bluuebunny/crossref_metadata_2025 huggingface dataset:
A cell-based phenotypic library selection and screening approach for the de novo discovery of novel functional chimeric antigen receptors
Authors: Fierle Julie K. , Abram-Saliba Johan , Atsaves Vasileios , Brioschi Matteo , de Tiani Mariastella , Reichenbach Patrick , Irving Melita , Coukos George , Dunn Steven M.
Published: January 2022

Anti-tumor therapies that seek to exploit and redirect the cytotoxic killing and effector potential of autologous or syngeneic T cells have shown extraordinary promise and efficacy in certain clinical settings. Such cells, when engineered to express synthetic chimeric antigen receptors (CARs) acquire novel targeting and activation properties which are governed and orchestrated by, typically, antibody fragments specific for a tumor antigen of interest. However, it is becoming increasingly apparent that not all antibodies are equal in this regard, with a growing appreciation that ‘optimal’ CAR performance requires a consideration of multiple structural and contextual parameters. Thus, antibodies raised by classical approaches and intended for other applications often perform poorly or not at all when repurposed as CARs. With this in mind, we have explored the potential of an in vitro phenotypic CAR library discovery approach that tightly associates antibody-driven bridging of tumor and effector T cells with an informative and functionally relevant CAR activation reporter signal. Critically, we demonstrate the utility of this enrichment methodology for ‘real world’ de novo discovery by isolating several novel anti-mesothelin CAR-active scFv candidates.
Wood ash biocatalyst as a novel green catalyst and its application for the synthesis of benzochromene derivatives
Authors: Rostamian Rezvaneh , Khalilzadeh Mohammad A. , Zareyee Daryoush
Published: January 2022

Wood ash is a naturally alkaline derived substance containing organic and inorganic constituents. This study investigates the catalytic activity of wood ash as a heterogeneous catalyst for the synthesis of benzochromene derivatives. Several wood ash catalysts, comprising calcium- and potassium-rich carbonates, were prepared from different natural resources under various combustion temperatures. The prepared catalysts were characterized by Fourier transform infrared, scanning electron microscopy, energy dispersive X-ray analysis, transmission electron microscopy, and X-ray diffraction techniques. Catalytic efficiency of the resultant catalysts was tested in the synthesis of benzochromene derivatives. The experimental studies clarified that the catalyst prepared at 850 °C could efficiently expedite the formation of three-component synthesis of benzochromene derivatives in water at 80 °C with high yields. Indeed, alkali, alkaline metal, and metal oxides such as Al2O3, SiO2, MgO, CaO, and Fe2O3, are widely utilized as both catalyst and catalyst support in the heterogeneous catalytic processes. The prepared wood ash catalysts (possessing metal oxides, e.g., CuO, Al2O3, SiO2, and CaO) could effectively prompt the electrophilic activity of the carbonyl groups during the nucleophilic attack intermediate, enhancing the efficiency of the reactions.
Prevalence and assessment of self-disorders in the schizophrenia spectrum: a systematic review and meta-analysis
Authors: Burgin Sam , Reniers Renate , Humpston Clara
Published: January 2022

Self-disorders have been proposed as the “clinical core” of the schizophrenia spectrum. This has been explored in recent studies using self-disorder assessment tools. However, there are few systematic discussions of their quality and utility. Therefore, a literature search was performed on Medline, Embase, PsychINFO, PubMed and the Web of Science. Studies using these assessment tools to explore self-disorders within schizophrenia spectrum disorders (SSDs) were included. A meta-analysis was performed on the outcomes of total self-disorder score and odds ratios of self-disorders, using Comprehensive Meta-Analysis software. Weighted pooled effect sizes in Hedge’s g were calculated using a random-effects model. 15 studies were included, giving a sample of 810 participants on the schizophrenia spectrum. Self-disorders showed a greater aggregation within schizophrenia spectrum groups compared to non-schizophrenia spectrum groups, as measured with the Bonn Scale for the Assessment of Basic Symptoms (Hedge’s g = 0.774, p < 0.01) and Examination of Anomalous Self-Experiences (Hedge’s g = 1.604, p < 0.01). Also, self-disorders had a greater likelihood of occurring within SSDs (odds ratio = 5.435, p < 0.01). These findings help to validate self-disorders as a core clinical feature of the broad schizophrenia spectrum.
Taming salophen in rare earth metallocene chemistry
Authors: Castellanos Ernesto , Benner Florian , Demir Selvan
Published: January 2022

An unprecedented series of salophen-bridged rare earth metallocenes, (Cp*2RE)2(μ-tBusalophen) (RE = Gd, Dy, and Y), has been crystallized. The solid and solution states have been unambiguously characterized by magnetic, spectroscopic and DFT methods.
MoS2 quantum dot-decorated MXene nanosheets as efficient hydrogen evolution electrocatalysts
Authors: Huang Huajie , Xue Ya , Xie Yongshuai , Yang Ying , Yang Lu , He Haiyan , Jiang Quanguo , Ying Guobing
Published: January 2022

A controllable assembly strategy is developed to fabricate 0D MoS2 quantum dots anchored onto 2D Ti3C2Tx MXene nanosheets, which show exceptional electrocatalytic ability toward the hydrogen evolution reaction.
From amides to urea derivatives or carbamates with chemospecific C–C bond cleavage at room temperature
Authors: Lv Cong , Liu Dan , Muschin Tegshi , Bai Chaolumen , Bao Agula , Bao Yong-Sheng
Published: January 2022

A general method for copper-catalyzed chemospecific C–C bond cleavage of amides to synthesize urea derivatives and carbamates at room temperature was reported.
Mélatonine
Authors: Boutin Jean A.
Published: January 2022

La mélatonine est une molécule naturelle dérivée du tryptophane. Son rôle est de servir de relai entre la rythmicité jour/nuit et notre corps. Elle sert donc de marqueur circadien : concentration haute pendant la nuit et basse pendant la journée. Elle sert aussi de marque saisonnière : plus les nuits sont longues et plus longuement elle est produite (et vice-versa), ce qui a un rôle primordial dans les cycles reproductifs des animaux. Mais elle est aussi affublée de multiples propriétés thérapeutiques concernant la plupart des maladies humaines, du cancer à la COVID-19 en passant par l’infection par le virus Ebola, ainsi que de capacités thérapeutiques vis-à-vis de multiples toxicités (métaux, venins, produits chimiques comme l’adriamycine [doxorubicine], le méthotrexate ou le paclitaxel). Alors que l’enthousiasme à propos de cette molécule est troublant, l’assise scientifique de ces descriptions est dans le meilleur des cas faible et dans la plupart des cas, inexistante. Dans ce commentaire, les données scientifiques bien établies liées à la mélatonine sont résumées et brièvement discutées, en tâchant de redessiner les limites entre ce qui est connu et bien établi et ce qui reste du domaine du fantasme.
Rôle du récepteur TREM-1 dans les maladies cardiovasculaires
Authors: Vandestienne Marie , Joffre Jérémie , Lemarié Jérémie , Ait-Oufella Hafid
Published: January 2022

La réponse immunitaire innée joue un rôle important dans le déclenchement et la progression des maladies cardiovasculaires ainsi que dans leurs complications, potentiellement mortelles. TREM-1, un récepteur membranaire principalement exprimé par les cellules myéloïdes, agit comme un chef d’orchestre de l’inflammation amplifiant la production de cytokines et de chimiokines. De récentes études expérimentales montrent que l’inhibition de TREM-1 limite le développement de l’athérosclérose, la dilatation aortique anévrismale, ainsi que les complications cardiaques et cérébrales lors de l’ischémie aiguë. Chez l’homme, la forme soluble de TREM-1, libérée après son activation, est un biomarqueur intéressant, qui permet d’identifier les patients à haut risque cardiovasculaire, et qui pourrait ouvrir la voie vers une approche immuno-modulatrice personnalisée des maladies cardiovasculaires.
Resultado funcional do procedimento de tenodese extra-articular lateral (TEL) como complemento à reconstrução do ligamento cruzado anterior: Uma metanálise
Authors: Aryana I Gusti Ngurah Wien , Subawa I Wayan , Dusak I Wayan Suryanto , Dharmayuda Cokorda Gde Oka , Nugraha Hans Kristian , Deslivia Maria Florencia
Published: January 2022

Objetivos O objetivo deste estudo é revisar e analisar sistematicamente o desfecho funcional do procedimento de tenodese extra-articular lateral (TEL) em complemento à reconstrução do ligamento cruzado anterior (RLCA) em de estudos com alto nível de evidências.

Métodos Realizamos a pesquisa bibliográfica para estudos clínicos comparando o método TEL como complemento à RCLA com a RLCA isolada. Os resultados principais foram a pontuação no Comitê Internacional de Documentação de Joelho (IKDC, na sigla em inglês), pontuação de Lysholm, e falhas no enxerto. Variáveis contínuas foram relatadas, como médias e intervalos de confiança (ICs) de 95%.

Resultados Seis estudos clínicos com 1,049 pacientes foram incluídos na metanálise. O período de seguimento foi de, em média, 24 meses (intervalo de 6–63 meses). A adição do procedimento TEL à reconstrução do LCA resultou em melhor resultado funcional com base no escore IKDC (p < 0,05). A falha do enxerto foi menor no grupo RLCA mais TEL (16 dos 342 pacientes) em comparação com o grupo apenas RLCA (46 dos 341 pacientes) (p < 0,05).

Conclusão Há evidências de alto nível de que o procedimento TEL como complemento à RLCA é preferível em termos de resultado funcional e falha do enxerto.
Prevalência de dor neuropática em pacientes com fratura da extremidade distal do rádio tratada com placa volar bloqueada
Authors: Silva Helbert Luiz Nomura da , Tanaka Giuliana Olivi , Pinheiro Thiago Barros , Abdouni Yussef Ali
Published: January 2022

Objetivo Avaliar a prevalência de dor persistente no pós-operatório de fratura da extremidade distal do rádio, assim como detectar precocemente sinais de dor neuropática com o intuito de desenvolver protocolos de prevenção da dor crônica pós-operatória.

Métodos Estudo prospectivo, realizado com 56 pacientes submetidos a redução aberta e fixação interna de fratura da extremidade distal do rádio com placa volar bloqueada no período de março a setembro de 2020. Os pacientes foram submetidos a avaliação de dor neuropática e capacidade funcional através dos questionários Douleur Neuropathique 4 questionnaire (DN4) e Quick Disabilities of the Arm, Shoulder, and Hand (Quick-DASH, na sigla em inglês). As variáveis qualitativas foram comparadas pelo teste de Mann-Whitney e sua correlação foi analisada pelos testes de correlação de Spearman e de Igualdade de Duas Proporções.

Resultados Foram incluídos no presente estudo 43 pacientes, com idades entre 18 e 66 anos; 39,5% dos participantes apresentaram pontuação ≥ 4 no questionário Douleur neuropathique 4 questionnaire (DN4). Em relação ao Quick-DASH, a média foi de 38,6. Não houve diferença estatística significante entre o sexo do paciente e o valor do DN4 (p = 0,921). Também não foi encontrada correlação estatística entre as variáveis quantitativas DN4 e Quick-DASH (p = 0,061).

Conclusões A prevalência de dor neuropática nos pacientes pós-operatórios analisados foi significativa e a presença de sinais e sintomas de dor neuropática foi fator preditivo positivo para a persistência da dor além de 2 meses em 100% dos casos. Assim, com diagnóstico precoce do componente neuropático de dor, associado ao componente nociceptivo, é possível obter o controle adequado da dor, impedindo sua cronificação e garantindo uma melhor reabilitação.
Determinação da capacidade de acesso anterior à coluna cervicotorácica conforme idade e gênero: Análise radiográfica de imagens de tomografia computadorizada
Authors: Sugino Rafael Lindi , Iutaka Alexandre Sadao , Cho Samuel K. , Cataldo Daniel R. , Marchi Luis , Herrero Carlos Fernando Pereira da Silva
Published: January 2022

Objetivo A capacidade de acesso anterior à região cervicotorácica com base na idade e gênero do paciente e a possibilidade de variações anatômicas em diferentes populações geográficas ainda não foram investigadas. O objetivo deste trabalho foi realizar uma análise radiográfica de pacientes brasileiros para avaliar a acessibilidade anterior da junção cervicotorácica conforme idade e gênero.

Métodos Análise radiográfica retrospectiva de 300 tomografias computadorizadas. Os pacientes foram separados por idade e gênero. Os parâmetros radiográficos estudados foram: nível horizontal acima do esterno (HLS, na sigla em inglês), angulação do corpo vertebral (VBA, na sigla em inglês), linha do disco intervertebral (IDL, na sigla em inglês) e angulação da linha do disco intervertebral (IDLA, na sigla em inglês).

Resultados Os HLS e IDL mais frequentes foram T2 (34,3%) e C7–T1 (46%), respectivamente. Os valores médios de VBA e IDLA foram de 18 ± 8,94 e 19 ± 7,9 graus, respectivamente. Os homens apresentaram valores maiores de IDLA (p = 0,003) e VBA (p = 0,02). Os grupos de maior idade apresentaram valores maiores de IDLA (p = 0,01) e VBA (p = 0,001). Não houve diferenças de HLS entre os gêneros masculino e feminino (p = 0,3) ou faixas etárias (p = 0,79). Não foram observadas diferenças na IDL entre os gêneros masculino e feminino (p = 0,3); entretanto, o grupo mais velho apresentou nível mais caudal do que os grupos mais jovens (p = 0,12).

Conclusões Em comparação a outras populações, nossa amostra apresentou IDL e HLS mais cefálicos. AVBA e a IDLA foram maiores no gênero masculino, enquanto VBA e IDLA foram maiores em grupos mais velhos. A IDL era mais caudal em pacientes idosos.
Medidas de desfechos clínicos na meniscectomia artroscópica: Pontuações de joelho segundo médicos e pacientes
Authors: Al-Dadah Oday , Shepstone Lee , Donell Simon T.
Published: January 2022

Objetivo O objetivo do presente estudo foi investigar a diferença entre instrumentos de desfechos preenchidos por médicos e pacientes na detecção de melhora após a meniscectomia artroscópica para tratamento de rupturas de menisco.

Métodos Trinta e quatro pacientes com rupturas de menisco foram avaliados de forma prospectiva usando 9 medidas de desfechos clínicos. Os cinco instrumentos de avaliação de joelho respondidos por médicos foram o Escore de Atividade de Tegner, o Escore de Joelho de Lysholm, o Escore de Joelho de Cincinnati, o Escore de Exame do Joelho do International Knee Documentation Committee (IKDC, na sigla em inglês) e o Escore de Classificação do Menisco de Tapper e Hoover. Os quatro instrumentos de avaliação do joelho respondidos por pacientes foram o Escore Subjetivo do Joelho do IKDC, a Pesquisa de Desfecho de Joelho – Escala de Atividades de Vida Diária (KOS-ADLS, na sigla em inglês), o Formulário Curto de Pesquisa em Saúde de 12 Itens (SF-12, na sigla em inglês) e o Escore de Desfecho de Osteoartrite e Lesões no Joelho (KOOS, na sigla em inglês). Vinte e nove dos 34 pacientes foram submetidos a uma meniscectomia artroscópica e reavaliados com todos os 9 instrumentos na sua consulta de acompanhamento.

Resultados Uma melhora longitudinal significativa foi observada em 4 dos 5 instrumentos respondidos por médicos (Tegner [p < 0,001], Lysholm [p = 0,004], Cincinnati [p = 0,002] e Tapper e Hoover [p < 0,001], mas não no IKDC [p = 0,332]). Por outro lado, o Escore Subjetivo do Joelho do IKDC (p = 0,021) foi o único instrumento respondido por pacientes a demonstrar melhora pós-operatória significativa.

Conclusão De modo geral, os instrumentos respondidos por médicos foram considerados inconsistentes em relação àqueles respondidos por pacientes. O modo de administração dos instrumentos pode ter influência significativa nos resultados, tanto para fins de pesquisa quanto para a prática clínica. A combinação de um instrumento respondido pelo médico com um instrumento respondido pelo paciente pode ser uma abordagem mais equilibrada para a avaliação e a quantificação das rupturas do menisco e do desfecho após a meniscectomia artroscópica.
Mesoscale eddies carry algae to shores, cause coastal choking
Authors: Piccone Ashley
Published: January 2022

Vortices in the Caribbean transport pelagic Sargassum that may impact the environment and economy.
(The) fact is …/(Die) Tatsache ist …focaliser constructions in English and German are similar but subject to different constraints
Authors: Hundt Marianne , Oppliger Rahel
Published: January 2022

N-is/istconstructions are elements in the left periphery of English/German sentences that have developed pragmatic meaning: they can be used as discourse markers with various functions, depending on the nominal element that is used in the construction. We use evidence from parallel and comparable corpora of English and German to investigate variable article use in these focaliser constructions and model factors that may play a role in article omission/retention (such as modification, choice of head noun, degree of syntactic integration of the focaliser). Our evidence shows that article use largely depends on the lexical head in German but is constrained by different factors in English (notably modification). We interpret our results against the backdrop of construction grammar, arguing that article omission plays a different role in the two languages. From a contrastive point of view, formal syntactic separation in English is easier to achieve than in German and thus facilitates use of EnglishN-isconstructions as focalisers.
e ubiity of polygray and its significan for e typology of iti systems
Authors: Osterkamp Sven , Schreiber Gordian
Published: January 2022

It has often been assumed that there is, or should be, a one-to-one correspondence between graphs and linguistic units in writing systems as the norm. This is not merely doubtful in terms of descriptive accuracy. Conceptualizing writing systems in such a way also has profound consequences for the application of typological categories to specific cases. In this paper we first suggest a working definition of polygraphy, also touching upon its demarcation from adjacent concepts such as ligatures and diacritics. Having demonstrated that polygraphy is in fact fundamental to a significant number of typologically diverse writing systems, we argue in favor of a typology of writing systems taking the ubiquity of polygraphy into due account, with definitions going beyond one-to-one correspondences as the default.
Phononic linear and quadratic nodal points in monolayer XH (X=Si, Ge, Sn)
Authors: Yu Wei-Wang , Liu Ying , Tian Lu , He Tingli , Zhang Xiaoming , Liu Guodong
Published: January 2022

Topological phases in two-dimensional (2D) systems have been attracting tremendous attention since the discovery of graphene. Since the experimental probing could proceed in the whole phonon spectrum, intensive research effort has been devoted to the topological quantum phases in phononic systems. Via first-principles calculations, we predict that a family of 2D hexagonal materials, XH (X = Si, Ge, Sn), hosts ideal linear nodal points (LNPs) and quadratic phononic nodal points (QNPs). Specifically, the LNPs appear at the two inequivalent valleys, akin to the 2D Dirac point in graphene, connecting by an edge arc. The QNP is pinned at the Γ point, two edge states emerge from their projections. Remarkably, both LNPs and QNP enjoy an emergent chiral symmetry, we then show that they feature nontrivial topological charges. As a consequence, our work discusses the nodal points in the phonon spectrum of 2D materials and provides ideal candidates to study the topology for bosonic systems.
Measurements of the fluctuating magnetic field in a DC motor by a flat inductor sensor
Authors: Chen Jun , Gao Ya
Published: January 2022

This paper describes, for the first time, a fluctuant phenomenon of the magnetic field in a DC motor. The magnetic field of the DC motor with 15 slots was simulated based on the mechanical and electrical parameters. From the simulation results, four key field positions in a commutation cycle were obtained, and the magnetic fields of the four positions represented the phenomenon of magnetic fluctuation. The flux densities of the magnetic fluctuation at three speeds (

1418 r mi

n

−
1

,

1277

r mi

n

−
1

, and

1108

r

mi

n

−

1

) were calculated with the help of the simulation data. To verify the phenomenon of magnetic fluctuation, a flat and single-layer inductor sensor was fabricated on a PCB board with thickness 0.2 mm and embedded into the motor to measure the induced electromotive forces generated by the magnetic fluctuation. The maximum and minimum combined uncertainties of the measured fluctuation periods were 0.08 ms and 0.07 ms, respectively. Finally, the practical experiments of speed measurement from

700

r

mi

n

−

1

to 1400 r min−1 were finished. The maximum and minimum relative errors between the set and measured speeds were 0.07% and 0.01%, respectively. The combined uncertainties of the measured speed were less than 0.09 r min−1, which represented the perfect accuracy of this method.
Overview and recent progress of KSTAR diagnostics
Authors: Lee S.G. , Nam Y.U. , Bak J.G. , Juhn J.W. , Lee J.H. , Lee K.D. , Seo S.H. , Ko W.H. , Ko J.S. , Lee J. , Lee W.C. , Kim J.H. , Jang J.
Published: January 2022

The 14th experimental campaign from the Korea Superconducting Tokamak Advanced Research (KSTAR) device has passed since the first experimental campaign was carried out in 2008. The basic diagnostic systems such as magnetic diagnostics, interferometer, inspection illuminator, visible spectrometer, ECE radiometer have been used for the first plasma experiment in KSTAR. Currently more than 50 diagnostic systems have been continuously installed including improved basic diagnostics and advanced imaging diagnostics in KSTAR. A recent progress and future plan of diagnostics for KSTAR are briefly discussed.
A miniaturized radiation monitor for continuous dosimetry and particle identification in space
Authors: Gohl St. , Malich M. , Bergmann B. , Burian P. , Granja C. , Heijne E. , Holik M. , Jacubek J. , Janecek J. , Marek L. , Oancea C. , Petro M. , Pospisil S. , Smetana A. , Soukup P. , Turecek D. , Vuolo M.
Published: January 2022

A Miniaturized Radiation Monitor (MIRAM) has been developed for the continuous measurement of the radiation field composition and ionizing dose rates in near earth orbits. Compared to currently used radiation monitors, the presented device has an order of magnitude lower weight while being comparable in power consumption and functionality. MIRAM is capable of on-board real-time self-diagnostic. Furthermore, it supports on-board analysis of the measured data to be able to work autonomously. The dose rate is calculated continuously based on the energy deposition in the Timepix3 detector. For the estimation of the particle species composition of the radiation environment, two methods are applied depending on the current flux. At lower fluxes (<104 particles per cm2 per s), a track-by-track analysis based on temporal coincidence is applied. At higher fluxes, a less power and memory consuming method is utilized. This method is using the averaged deposited energy per pixel to estimate the electron and proton content of the radiation field.
Spatial patterns and drivers of smallholder oil palm expansion within peat swamp forests of Riau, Indonesia
Authors: Zhao Jing , Lee Janice Ser Huay , Elmore Andrew J , Fatimah Yuti Ariani , Numata Izaya , Zhang Xin , Cochrane Mark A
Published: January 2022

Protecting the tropical peat swamp forests in Southeast Asia is critical for addressing global sustainability challenges such as climate change and biodiversity loss. However, more than half of these forests have been lost since 1990 due to the rapid expansion of drainage-based agriculture and forestry. Within the oil palm sector, the number of regional smallholder oil palm plantings on peat soils has risen quickly. These activities are challenging to govern and manage, due to their fragmented nature and the numerous farmers involved. It is imperative to understand the spatial distribution and drivers of the smallholder oil palm-related conversion of peat swamp forests. In contrast to existing studies based on farm surveys, we used state-of-art maps of smallholder oil palm plantings, derived from 2019 remote sensing data. Spatial data about socioeconomic and biophysical factors (e.g. mills, roads, water ways, and concessions) was then used to develop logistic regression models to investigate the relative influence of these factors. We show that the spatial patterns of smallholder oil palm plantings are distinct from those of industrial oil palm plantations, revealing the critical roles of roads, especially service roads, residential roads and tracks, in driving smallholder oil palm expansion within peatlands. We found that 90% of smallholder oil palm areas were located within 2 km of roads and 25 km of mills. The mean likelihood of a given land area being converted from peat swamp forests to smallholder oil palm declined rapidly with increasing distance from roads and mills. In addition to roads and mills, land use zones (e.g. the setting of concessions and migration settlements) and other environmental factors (e.g. precipitation and elevation) were identified as important drivers of smallholder oil palm expansion on peatland. Based on these findings, we identify priority regions for the protection of the remaining peat swamp forests in Indonesia and discuss strategies for tackling these sustainability challenges on local and global scales.
Aliphatic and aromatic amine based nitrogen-doped carbon dots: a comparative photophysical study
Authors: Mishra Leepsa , Behera Ranjan Kumar , Panigrahi Aradhana , Bera Kallol , Sarangi Manas Kumar
Published: January 2022

The quantum confinement effect in nanoscale material is critical not just in the viewpoint of dimensions but also influences their photophysics such as optical, excitonic, and electrical properties compared to their bulk counterpart. This effect makes the semiconducting quantum dots fluorescent with size and band tunability, which is an asset for their applications in sensors, LEDs, solar cells, etc. The current study highlights the synthesis and photo-induced properties of N-doped carbon dots (CDs) from two precursors, one with ethylenediamine (ECDs) and the other with 2-phenethylamine (PCDs). With the use of both microscopic and spectroscopic approaches, we observe distinct changes in the dimensionality and optical properties of the phenylethylamine-induced CD compared to ethylenediamine-based CDs. The aftermath of doping with Zeta potential measurement indicates positively and negatively charged surfaces for ECDs and PCDs respectively. Through different time-resolved PL lifetime and anisotropy measurements, we report that the incorporation of the phenyl ring in PCDs significantly reduces their water solubility, rotational diffusivity, and PL quantum yield compared to that of the ECDs.
OP14 Interpreting genome-wide association studies of Inflammatory Bowel Disease through the lens of single-cell sequencing
Authors: Krzak M , Taylor L , Alegbe T , Ghouraba M , Strickland M , Przybilla M , Noell G , Iyer V , Cheam A X , Matte J , Parkes M , McIntyre R , Raine T , Anderson C
Published: January 2022

Background

Inflammatory bowel disease (IBD) is a complex disease characterised by chronic inflammation of the digestive tract. Genome-wide association studies (GWAS) have identified 241 risk loci significantly associated with the two common forms of IBD, Crohn’s disease and ulcerative colitis. The vast majority of these risk loci reside in non-coding regions of the genome, and we only know which gene is dysregulated to increase risk of disease for a minority. This knowledge gap makes it difficult to draw insights into disease pathology and identify new candidate drug targets.

Methods

To improve biological insights from IBD GWAS, we generated single cell RNA-sequencing data from ileal biopsies ascertained from 25 CD patients with active ileal inflammation and 26 non-IBD controls. We identified 49 different cell types among the ~140K sequenced cells (Fig.1), including all major immune, enterocyte, secretory and mesenchymal populations. Our optimized single-cell dissociation protocol preserves the top of villus epithelial cells, which are inherently prone to anoikis, enabling generation of high-quality transcriptomes for the first time.

Fig. 1

Single-cell atlas of terminal ileum biopsies from Crohn’s disease and non-IBD individuals.

Results

We identified 797 unique genes differentially expressed between CD patients and controls, with notable expression differences in stem cell, secretory, and enterocyte populations. Genes involved in antigen presentation and interferon-gamma signaling were enriched among those most frequently dysregulated cell types. In an attempt to identify which of these expression differences are likely causal of disease, rather than simply a consequence of it, we integrated results from the latest IBD GWAS to assess the extent to which genes captured disease heritability, and in which cell-types. Genes specifically expressed in Tregs, monocytes and IL10RA-negative monocyte-derived macrophages captured a significant fraction of disease heritability, strongly implicating these cell types in disease pathogenesis. We investigated which genes were driving these enrichment signals and identified candidate effector genes at many IBD risk loci. Reassuringly, many confirmed IBD effector genes known to have a role in the normal functioning of these cell types were found, including NOD2, IL18RAP, IL23R, NCF4, and IL2RA.

Conclusion

Single-cell analysis combined with IBD genetics has generated strong evidence for a causal role of novel disease mechanisms that have therapeutic potential. Further experiments are underway to validate this finding. At ECCO we will present an updated version of this analysis, including genetic mapping of gene-regulation across cell types to identify IBD effector genes and causal variants.
OP19 Classifying perianal fistulising Crohn’s Disease: An expert-consensus to guide decision-making in daily practice and clinical trials
Authors: Geldof J , Iqbal N , LeBlanc J F , Sawyer R , Buskens C , Bemelman W , Gecse K , Lundby L , Lightner A L , Danese S , Spinelli A , Carvello M , Faiz O , Warusavitarne J , Lung P , De Looze D , D’Hoore A , Vermeire S , Hart A , Tozer P
Published: January 2022

Background

Perianal fistulising Crohn’s disease (CD) is an aggressive disease phenotype that can have a significant impact on patients’ quality of life. Current biological understanding of perianal fistulising CD remains inadequate and previous classification systems have not provided clear guidance on therapy in clinical practice nor on defining patient cohorts within clinical trials. To counter this unmet need, we propose a new classification system for perianal fistulising CD.

Methods

The proposed classification system was developed through a modified nominal group technique expert consensus process involving open discussion and formal voting on previously defined statements. Consensus agreement was defined a priori as 80% voting “strongly agree” or “agree with minor reservation”. Participants included gastroenterologists, radiologists, surgeons active in a tertiary IBD centre and a patient representative.

Results

The classification identifies four groups of patients with perianal fistulising CD. Key elements include stratification according to disease severity as well as disease outcome; synchronisation of patient and clinician goals in decision making, with a proactive, combined medical and surgical approach, on a ‘treat to patient goal’ basis; and identification of indications for curative fistula treatment, diverting ostomy and proctectomy. The new classification retains an element of flexibility, in which patients can cycle through different classes over time. Furthermore, with each specific class comes a paired treatment strategy suggestion and description of clinical trial suitability.

Conclusion

The proposed classification system is the first of its kind and is an important step towards tailored standardisation of clinical practice and research in patients with perianal fistulising CD.
OP25 Patients with moderate to severe Crohn’s Disease with and without prior biologic failure demonstrate improved endoscopic outcomes with risankizumab: Results from phase 3 induction and maintenance trials
Authors: Ferrante M , Cao Q , Fujii T , Rausch A , Neimark E , Song A , Wallace K , Kligys K , Zhou Q , Kalabic J , Feagan B G
Published: January 2022

Background

Risankizumab (RZB), a selective interleukin-23 inhibitor, demonstrated clinically meaningful improvements in endoscopic outcomes in patients with moderate to severe Crohn’s disease (CD) during two phase 3 induction trials (ADVANCE and MOTIVATE) and the maintenance study (FORTIFY). Here, we compared the efficacy of RZB in inducing and maintaining improvements in endoscopic outcomes in patients with CD who demonstrated intolerance and/or inadequate response (IR) to biologic therapies (with prior bio-failure) versus those who demonstrated IR to conventional therapies only (without prior bio-failure).

Methods

Data included in this subgroup analysis included pooled data from patients randomized to receive intravenous (IV) RZB 600mg (N=527) or placebo (PBO) IV (N=362) every 4 weeks (wks) for 12wks during induction (ADVANCE+MOTIVATE), and data from patients receiving subcutaneous (SC) RZB 360mg (N=141) or withdrawn from RZB IV to receive PBO SC (withdrawal [PBO SC], N=164) every 8wks for 52-wks during maintenance. At Wks 12 and 52, endoscopic response, endoscopic remission, ulcer-free endoscopy (absence of ulceration), and deep remission (Wk52 only) were evaluated both in the overall population and in subpopulations of patients with and without prior bio-failure. (Endpoints are defined in Table footnotes). Safety was assessed throughout the studies.

Results

Approximately three-quarters of randomized patients included in this subgroup analysis had prior bio-failure (ADVANCE+MOTIVATE: 75.4%; FORTIFY: 73.8%). Higher rates of endoscopic response, endoscopic remission, and ulcer-free endoscopy were observed at Wk12 among patients receiving induction with RZB IV versus PBO IV. Subgroup analysis demonstrated treatment effects with risankizumab in patient subpopulations with and without prior bio-failure, with greater adjusted differences versus PBO in patients without prior bio-failure (Figure). At Wk52, endoscopic response, endoscopic remission, ulcer-free endoscopy, and deep remission rates favored RZB SC compared to withdrawal (PBO SC). Again, treatment effects were observed in patients with and without prior bio-failure, with greater adjusted differences versus withdrawal (PBO SC) in patients without prior bio-failure. RZB maintenance treatment was well-tolerated and no new safety signals were observed. The safety profile of RZB has been reported previously.1,2

Conclusion

Induction and maintenance therapy with risankizumab achieved higher rates for endoscopic endpoints in patients with moderate to severe Crohn’s disease versus placebo, regardless of prior bio-failure status. However, numerically higher efficacy rates were observed in patients without prior bio-failure.

1 D’Haens, G. et al. in DDW 2021 2 Ferrante, M. et al. in UEGW 2021
OP30 Upadacitinib modulates inflammatory pathways in gut tissue in patients with Ulcerative Colitis: Transcriptomic profiling from the Phase 2b study, U-ACHIEVE
Authors: Verstockt B , Blink Polakow S , Mahi N , Lee J , Wang J , Guay H , Salas A , Panés J , Ungaro R C , Vermeire S
Published: January 2022

Background

Upadacitinib (UPA), an oral, reversible, Janus kinase (JAK)-1 selective inhibitor can induce clinical and endoscopic remission after 8 weeks in patients (pts) with moderately to severely active Ulcerative Colitis (UC). To provide mechanistic insights into downstream effects of UPA in the intestinal mucosa, we evaluated pharmacodynamic modulation of gene expression in colon biopsies from pts with UC in the Phase 2b study, U-ACHIEVE (NCT02819635). These analyses aimed to link molecular changes to clinical endpoints.

Methods

Transcriptomic data were collected from rectosigmoid biopsies at baseline (BL) and Week (Wk) 8 in a subset of pts in sub-study 1 of U-ACHIEVE (N=88: placebo [PBO], n=15; pooled UPA 15, 30 & 45 mg, n=73). Samples underwent bulk RNA sequencing and differentially expressed genes (DEG) (false discovery rate [FDR]<0.05 & |log fold change [FC]|>1) from BL to Wk 8 were identified with linear mixed-effect models. DEG were analysed with KEGG and GO pathway enrichment and clinical endpoint responder analysis. Cellular profiling with gut cell deconvolution based on defined cell types was undertaken.1

Results

At Wk 8, expression of 695 gut genes was modulated (FDR<0.05 & |logFC|>1) from BL after UPA treatment compared with no DEG in PBO pts (including responders). Of these genes, ~70% (n=492) were downregulated and enriched in inflammatory pathways including T- and B-cell effector responses, neutrophil-mediated immunity, and leukocyte chemotaxis. Also, irrespective of directionality, most DEG from BL to Wk 8 in UPA-treated pts were associated with clinical response and remission, and histologic and endoscopic improvement. At Wk 8, deconvoluted cell fractions associated with adaptive but also innate inflammatory cells in the gut of UPA responders were decreased compared with non-responders; in contrast, fractions associated with enterocyte, secretory goblet cell and myofibroblast cells were increased in responder gut tissue (Fig 1). Modulation of genes associated with UC disease activity (OSM & S100A8/9 [calprotectin]), Th1 (TBX21, IFNG), Th2 (GATA3, IL5RA, IL13RA2), Th9 (SPI1), Th17 (IL17A, IL23A, IL21R), B-cell responses (BTK, CD40), barrier function (ESPN, VIL1, CLDN23, OCLN, MUC1/2/12/16/20) and wound repair (ANXA1/6/13, MMP7/9) were associated with clinical improvement at Wk 8 (Fig 2).

Conclusion

JAK inhibition with UPA is associated with transcriptional changes in colonic mucosa that are seen with UC disease pathophysiology. Clinical benefit mediated by UPA is associated with modulation of molecular biomarkers of UC disease activity, T-helper-cell differentiation, B-cell-mediated responses, gut barrier function and wound healing.

Reference

1. Menden K, et al. Sci Adv 2020;6:eaba2619
OP35 Natural history of anal ulcerations in pediatric-onset Crohn’s Disease: A population-based study
Authors: Mortreux P , Leroyer A , Dupont C , Ley D , Bertrand V , Spyckerelle C , Guillon N , Desreumaux P , Gower-Rousseau C , Savoye G , Fumery M , Turck D , Siproudhis L , Sarter H
Published: January 2022

Background

Anal ulcerations are frequently observed in Crohn’s disease (CD). Their natural history remains poorly known, especially in pediatric-onset CD. The aims of this study were: to determine in a population-based study the risk of anal ulcerations in pediatric onset CD; to identify risk factors for anal ulcerations; to evaluate the risk of progression towards suppurative lesions; to evaluate the risk factors of progression towards suppurative lesions.

Methods

All patients with a diagnosis of CD before the age of 17 years between 1988 and 2011 within the population-based registry EPIMAD were followed retrospectively until 2013. A specific collection of additional data was performed in patients with anal ulcerations at diagnosis or during follow-up. The variables collected included: proctological examination, diagnostic management (perineal MRI, endoscopic ultrasound, examination under general anaesthesia) and treatment (medical or surgical). Multivariate Cox models were used to identify factors associated with anal ulcerations and factors of progression towards suppurative lesions. An adjusted time-dependent Cox model was used to evaluate the risk of progression of anal ulcerations towards suppurative lesions.

Results

1005 patients were included (females, 450 (44.8%); median age at diagnosis 14.4 years (IQR, 12.0–16.1)). 257 (25.6%) had anal ulceration at diagnosis. Cumulative incidence of anal ulceration at 5 and 10 years from diagnosis was 38.4% (CI95%, 35.2–41.4) and 44.0% (CI95%, 40.5–47.2).

The presence of extra-intestinal manifestations (HR 1.46, CI95% 1.19–1.80, p=0.0003) and upper digestive location (HR 1.51, CI95% 1.23–1.86, p<0.0001) at diagnosis were associated with the occurrence of anal ulceration. Conversely, ileal location at diagnosis was associated with a lower risk of anal ulceration (L2 vs L1 HR 1.51, CI95% 1.11–2.06, p=0.0087; L3 vs L1 HR 1.42, CI95% 1.08–1.85, p=0.0116). Among the 352 patients with at least one episode of anal ulceration, 82 (23.3%) developed perianal suppuration after a median follow-up of 5.7 years (IQR, 2.8–10.6). The risk of perianal suppuration was doubled in patients with anal ulceration compared to those who did not have any ulceration (HR 2.0, CI95% 1.45–2.74, p<0.0001).

In patients with anal ulceration, the diagnostic period (before or since the “biologic era”), exposure to immunosuppressants and/or anti-TNF did not influence the risk of perianal suppuration.

Conclusion

Anal ulceration is frequent in pediatric-onset CD, with nearly half of patients presenting with at least one episode after 10 years of evolution. Perianal suppurations are twice as frequent in patients with present or past anal ulceration. These results plead for a proactive therapeutic approach in case of anal ulcerations.
DOP02 Increasing incidence of Inflammatory Bowel Disease in a high prevalence country: A nationwide study in Finland
Authors: Kontola K , Oksanen P , Huhtala H , Jussila A T
Published: January 2022

Background

The burden of inflammatory bowel disease (IBD) in health care is high and the incidence and prevalence rates of IBD in Finland are among the highest in the world. Our aim was to assess the actual incidence and the trends of IBD in Finland during 2000–2020 using nationwide registry-based data. We also estimated the nationwide prevalence of IBD in 2000 and 2020.

Methods

This study included patients to whom IBD reimbursement was newly attributed between January 1, 2000 and December 31, 2021. Data were retrieved from the Social Insurance Institution of Finland. Incidence and prevalence rates were calculated by dividing the number of annual new IBD cases by the size of the population at risk during each calendar year.

Results

A total of 42,498 new IBD cases were identified during years 2000–2020; 31,372 with ulcerative colitis (UC) and 11,126 with Crohn’s disease (CD).The crude annual incidence per 100,000 increases in CD from 7.5 to 13.4 (IRR 1.02, CI 1.019 - 1.025) and in UC from 20.4 to 34.7 (IRR 1.03, CI 1.023 - 1.027) (Fig. 1). The crude prevalence of IBD increases from 376 to 972 per 100,000 (PRR 1.05, CI 1.046–1.047).Men have significantly higher incidence than women in UC (IRR 1.26, CI 1.228–1.284). In contrast, there is no difference between genders among CD patients (IRR 0.98, CI 0.95–1.02). In UC, the peak incidence occurs in the age group 25–29 (Fig. 2), whereas in CD, the incidence is highest in slightly younger patients (Fig. 3).

Figure 1. Incidence of ulcerative colitis and Crohn`s disease in Finland during 2000–2020

Figure 2. Annual incidence of UC by age groups during 2000–2020

Figure 3. Annual incidence of CD by age groups during 2000–2020

Conclusion

During the first two decades of the 21st century, the incidence of UC and CD continues to increase in Finland, and almost one percent of the population has IBD.
DOP07 Chronic abdominal pain in IBD patients in remission: Real-world data on contributing factors
Authors: Rezazadeh Ardabili A , Janssen L M , Romberg-Camps M J L , Keszthelyi D , Jonkers D M A E , van Bodegraven A A , Pierik M J , Mujagic Z
Published: January 2022

Background

Chronic abdominal pain is highly prevalent in IBD patients in remission. The aetiology is incompletely understood, although persistent histologic inflammation, post-inflammatory visceral hypersensitivity, and altered gut-brain interaction are believed to contribute. Data on the characteristics of IBD patients suffering from chronic abdominal pain are sparse, yet essential for the identification of treatment targets. We investigated clinical, lifestyle and psychosocial factors associated with chronic abdominal pain in a real-world cohort of IBD patients in remission.

Methods

A prospective multicentre study was performed enrolling consecutive IBD patients, between Jan 1, 2020 and Jul 1, 2021, using myIBDcoach, an established remote monitoring platform for IBD. Patient reported outcome measures on disease activity, lifestyle and psychosocial factors (i.e. depressive symptoms, anxiety, stress, and life events) were assessed in three-monthly intervals. Chronic abdominal pain in IBD in remission (IBDremissionPain+) was defined as an abdominal pain score ≥3 (1–10 numeric rating scale (NRS)) at ≥1/3 of all assessments combined with faecal calprotectin <150 μg/g in 90 days around periodic assessments. Multivariable logistic regression, adjusting for relevant confounders, was performed to identify risk factors for IBDremissionPain+ compared to patients in remission without chronic abdominal pain (IBDremissionPain-).

Results

In total, 559 patients were followed prospectively, of which 429 (76.7%) were in biochemical remission. Of these, 198 (46.2%) fulfilled the criteria for chronic abdominal pain. IBDremissionPain+ patients were characterized by female sex, higher BMI, and shorter disease duration compared to IBDremissionPain- (Table 1). IBDremissionPain+ patients reported significantly higher levels of stress, fatigue, depressive and anxiety symptoms, and occurrence of life events (Table 2). On multivariable logistic regression, female sex (aOR 2.58), shorter disease duration (<10years, aOR 2.31), higher BMI (aOR 1.06), higher levels of stress (aOR 1.19), fatigue (aOR 4.73), and life events (aOR 1.65) were all significantly associated with chronic abdominal pain (Table 3). The univariable association between pain and anxiety and depressive symptoms was modulated by stress in the multivariable analysis.

Conclusion

In this real-world population of IBD patients in remission, 46.2% experience chronic abdominal pain, characterized by female sex, shorter disease duration, higher BMI, fatigue and psychosocial factors. The gut-brain interaction in this population is represented by higher levels of depressive and anxiety symptoms, but the relation to abdominal pain is potentially modulated through increased levels of perceived stress.