Kaufmann U , Gerbeth L , Sand A , Brunkhorst M , Wang Y , Böttcher C , Schlickeiser S , Fernández-Zapata M C , Kunkel D , Siegmund B , Feske S , Weidinger C
Published: May 2021

Background

Inflammatory bowel disease (IBD) comprises ulcerative colitis (UC) and Crohn’s disease (CD), both representing major clinical challenges in need of new treatment modalities to improve patient care. Store-operated calcium entry (SOCE) is the predominant calcium influx pathway in immune cells regulating many of their functional properties. Conditional knockout mice, in which SOCE signaling components are deleted in T cells, have revealed that SOCE is required for the induction of intestinal inflammation in mouse models of colitis. However, it is currently unknown whether the pharmacologic inhibition of SOCE is a suitable drug target in IBD and it remains elusive, which immune cell subsets are affected by the pharmaceutical blockade of SOCE. Therefore, we here aimed to investigate the effects of the SOCE inhibitor BTP-2 on the function and activation of lymphocytes isolated from IBD patients.

Methods

PBMC and/or lamina propria lymphocytes (LPMC) were isolated from UC and CD patients undergoing colon resection. Cells were ex -vivo stimulated with PMA/Ionomycin in the presence or absence of increasing concentrations of BTP-2, fixed and stored at -80°C until acquisition by mass cytometry. LPMCs were stained using 37 lineage and functional markers targeting B, T, NK or myeloid cells and the resulting flow cytometry standard (FCS) files were analyzed by using cytobank and the R/Bioconductor 9 packages. Additionally, Ca2+ influx measurements were performed in order to assess the impact of SOCE inhibition on the calcium homeostasis of various immune cell subsets.

Results

Data on B, T, NK, and myeloid cells revealed that treatment with BTP-2 causes a dose-dependent inhibition of calcium influx, demonstrating that BTP-2 is a potent inhibitor of SOCE in human LPMCs and PBMCs. By applying mass cytometry, we investigated how the gradual pharmacologic inhibition of SOCE affects the activation and pro-inflammatory functions of various immune cell subsets obtained from colon specimens of patients with UC and CD, which were characterized by the accumulation of CD4+ effector T cells, IFNγ-producing CD8+ T cells and IL-17-producing innate lymphoid cells (ILCs) compared to non-inflamed specimens. Remarkably, inhibition of SOCE attenuated the production of cytokines including IL-2, IL-4, IL-6, IL-17, TNF-α and IFNγ by T cells and ILCs, reduced the activation of B cells and decreased the production of IFNγ by myeloid cells without affecting the viability of primary human epithelial cells.

Conclusion

Our data reveal for the first time that the cytokine production and the activation of several immune cell subtypes can be modulated by SOCE blockade in human intestinal inflammation, identifying SOCE as a novel therapeutic target in colitis.
P052 Comprehensive proteomic profiling of stool from UC and CD patients reveals expected and novel mucosal pathobiology, enabling identification of candidate non-invasive biomarkers to monitor mucosal disease activity
Authors: Harder B , Casavant E , McBride J , Park K T , Mathews W R , Anania V G , Lekkerkerker A
Published: May 2021

Background

Inflammatory bowel disease (IBD) is a multifactorial disorder characterized by chronic gastrointestinal (GI) inflammation. In clinical practice, physicians urgently need biomarkers to monitor changes in mucosal disease to manage treatment. Non-invasive tools such as fecal biomarkers could allow for frequent monitoring of mucosal disease activity and may reflect inflammation of the entire GI tract. Towards identification of novel non-invasive fecal biomarkers, we performed a comprehensive, unbiased, analysis of the human fecal proteome from ulcerative colitis (UC), Crohn’s disease (CD) patients, and healthy controls (HC), focusing on human secreted proteins using proteomic approaches.

Methods

Fecal extraction processes optimized for recovery of secreted proteins were applied to stool samples of mild to severe UC and CD patients and HCs, 20 samples per group. An unbiased survey of the human fecal proteome of the IBD and HC stool extracts was performed using both data-dependent acquisition and data-independent acquisition methods on QExactive HF and Fusion Lumos mass spectrometers. Data were analyzed in Spectronaut for peptide identification, followed by analysis in MS Stats for protein quantification. Fecal calprotectin (fCAL) levels were measured in these stool samples using the Buhlmann EK-CAL immunoassay kit to correlate fCAL levels to proteomic calprotectin (S100A8/S100A9 heterodimer).

Results

We identified and quantified 594 differentially expressed proteins in stool using proteomics, including known proteins perturbed in IBD pathobiology. Elevated levels of neutrophilic proteins, e.g. fCal, neutrophil elastase, lactoferrin and leucine-rich Α-2 glycoprotein 1 were detected as well as proteins linked to rectal bleeding and ulceration e.g. hemoglobin subunit alpha 1 and beta. Pancreatic enzymes, suggested to be associated with active disease, were also detected. Overall, UC and CD contained many proteins not detected in HC. Differential abundances were observed between UC and CD patients, possibly reflecting differences in mucosal pathophysiology. The abundance of proteomic calprotectin correlated highly with the fCAL levels as determined by immunoassay (Spearman rank order > 0.9 for S100A8 and S100A9 to fCAL), validating the fecal proteomic approach to uncover known and novel proteins of IBD biology.

Conclusion

We developed and qualified methods to perform fecal proteomics on IBD stool samples, enabling identification of known and novel proteins of mucosal UC and CD disease biology. In depth analysis of these proteomic datasets may reveal novel fecal biomarker candidates, targeted to reflect mucosal disease activity and potentially serve as non-invasive surrogates for endoscopy and help guide treatment in IBD patients.
P056 Crohn’s Disease associated fibrosis modulates the expression of collagen receptors
Authors: Coll S , Bauset C , Cosín-Roger J , Ortiz-Masià D , Gisbert-Ferrándiz L , Navarro-Vicente F , Barrachina D , Calatayud S
Published: May 2021

Background

Crohn’s Disease (CD) patients often develop stenotic complications as immunomodulatory treatments do not prevent the fibrogenic response in the affected tissues, where a dysregulated activation of stromal cells provokes an excessive deposition of extracellular matrix (ECM). Recent evidences support the notion that local cells can sense the consequent alterations in tissue structure and rigidity through receptors that respond to some ECM components, and this may perpetuate the fibrogenic process even in the absence of inflammation. We aim to analyse the relevance of these signalling pathways in the fibrotic process associated to CD.

Methods

We obtained fibrotic ileal tissues from CD patients and healthy ileal samples from colon carcinoma patients (control), and analysed the expression (RT-PCR, IHQ) of collagen receptors (integrins, discoidin domain receptors/DDR) and of markers for some stromal cells (fibroblasts, endothelial cells). The relationship between these sets of data was analysed by Pearson’s correlation and the results organized as a correlation matrix. The expression of collagen receptors was also analysed in endothelial cells (HUVEC) treated with TGFβ 2 (1ng/ml, 48h).

Results

Ileal samples from CD patients present a differential gene expression of collagen receptors (Fig 1), with increased levels of ITGA10, ITGA11 and DDR2, and reduced expression of DDR1. In CD tissues, the expression of ITGA11 and DDR1 showed a significant correlation, positive and negative respectively, with that of endothelial markers (Fig 2). These correlations do not occur in control tissues.

Integrin-α11 was detected in endothelial cells of submucosal vessels (IHQ). In HUVEC, TGFβ 2 increased the expression of ITGA11 (8.1±0.7 fold induction, p<0.01) and reduced that of DDR1 (0.74±0.06 fold induction, p<0.01), without affecting that of the other collagen receptors.

Conclusion

Intestinal tissues from CD patients affected by fibrosis present an altered pattern of expression of collagen receptors, which suggests a regulatory role of the ECM in the fibrotic response, while the correlation analysis and the changes induced by the fibrotic cytokine TGFβ in endothelial cells insinuates a particular relevance of these stromal cells in this process.
P058 Proteomic analysis-based discovery of a novel biomarker that differentiates intestinal Behçet’s disease from Crohn’s disease
Authors: Park J , Daeun J , Youn Wook C , Jae Hee C , Ji-Hwan R
Published: May 2021

Background

Intestinal Behçet’s disease (BD) and Crohn’s disease (CD) present similar manifestations, but there are no specific pathognomonic clinical, laboratory, or histological diagnostic tests to differentiate intestinal BD from CD. We used a proteomic approach to discover a novel diagnostic biomarker specific to intestinal BD.

Methods

The colon mucosa tissue samples were obtained using colonoscopy-guided biopsy of the affected bowel from patients with intestinal BD or CD at the Inflammatory Bowel Disease Clinic of Severance Hospital, Seoul, Korea. Peptides from seven intestinal BD and seven CD patients were extracted and labeled using tandem mass tag (TMT) reagents. The labeled peptides were identified and quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The differentially expressed proteins were further validated using immunohistochemical (IHC) analysis with tissue samples and an ELISA test with serum samples from 20 intestinal BD and 20 CD patients.

Results

A total of 3,266 proteins were identified using TMT/LC-MS/MS-based proteomic quantification, including 39 candidate proteins differentially expressed between intestinal BD and CD. Beta-2 glycoprotein 1 (APOH) and maltase-glucoamylase (MGAM) showed significantly higher intensity in the IHC staining of the intestinal BD tissues than that of CD tissues. Furthermore, the serum MGAM level was significantly higher in patients with intestinal BD than in patients with CD.

Conclusion

Our proteomic analysis revealed that some proteins were differentially expressed in intestinal BD patients compared to CD patients. Differential MGAM expression in intestinal BD suggests its role as a potential novel diagnostic biomarker in the differentiation of intestinal BD from CD.
P060 A2B adenosine receptor deficiency ameliorates chronic murine Crohn’s-like-ileitis
Authors: O Connell L , Olli K , Wilkinson C , Collins C , Jedlicka P , Aherne C
Published: May 2021

Background

The A2B adenosine receptor (Adora2b) has been demonstrated to play an immunomodulatory and epithelial barrier protective role in acute murine colitis. A2B agonist treatment during acute murine colitis has been demonstrated to decrease colonic inflammation and damage suggesting targeting the A2B adenosine receptor may protect the intestinal barrier in acute intestinal inflammation. Crohn’s disease (CD) is associated with chronic inflammation and damage in the small intestine, most often the ileum. To date the role, if any, of the A2B adenosine receptor in the small intestine and in CD is unknown.

Methods

The TNFΔARE model of Crohn’s-like ileitis was used to investigate a possible role for A2B in small intestinal inflammation. TNFΔARE mice develop discontinuous, transmural inflammation in the distal ileum that progresses with age and is representative of the chronic inflammation observed in CD. Whole body A2B receptor deficient (Adora2b -/-) mice were crossed on to the TNFΔARE background to generate TNFΔARE mice deficient in the A2B adenosine receptor (Adora2b -/-/TNFΔARE+/-). Whole ileum was harvested from Adora2b -/-/TNFΔARE+/- and wildtype TNFΔARE mice for histological analysis during early (6–8 weeks), active (10–12 weeks) and chronic disease (>20 weeks). Histological scoring was performed by a board-certified pathologist blinded to the study. Whole tissue was also harvested for digestion to perform live cell counts and cytokine analysis.

Results

Histological analysis revealed no significant difference between wildtype and Adora2b deficient TNFΔARE mice during early or active disease. However, during chronic disease Adora2b -/-/TNFΔARE+/- histological scores for active inflammation, chronic inflammation and degree of tissue damage were significantly reduced (approximately 25%) compared to wildtype TNFΔARE mice. This dramatic improvement in histological tissue health in mice with chronic disease was accompanied by an approximately 50% reduction in live cell counts in the ileum of Adora2b -/-/TNFΔARE+/- mice compared to wildtype TNFΔARE mice with a corresponding reduction in pro-inflammatory mediators CXCL1 and IL-1β

Conclusion

Our findings demonstrate that sustained loss of A2B receptor expression improves the outcome of chronic small intestinal inflammation. Previous studies demonstrate that A2B receptor expression promotes pro-fibrotic responses in chronic lung fibrosis. Our future studies will address the possible functional role of A2B in pro-fibrotic responses associated with chronic intestinal inflammation.