bluuebunny/crossref_metadata_2025 huggingface dataset:
Koreans and the Early Cold War
Authors: Woo Susie
Published: January 2023

The Cold War turned hot in Asia. Wars in Korea and Vietnam evidenced that the Cold War, the ideological contest between democracy and communism, met violent ends in the Pacific. While considered one of America’s “forgotten wars,” what unfolded in Korea sent geopolitical ripples around the world and had devastating consequences that would forever change Korea. The war claimed over three million Korean lives, the majority civilians. The United States played an outsized role in the conflict. The United States sent 350,000 servicemen, making up 90 percent of UN forces in Korea. What began as an effort to contain communism north of the 38th parallel, a dividing line drawn up by two US colonels in 1945, shifted to remove communism from the peninsula entirely. Fighting escalated in October 1950 when the People’s Republic of China entered on the side of North Korea. Between 1950 and 1953, the United States dropped 635,000 tons of bombs on the peninsula, which is roughly the size of Minnesota. An August 1953 armistice brought an end to combat but not the war. Korea remained divided, only this time with more than half the population either killed, wounded, missing, or permanently separated from their families. The unended war went on to shape the geopolitical landscape of US-Korea relations, expanded the Korean diaspora, and had a disproportionate impact upon Korean civilians, especially women and children.

In the United States, the violence of war was obscured by media that figured Koreans as wartime waifs, assimilating adoptees, and talented entertainers, like the Korean Children’s Choir and Kim Sisters, representations that fostered internationalist scripts of rescue and care. Images of Koreans as model Cold War citizens helped Americans move on from the war, while overwriting the actual experiences of displaced Korean women and children. Between 1953 and 1965, an estimated 7,700 Korean “war brides” and six thousand Korean and mixed-race adoptees arrived in interracial households scattered across a still-segregated United States. The migration of Korean women and children was directly tied to US militarization in South Korea. Camptowns catering to US servicemen that cropped up near bases during the war became permanent sites of prostitution. The presumption that Korean brides were former prostitutes was symptomatic of how the US military impacted the social construction of Korean women. Also resulting from US militarization was the birth of “GI babies.” The mixed-race children of US servicemen and Korean women anchored postwar missionary appeals for Americans to adopt from Korea, campaigns that opened the path to transnational adoptions. Ultimately, what transpired in Korea placed civilians at the crossroads of the Cold War navigating life in Korea, the United States, and spaces in between.
Irregular and Guerrilla Warfare during the Civil War
Authors: Stith Matthew M.
Published: January 2023

Irregular and guerrilla warfare decisively shaped the course, consequences, and nature of the American Civil War. As Confederate irregular efforts intensified, so deepened the level and tenacity of the US war against increasingly large portions of the Confederate South. While never fully committed, supported, or thorough, the Confederacy waged an irregular war in pockets of the South that ultimately backfired. The irregular war forced a harder, and, in some places, total war upon the Confederate civilian population, which brought the war to an end faster and indelibly shaped the nature of the larger conflict. Supporters of the United States—Unionists—lived throughout the South, and they formed something of a fourth theater of war by foisting upon the Confederacy their own internal civil war from Texas to North Carolina, one that was intricately connected to the larger irregular war. Civilians rapidly became a significant focus of the guerrilla war, and those living in the wartime South found themselves in a years-long fight for survival. In a manner of speaking, they became combatants. In the end, the irregular war alone might not have decided the Civil War’s outcome, but it helped redefine the course and consequences of the larger conflict.
Sufi Communities in Secular Mexico
Authors: Cirianni Salazar Lucía
Published: January 2023

The emergence of an organized presence of Sufi communities in Mexico dates to the last two decades of the 20th century. Sufis constitute a part of Mexico’s minority Muslim community. Their groups are mostly made of Mexican and other Latin American converts who follow the leadership of Western sheikhs, who themselves converted to Islam and were initiated into Sufi orders as adults. These characteristics shape many of the particularities of Mexican Sufi communities and their relationship to the Sufi orders from which they originated.

The oldest and most established Sufi community in Mexico is the Nur Ashki Jerrahi order, an offshoot of the Turkish Halveti-Jerrahi order. The second community of Sufi Muslims to have been established in Mexico is the Murabitun community, a branch of the Murabitun World Movement that settled in the southern state of Chiapas in 1995. Apart from these two larger communities, other Sufi orders have representatives in Mexico who guide smaller groups of followers. Some Sufi groups in Mexico have combined traditional gatherings with commercial activities, especially in the form of workshops and alternative therapeutic services that are advertised as being based on Sufi concepts and ritual practices. These groups have also offered intellectual approaches to Sufism, such as reading circles and seminars.

By considering groups whose Sufi dimension has been overlooked, either because they are secular communities or because they are organizations focused on social transformation with little or no mystical emphasis, scholars can query the conventional Western construal of Sufism as Islamic mysticism.
Muslims and Business in North America
Authors: Jeffries Bayyinah S.
Published: January 2023

Muslim business and trade has a long history in North America. Even with the onslaught of Islamophobia and the rising anxiety among non-Muslims concerning a perceived lack of assimilation, as well as alleged threats to Christianity, Muslims of all ethnicities continue to contribute to the political economy of both the United States and Canada. As a multicultural religious group, Muslims in North America have made tremendous strides in institution building, home ownership, wealth accumulation, financial institutions, education, and politics, all of which fuel the American capitalist economy.
Evaluative Morphology in the Romance Languages
Authors: Grandi Nicola
Published: January 2023

The vast majority of evaluative constructions are formed by means of morphological strategies. An evaluative construction must include at least the explicit expression of the standard (by means of a linguistic form that is lexically autonomous and is recognized by the speakers of the language as an actual word) and an evaluative mark. Therefore, in the Italian word gattino ‘kitten, dear little cat,’ the standard is expressed by the lexical morpheme gatt- (which occurs in masculine gatto and feminine gatta), while the evaluative mark is the suffix -ino.

A construction can be defined as evaluative if it satisfies two conditions, one relating to semantics and the other to the formal level. The first condition indicates that an evaluative construction indicates a deviation from a standard (or default) value without resorting to any parameter of reference external to the concept itself. The second condition indicates that an evaluative construction must include the explicit expression of this standard and an evaluative mark.

Among the world’s languages, evaluative morphology has a quite uneven diffusion: Eurasian languages, and Romance languages in particular, show the highest degree of evaluative morphology diffusion, considering the number of word formation processes involved, the word classes they apply to, and the semantic categories they express.

From a historical point of view, evaluative affixes reveal an unstable behavior: they are often subject to a renovation. As a matter of fact, present-day Romance evaluative affixes do not coincide with Latin evaluative affixes: they derive from affixes that in Latin had different functions from ‘evaluation’ or from non-Latin affixes.

From a synchronic point of view, Romance evaluative affixes prototypically exemplify all the cross-linguistically more frequent properties of evaluative morphology: categorial neutrality, insensitivity to the word class of the base, prefix-suffix neutrality, and so forth.
Evaluative Adverbs in Chinese
Authors: Shi Dingxu
Published: January 2023

Chinese lexical items like queshi, zhende, and pianpian represent the speaker’s evaluation of or attitude toward the proposition of the clause in which they appear and form a new proposition together with the at-issue proposition. They are termed evaluative adverbs (EA) even though they do not modify the predicate or the clause in the usual sense. Theoretical and practical considerations for analyzing them as adverbs are discussed with reference to similar cases in other languages, and reasons for treating them as evaluative items are presented with reference to their discourse functions. Examples are given to illustrate their properties and functions, including EA of mirativity, EA of confirmation, and EA of probability. Examples are also selected to show the relationship between EA and expected result, as well as that between EA and refutation. The linear order of EA and other preverbal elements is discussed in detail and evidence is presented that EA is not the same as predicative adjectives. These properties and behaviors are summarized into patterns to serve as the basis for analysis within the framework of cartography of left periphery. EA is assumed to have its own maximal projection Eval(uative)P, which is a layer of Split CP and takes TP as a complement directly or indirectly. The structural relationship of EvalP and other layers of Split CP is discussed as a means to explain the behaviors and interaction of these constituents, including ModEpisP, the maximal projection of epistemic modal; NegP, the maximal projection of negator; and EmphP, the maximal projection of emphatic marker shi.
Changing Disaster Vulnerability and Capability in Aging Populations
Authors: Whytlaw Jennifer , Hutton Nicole S.
Published: January 2023

The aging population, also referred to as elderly or seniors, represents a demographic of growing significance for disaster management. The population pyramid, an important indicator of population growth, stability, and decline, has shifted from the typical pyramid shape into more of a dome shape when viewing trends globally. While these demographic shifts in age structure are unique to individual countries, adjustments in disaster management are needed to reduce the risk of aging populations increasingly affected by hazards.

Risk is especially evident when considering where aging populations live, as proximity to environmental hazards such as flooding, tropical storm surge, fires, and extreme weather resulting in heat and cold increase their risk. Aging populations may live alone or together in retirement communities and senior living facilities where the respective isolation or high density of older adults present specific risks.

There is a concern in areas with high economic productivity, also considered post-industrial areas, where the population consists more of those who are aging and less of those who are younger to support the labor needs of the market and more specifically to support and engage aging populations. This disparity becomes even more prominent in specific sectors such as healthcare, including senior living assistance. In developing economies, the young are increasingly leaving traditionally intergenerational households to seek greater economic opportunities in cities, leaving many seniors on their own. Thus, risk reduction strategies must be conscious of the needs and contributions of seniors as well as the capacity of the workforce to implement them.

The integration of aging populations within disaster management through accommodation and consultation varies across the globe. Provision of services for and personal agency among senior populations can mitigate vulnerabilities associated with age, as well as compounding factors such as medical fragility, societal interaction, and income. Experience, mobility, and socioeconomic capabilities affect decision making and outcomes of aging populations in hazardous settings. Therefore, the means of involvement in disaster planning should be adapted to accommodate the sociocultural, economic, and environmental realities of aging populations.
Kagawa, Toyohiko
Authors: Akimoto Tatsuru
Published: January 2023

A Christian social reformer, evangelist, and leader of social movements, Toyohiko Kagawa’s work spanned a wide range; he led advocacy work in urban slum settlements, argued for the betterment of the welfare of children and women, and was involved in the cooperative movement, the labor movement, the farmers’ movement, and the peace movement. His direct field of practice was mainly in Japan and later social movements in the country have been said to owe their existence to his achievements one way or another. His philosophical thoughts and ideas, however, went far beyond the borders of Japan. His ideas on the cooperative movement were welcomed by President Roosevelt, his nonviolence/pacifist thinking was once mentioned along with those of Gandhi and Schweitzer and his ideas on cooperation also interested early leaders of the European Union.
Time-Varying Exposures and Miscarriage: A Comparison of Statistical Models Through Simulation
Authors: Sundermann Alexandra C , Slaughter James C , Velez Edwards Digna R , Hartmann Katherine E
Published: January 2023

Epidemiologists face a unique challenge in measuring risk relationships involving time-varying exposures in early pregnancy. Each week in early pregnancy is distinct in its contribution to fetal development, and this period is commonly characterized by shifts in maternal behavior and, consequently, exposures. In this simulation study, we used alcohol as an example of an exposure that often changes during early pregnancy and miscarriage as an outcome affected by early exposures. Data on alcohol consumption patterns from more than 5,000 women in the Right From the Start cohort study (United States, 2000–2012) informed measures of the prevalence of alcohol exposure, the distribution of gestational age at cessation of alcohol use, and the likelihood of miscarriage by week of gestation. We then compared the bias and precision of effect estimates and statistical power from 5 different modeling approaches in distinct simulated relationships. We demonstrate how the accuracy and precision of effect estimates depended on alignment between model assumptions and the underlying simulated relationship. Approaches that incorporated data about patterns of exposure were more powerful and less biased than simpler models when risk depended on timing or duration of exposure. To uncover risk relationships in early pregnancy, it is critical to carefully define the role of exposure timing in the underlying causal hypothesis.
The Self-Rated Effects of Alcohol Are Related to Presystemic Metabolism of Alcohol
Authors: Bramness Jørgen G , Skulberg Knut R , Skulberg Andreas , Moe Jenny Skumsnes , Mørland Jørg
Published: January 2023

Aims

A high number of alcohol units required to feel a subjective effect of alcohol predicts future alcohol use disorders (AUDs). The subjective response to alcohol can be measured using the validated retrospective self-rated effects of alcohol (SRE) questionnaire. Few studies have investigated the specific relationship between SRE and blood alcohol concentration (BAC) in an experimental setting.

Methods

Twenty healthy young adult male volunteers who had experience with binge drinking, but did not have AUD, filled out the SRE-questionnaire and were served with a fixed amount of alcohol per body weight. BACs were measured throughout a 12-hour period, reaching a maximum BAC of ~0.13%. Median split of SRE-scores was utilized to compare BACs among participants with relatively high effects (low SRE) and relatively low effects (high SRE) of alcohol.

Results

Participants reporting a relatively low SRE-score had a statistically significant higher measured BAC at all time points until alcohol was eliminated. This was especially pronounced during the first 2 hours after alcohol (P = 0.015) without a significant difference in the alcohol elimination rate being detected.

Conclusion

The study indicates that a self-ated SRE-score is related to BACs after the ingestion of a standardized amount of alcohol per body weight. Reporting a higher number of alcohol units before feeling an effect was related to a lower BAC. As the differences in BAC between relatively high and low self-rated effects appeared rapidly after intake, this could be interpreted as an effect of presystemic metabolism of alcohol.
A Novel Sampling Device for the Quantification of Primary Aromatic Amines on Surfaces
Authors: Ceyhan Kubilay , Drawe Patrick , Schupp Thomas
Published: January 2023

Primary aromatic amines (PAAs) are a class of hazardous substances where many compounds are classified as carcinogen, mutagen, and reproduction toxin (CMR). PAAs can be taken up by dermal exposure. In the polyurethane industry, a valid and trustworthy method for the quantification of PAAs in the presence of isocyanates that could interfere is of great interest, especially on workplaces where a regular contact to PAAs cannot be excluded. The aim of this work is the development, validation, and verification of a novel sampling device to quantify selectively the PAA load on work surfaces. We describe the synthesis of Cell-ßALA-PEMSA analytical papers and their characterization by infrared spectroscopy and thermogravimetric analysis. The recovery of TDA and MDA spiked on these filters is satisfactory. An excellent selectivity of Cell-ßALA-PEMSA papers towards PAAs in the presence of isocyanates of almost 100% was found by wipe tests of amine/isocyanate contaminated surfaces. First positive field tests were achieved at certain areas in a Polyurethane Technical Application Department where surface contamination with PAAs was expected, and the Cell-ßALA-PEMSA analytical papers were superior to an established method of surface sampling. However, recovery of these amines from surfaces shows a large variability, and more work is required to address influencing surface properties.
Denoising adaptive deep clustering with self-attention mechanism on single-cell sequencing data
Authors: Su Yansen , Lin Rongxin , Wang Jing , Tan Dayu , Zheng Chunhou
Published: January 2023

A large number of works have presented the single-cell RNA sequencing (scRNA-seq) to study the diversity and biological functions of cells at the single-cell level. Clustering identifies unknown cell types, which is essential for downstream analysis of scRNA-seq samples. However, the high dimensionality, high noise and pervasive dropout rate of scRNA-seq samples have a significant challenge to the cluster analysis of scRNA-seq samples. Herein, we propose a new adaptive fuzzy clustering model based on the denoising autoencoder and self-attention mechanism called the scDASFK. It implements the comparative learning to integrate cell similar information into the clustering method and uses a deep denoising network module to denoise the data. scDASFK consists of a self-attention mechanism for further denoising where an adaptive clustering optimization function for iterative clustering is implemented. In order to make the denoised latent features better reflect the cell structure, we introduce a new adaptive feedback mechanism to supervise the denoising process through the clustering results. Experiments on 16 real scRNA-seq datasets show that scDASFK performs well in terms of clustering accuracy, scalability and stability. Overall, scDASFK is an effective clustering model with great potential for scRNA-seq samples analysis. Our scDASFK model codes are freely available at https://github.com/LRX2022/scDASFK.
SCAMPP+FastTree: improving scalability for likelihood-based phylogenetic placement
Authors: Chu Gillian , Warnow Tandy
Published: January 2023

Phylogenetic placement is the problem of placing ‘query’ sequences into an existing tree (called a ‘backbone tree’). One of the most accurate phylogenetic placement methods to date is the maximum likelihood-based method pplacer, using RAxML to estimate numeric parameters on the backbone tree and then adding the given query sequence to the edge that maximizes the probability that the resulting tree generates the query sequence. Unfortunately, this way of running pplacer fails to return valid outputs on many moderately large backbone trees and so is limited to backbone trees with at most ∼10 000 leaves. SCAMPP is a technique to enable pplacer to run on larger backbone trees, which operates by finding a small ‘placement subtree’ specific to each query sequence, within which the query sequence are placed using pplacer. That approach matched the scalability and accuracy of APPLES-2, the previous most scalable method. Here, we explore a different aspect of pplacer’s strategy: the technique used to estimate numeric parameters on the backbone tree. We confirm anecdotal evidence that using FastTree instead of RAxML to estimate numeric parameters on the backbone tree enables pplacer to scale to much larger backbone trees, almost (but not quite) matching the scalability of APPLES-2 and pplacer-SCAMPP. We then evaluate the combination of these two techniques—SCAMPP and the use of FastTree. We show that this combined approach, pplacer-SCAMPP-FastTree, has the same scalability as APPLES-2, improves on the scalability of pplacer-FastTree and achieves better accuracy than the comparably scalable methods.

Availability and implementation

https://github.com/gillichu/PLUSplacer-taxtastic.

Supplementary information

Supplementary data are available at Bioinformatics Advances online.
PyGenePlexus: a Python package for gene discovery using network-based machine learning
Authors: Mancuso Christopher A , Liu Renming , Krishnan Arjun
Published: January 2023

PyGenePlexus is a Python package that enables a user to gain insight into any gene set of interest through a molecular interaction network informed supervised machine learning model. PyGenePlexus provides predictions of how associated every gene in the network is to the input gene set, offers interpretability by comparing the model trained on the input gene set to models trained on thousands of known gene sets, and returns the network connectivity of the top predicted genes.

Availability and implementation

https://pypi.org/project/geneplexus/ and https://github.com/krishnanlab/PyGenePlexus.

Supplementary information

Supplementary data are available at Bioinformatics online.
Postoperative delirium is associated with grey matter brain volume loss
Authors: Kant Ilse M J , de Bresser Jeroen , van Montfort Simone J T , Witkamp Theodoor D , Walraad Bob , Spies Claudia D , Hendrikse Jeroen , van Dellen Edwin , Slooter Arjen J C ,   BioCog consortium, Spies Claudia , Winterer Georg , Pischon Tobias , Boraschi Diana , Schneider Reinhard , Nürnberg Peter , Zacharias Malte Pietzsch Norman , Morgeli Rudolf , Olbert Maria , Lachmann Gunnar , Borchers Friedrich , Ofosu Kwaku , Yurek Fatima , Wolf Alissa , Gallinat Jurgen , Hendrikse Jeroen , Slooter Arjen , van Dellen Edwin , Stamatakis Emmanuel , Preller Jacobus , Menon David , Moreno-Lopez Laura , Winzeck Stefan , Feinkohl Insa , Italiani Paola , Melillo Daniela , Camera Giacomo Della , Krause Roland , Heidtke Karsten , Kuhn Simone , Kronabel Marion , Dscietzig Thomas Bernd , Armbruster Franz Paul , Hafen Bettina , Ruppert Jana , Bocher Axel , Helmschrodt Anja , Weyer Marius , Hartmann Katarina , Diehl Ina , Weber Simon , Fillmer Ariane , Ittermann Bernd
Published: January 2023

Delirium is associated with long-term cognitive dysfunction and with increased brain atrophy. However, it is unclear whether these problems result from or predisposes to delirium. We aimed to investigate preoperative to postoperative brain changes, as well as the role of delirium in these changes over time. We investigated the effects of surgery and postoperative delirium with brain MRIs made before and 3 months after major elective surgery in 299 elderly patients, and an MRI with a 3 months follow-up MRI in 48 non-surgical control participants. To study the effects of surgery and delirium, we compared brain volumes, white matter hyperintensities and brain infarcts between baseline and follow-up MRIs, using multiple regression analyses adjusting for possible confounders. Within the patients group, 37 persons (12%) developed postoperative delirium. Surgical patients showed a greater decrease in grey matter volume than non-surgical control participants [linear regression: B (95% confidence interval) = −0.65% of intracranial volume (−1.01 to −0.29, P < 0.005)]. Within the surgery group, delirium was associated with a greater decrease in grey matter volume [B (95% confidence interval): −0.44% of intracranial volume (−0.82 to −0.06, P = 0.02)]. Furthermore, within the patients, delirium was associated with a non-significantly increased risk of a new postoperative brain infarct [logistic regression: odds ratio (95% confidence interval): 2.8 (0.7–11.1), P = 0.14]. Our study was the first to investigate the association between delirium and preoperative to postoperative brain volume changes, suggesting that delirium is associated with increased progression of grey matter volume loss.
Neural suppression in odor recognition memory
Authors: Eek Tom , Lundin Fredrik , Larsson Maria , Hamilton Paul , Georgiopoulos Charalampos
Published: January 2023

Little is known about the neural basis of lower- and higher-order olfactory functions such as odor memory, compared with other sensory systems. The aim of this study was to explore neural networks and correlates associated with 3 functions: passive smelling (PS), odor encoding (OE), and in particular odor recognition memory (ORM). Twenty-six healthy participants were examined using functional magnetic resonance imaging conducted across 3 sessions, one for each function. Independent component analysis revealed a difference between sessions where a distinct ORM component incorporating hippocampus and posterior cingulate showed delayed triggering dissociated from odor stimulation and recognition. By contrasting Hit for ORM (target odors correctly recognized as old) and a combination of PS and detected odors from OE, we found significantly lower activations in amygdala, piriform cortex, insula, thalamus, and the inferior parietal lobule. Region of interest analysis including anterior insula, posterior cingulate gyrus, dentate gyrus, left middle frontal gyrus, amygdala, and piriform cortex demonstrated that Hit were associated with lower activations compared with other memory responses. In summary, our findings suggest that successful recognition of familiar odors (odor familiarity) is associated with neural suppression in the abovementioned regions of interest. Additionally, network including the hippocampus and posterior cingulate is engaged in a postrecognition process. This process may be related to incidental encoding of less familiar and more novel odors (odor novelty) and should be subject for future research.
Body size dictates physiological and behavioural responses to hypoxia and elevated water temperatures in Murray cod (Maccullochella peelii)
Authors: McPhee Darren , Watson Jabin R , Harding Doug J , Prior Andrea , Fawcett James H , Franklin Craig E , Cramp Rebecca L
Published: January 2023

Increasing drought frequency and duration pose a significant threat to fish species in dryland river systems. As ectotherms, fish thermal and hypoxia tolerances directly determine the capacity of species to persist in these environments during low flow periods when water temperatures are high and waterbodies become highly stratified. Chronic thermal stress can compound the impacts of acute hypoxic events on fish resulting in significant fish mortality; however, it is not known if all size classes are equally susceptible, or if the allometric scaling of physiological processes means some size classes are disproportionately affected. We investigated the physiological responses of Murray cod (Maccullochella peelii) over a four-fold body size range (0.2–3000 g) to acute changes in water temperature and oxygen concentration following 4 weeks of acclimation to representative spring (20°C) and summer (28°C) water temperatures. We recorded maximum thermal tolerance (CTmax), oxygen limited thermal tolerance (PCTmax), lowest tolerable oxygen level (as the oxygen level at which lose equilibrium; O2,LOE), gill ventilation rates and aerial surface respiration threshold, blood oxygen transport capacity and lactate accumulation. Acclimation to elevated water temperatures improved thermal and hypoxia tolerance metrics across all size classes. However, body size significantly affected thermal and hypoxia responses. Small M. peelii were significantly less hypoxia tolerant than larger individuals, while larger fish were significantly less thermal tolerant than smaller fish. Hypoxia constrained thermal tolerance in M. peelii, with both small and large fish disproportionally compromised relative to mid-sized fish. Our findings indicate that both very small/young (larvae, fry, fingerlings) and very large/older M. peelii in dryland rivers are at significant risk from the combined impacts of a warming and drying climate and water extraction. These data will inform policy decisions that serve to balance competing demands on precious freshwater resources.
OP01 Sequencing-based gene network analysis reveals a profound role for ferroptosis key gene GPX4 in post-operative endoscopic recurrence in Crohn’s disease
Authors: Verstockt S , Machiels K , Dehairs J , Rems K , De Greef I , Jans D , Sabino J , Ferrante M , Vermeire S , Verstockt B
Published: January 2023

Background

An ileocolonic resection with ileocolonic anastomosis is often required in patients with Crohn’s disease (CD). Postoperative recurrence (POR) is common, with host-luminal interactions being implicated. However, these interactions are poorly understood. We aimed to obtain insights in the early mechanisms of POR CD focusing on sequencing-based gene networks in the mucosa.

Methods

We included 36 CD patients who underwent ileocolonic resection with ileocolonic anastomosis, and collected mucosal biopsies from the neoterminal ileum 6 months after surgery (Table 1). We defined POR by a Rutgeerts score ≥i2b at month 6, and compared this to complete absence of endoscopic activity (i0). All biopsies underwent single-end RNA sequencing (Illumina TruSeq Stranded mRNA). Gene co-expression network clusters were identified using weighted gene co-expression network analysis (R\WGCNA), were tested for correlation with the primary outcome POR and clinical factors, and multiple testing correction was applied (FDR<0.05). Cellular deconvolution was performed using xCell; and top enriched pathways and upstream regulators were analysed using IPA (p<0.05).

Results

WGCNA analysis identified 25 co-expression clusters, of which five correlated with the postoperative outcome (clusters V, VI, IX, XV, XXV) (Fig.1). All but cluster XXV were upregulated in POR, with a profound immune-related enrichment in cluster V and VI (eg. (a)granulocyte adhesion and diapedesis, and IL17 signalling); microRNA biogenesis (cluster IX) and wound healing and fibrosis signalling (cluster XV). Interestingly, one cluster (XXV) was inversely correlated with POR, and genes within this cluster were mainly involved in autophagy, ferroptosis and oxidative stress response. The main hub gene (r=0.95, FDR=8.17E-19) within this cluster XXV was GPX4 (Glutathione peroxidase 4), a negative regulator of ferroptosis. Moreover, after cellular deconvolution, we found a positive correlation between the epithelial gene enrichment signature and the expression of GPX4 (r=0.52, p=0.0011). Finally, the main upstream regulator of the genes within this cluster XXV was HNF4A, a transcription factor known to regulate ferroptotic response.

Conclusion

We identified a mucosal transcriptomic signature associated with postoperative CD recurrence. Both autophagy and ferroptosis were found to be key protective pathways for recurrence with GPX4 as central hub. Our results complement recent findings of impaired epithelial GPX4 activity in ileal CD lesions evoking an inflammatory response to dietary lipids (Mayr et al Nat Comm 2020).
OP05 High-dimensional single-cell analysis identifies cellular signatures associated with response to vedolizumab therapy in ulcerative colitis
Authors: Pibiri P , Sun S , Karmi N , Oelen R , de Jong S , Bangma A , Teunis J , Hermoso M A , Paraskevopoulou M D , Farahmand S , Bleck B , Xia G , Weersma R K , Bigaeva E , Festen E A
Published: January 2023

Background

The unpredictability of response to biological therapy in ulcerative colitis (UC) patients, including vedolizumab (VDZ), an anti-α4β7 integrin antibody, poses a serious challenge for medical care. This study aims to identify the relevant cellular and molecular signatures that mark response to VDZ by combining single-cell transcriptomics (scRNAseq) and high-dimensional flow cytometry (Cytek).

Methods

Gut biopsies and peripheral blood mononuclear cells (PBMCs) from patients with active UC were collected 2 weeks prior and 14 weeks after starting VDZ therapy. Response was evaluated at week 14 based on endoscopy and Physician Global Assessment. Transcriptome profiles of 159.188 and 95.057 high-quality single cells were generated from biopsies and PBMCs, respectively. Additional 797.670 CD45+ mucosal cells and 900.000 PBMCs were processed for validating scRNAseq results by Cytek.

Results

From a total of 25 UC patients (mean age 41±12.7 years, 52% female, 36% anti-TNFα naive), 15 patients (60%) reached response at week 14. Patients with no prior use of anti-TNFα were more likely to achieve remission with VDZ compared to anti-TNFα exposed patients (89% vs 44% response rate, respectively). Analysis of cell abundances revealed a partial recovery of the epithelial and stromal cell mucosal compartments in responders at week 14. Both scRNAseq and Cytek show that in responders VDZ prevented T cells (CD8+IL17+ and CD4+PD1+ subsets) and innate immune cells (NKs, DCs and inflammatory monocytes) from entering mucosa, resulting in their enrichment in PBMCs. In contrast, non-response to VDZ was marked by an expansion of inflammatory fibroblasts and activated endothelial cells, and depletion of most epithelial subsets. VDZ retained CD4 T cells in PBMCs in non-responders, but failed to halt active mucosal inflammation at week 14. Strikingly, involvement of the innate immune cells in UC inflammation prior to VDZ treatment was much more prominent in non-responders who showed higher baseline abundance of NKs, ILCs, γδ-T cells, DCs and inflammatory monocytes in their peripheral blood and mucosa compared to responders. While VDZ inhibited integrin β7 expression on circulating T cells in all patients, only in responders it coincided with the lower mucosal abundance of lymphocytes, suggesting that T cells in non-responders might employ alternative, β7-independent trafficking routes.

Conclusion

This is the largest prospective scRNAseq study addressing the response to biological therapy in UC. We showed that active, innate immune cell-mediated inflammation marks the primary non-response to VDZ that persists prior to and throughout the treatment, accompanied by β7-independent lymphocyte migration.
OP07 Absolute and relative risks of kidney and urological complications in patients with Inflammatory Bowel Disease
Authors: Yang Y , Ludviggson J F , Olén O , Sjölander A , Carrero J J
Published: January 2023

Background

Kidney-related complications are considered relatively common extraintestinal manifestations of inflammatory bowel disease (IBD), but absolute risks are not well characterized. We aimed at providing a comprehensive characterization of the burden of kidney-related complications in people with incident IBD by analysing issued clinical diagnoses and trajectories of estimated glomerular filtration rate (eGFR) in the complete population of Stockholm, Sweden.

Methods

We included 1,682,795 participants aged 11 or older, free from IBD or chronic kidney disease (CKD) diagnosis and who had a measurement of eGFR during 2006-2018. We analysed the association between developing IBD (time-varying exposure) and the risk of receiving a CKD diagnosis, acute kidney injury (AKI), kidney stones, or secondary amyloidosis, and experiencing the composite of declining their eGFR at least 30% from baseline or kidney failure (collectively termed as CKD progression). Absolute risks were calculated at 5- and 10-year of follow-up, and relative risks were calculated with Cox regression. We compared kidney-related risks overall and for Crohn’s disease (CD) and ulcerative colitis (UC) separately.

Results

After median 9 years, 10,117 participants newly developed IBD. Their mean age was 45 years. Compared with non-IBD periods, developing IBD associated with higher relative risks: the HR (95% CI) for the risk of receiving a CKD diagnosis was 1.24 (1.10-1.40), 1.11 (1.00-1.24) for the risk of CKD progression, and 1.25 (1.14-1.36) for the composite outcome of these two events. Within 10 years from IBD diagnosis, 6.4% (5.8-7.0%) of participants received a diagnosis of CKD, but 11.4% (10.4-12.4%) had a clinically relevant reduction in eGFR. The risks of AKI (HR 1.97 [1.70-2.29]; 10-y absolute risk 3.6%), kidney stones (HR 1.69 [1.48-1.93]; 10-y risk 5.6%) and secondary amyloidosis (HR 2.77 [1.44-5.35]; 10-y risk 0.2%) were also higher in persons developing IBD compared to non-IBD periods. In general, CD patients exhibited higher absolute and relative kidney risks than UC patients.

Conclusion

One in ten persons with IBD develop chronic kidney disease within 10 years from diagnosis, with many of these events not being identified through diagnostic codes. This, together with higher risks of AKI and kidney stones emphasizes the need for monitoring of kidney function and established protocols for referral to nephrological/urological care.
OP11 Ileocecal resection for recently diagnosed ileocecal Crohn’s disease is associated with improved long-term outcomes compared to anti-tumor necrosis factor therapy: a population-based study
Authors: Agrawal M , Ebert A , Poulsen G , Ungaro R , Faye A , Jess T , Colombel J F , Allin K
Published: January 2023

Background

Early treatment of Crohn’s disease (CD) often involves biologics such as anti-tumor necrosis factor (anti-TNF) agents. Ileocecal resection (ICR), while a therapeutic option in early CD, is generally reserved for complicated CD or when medical treatment fails. We aimed to compare long-term outcomes of ICR and anti-TNF therapy as index treatment for ileocecal CD, initiated within one year of diagnosis, in the Danish nationwide cohort.

Methods

Using cross-linked nationwide registers, we identified all individuals who lived in Denmark and were diagnosed with ileal CD between 2003 and 2018. We included individuals who underwent ICR or received anti-TNF drugs as index treatment for ileocecal CD within one year of diagnosis. We excluded patients who did not have pathology information confirming disease in the ileocecal region. The primary outcome was a composite of CD-related hospitalization, systemic corticosteroid exposure, CD-related surgery, and perianal CD diagnosis. We conducted Cox proportional hazards regression analyses to compare outcomes in the two groups after adjusting for potential confounders. We also determined the proportion of individuals initiated on immunomodulator (IMM), anti-TNF, or no therapy at 5 years after ICR.

Results

Of the 16,443 individuals diagnosed with ileocecal CD between 2003 and 2018, 581 (3.5%) and 698 (4.2%) individuals with confirmed disease in the ileocecal region underwent ICR and received anti-TNF as the index treatment, respectively. The composite outcome occurred in 273 individuals (IR 110.3/100,0 person years (PY)) in the ICR group and in 318 individuals (IR 201.9/100,0 PY) in the anti-TNF group. The risk of the composite outcome was 33% lower in the ICR group compared to the anti-TNF group (aHR 0.67; 95% CI 0.54, 0.83), after adjusting for demographic and clinical variables. On analysis of individual outcomes, ICR was associated with reduced risk of systemic corticosteroid exposure and CD-related surgery, but not CD-related hospitalization or perianal CD diagnosis. Of individuals who underwent ICR, the proportion that was initiated on IMM, anti-TNF treatment or no treatment at 5 years of follow up was 47.5%, 17.1%, and 50.3%, respectively.

Conclusion

These data support the role of ICR as an index treatment for ileocecal CD and challenge the current paradigm of reserving surgery for complicated CD refractory or intolerant to medications. Further studies will help identify characteristics of individuals who needed no treatment after ICR.
OP14 Prevention of postoperative recurrence of Crohn's disease with vedolizumab: First results of the prospective placebo-controlled randomised trial REPREVIO
Authors: D'Haens G , Taxonera C , Lopez-Sanroman A , Nos Mateu P , Danese S , Armuzzi A , Roblin X , Peyrin-Biroulet L , West R , Witteman B , Duijvestein M , Gecse K , Hulshoff M , Mostafavi N , Clasquin E , Bouhnik Y , Laharie D
Published: January 2023

Background

Crohn’s disease (CD) is a chronic, immune-mediated inflammatory condition of the intestine, for which the majority of patients still needs to undergo surgical resection. Following the most common intervention ileocolonic resection, the vast majority of patients suffers from recurrence of CD in the neoterminal ileum. Endoscopic lesions usually precede symptoms in the first months after resection and predict the severity of the further disease course. No treatments have been approved for recurrence-prevention of CD. REPREVIO is a prospective placebo-controlled randomized trial investigating the preventive effect of vedolizumab, an anti-integrin antibody, on recurrence of CD.

Methods

Following ileocolonic resection, patients were treated with vedolizumab (300 mg IV at week 0,8,16 and 24) or PLC (1:1) at 12 sites in the Netherlands, France, Italy and Spain. Treatment was initiated within 4 weeks following ileocolonic resection with anastomosis. Six months following surgery, patients underwent ileocolonoscopy for assessment of recurrent lesions. Video recordings were centrally scored using the modified Rutgeerts’ score by 2 readers with adjudication in case of disagreement. The primary endpoint was endoscopic recurrence (ER) of CD (non-parametric); secondary endpoints were the proportion of patients with ER >i2a and clinical recurrence. Adverse events were recorded.

Results

95 pts were screened and 80 randomized. All patients have reached month 6 and the videos are being analysed. We will receive the results of all statistical analysis in December, 2022.

Conclusion

The efficacy of vedolizumab postoperative recurrence-prevention treatment was studied in the REPREVIO study.
OP16 Endoscopic and clinical outcomes of upadacitinib in patients with moderately to severely active Crohn’s disease by number and type of prior biologics
Authors: Peyrin-Biroulet L , Parkes G , Rodríguez C , Siffledeen J , Wright J , Broide E , Ford S , Lacerda A P , Oomen J , Garrison A , Berg S , Rubin D T
Published: January 2023

Background

Biologic therapies are used to treat moderate-to-severe Crohn’s Disease (CD), but many patients eventually lose response to them. With new potential therapies for CD, understanding their efficacy after patients undergo biologic treatment is important for clinical decision-making. This post hoc analysis assessed the outcomes of upadacitinib (UPA), an oral selective Janus kinase inhibitor, in patients with CD who had failed a biologic, by the number and type of prior biologic therapies.

Methods

In the 2 induction studies, U-EXCEL (NCT03345849) and U-EXCEED (NCT03345836), patients with moderate-to-severe CD received oral UPA 45 mg once daily (QD) therapy or placebo (PBO) for 12 weeks. Patients achieving clinical response to UPA induction were re-randomised in the maintenance study, U-ENDURE (NCT03345823), to receive UPA 15 mg QD, UPA 30 mg QD, or PBO for 52 weeks. This analysis assessed clinical, endoscopic, and safety outcomes in patients with inadequate response or intolerance to biologic therapy by number and type of biologics failed. Data from the U-EXCEL and U-EXCEED studies were pooled.

Results

At baseline, patient (n=733) characteristics were similar for UPA vs PBO within each subgroup by number of prior biologics (1, n=279; 2, n=223; >2, n=231); patients who received ≥ 2 prior biologics had longer disease duration (median, years: 1, 6.2; 2, 9.4; >2, 12.9) and were more likely to have used steroids (1, 27.7%; 2, 40.4%; >2, 45.0%). Across subgroups, greater proportions of patients receiving UPA vs PBO achieved clinical remission (Figure 1) and endoscopic response and remission (Figure 2) at week 12 of induction and week 52 of maintenance; response rates were generally higher for patients who had failed fewer biologics. When analyzed by type of prior biologic (tumor necrosis factor inhibitor [yes/no], n=704/29; ustekinumab [yes/no], n=272/461; vedolizumab or natalizumab [yes/no], n=220/513), the proportion of patients achieving clinical and endoscopic outcomes was slightly higher for those without prior exposure to each biologic. Adverse events (AEs) occurred at numerically higher rates for patients who had failed multiple biologics in the induction and maintenance studies across both PBO and UPA treatment arms. AEs of special interest occurred at similar rates across subgroups. No non-melanoma skin cancers, major adverse cardiovascular events, or venous thromboembolic events were reported.

Conclusion

Clinical and endoscopic improvements were observed with UPA induction and maintenance therapy in patients with moderate-to-severe CD, regardless of number and type of prior biologics failed; greater benefits and fewer AEs were observed in patients who failed fewer biologic therapies.